Cochrane Database Syst Rev. 2010 Jan 20;(1):CD007595. doi:
10.1002/14651858.CD007595.pub2.
Repeated use of pre- and postcoital hormonal
contraception for prevention of pregnancy.
Halpern V, Raymond EG, Lopez LM.
Author information
Abstract
BACKGROUND:
Repeated use of postcoital hormonal contraception is not currently recommended due to the
higher risk of side effects and lower contraceptive effectiveness compared to other modern
methods of contraception. However, emerging evidence indicates renewed interest in a regular
coitally-dependent method of oral contraception. We re-evaluated the existing data on safety and
effectiveness of pericoital use of levonorgestrel and other hormonal drugs to prevent pregnancy.
OBJECTIVES:
To determine the effectiveness and safety of repeated use of pre- and postcoital hormonal
contraception for pregnancy prevention
SEARCH STRATEGY:
We searched the computerized databases MEDLINE, POPLINE, CINAHL, LILACS, EMBASE
and CENTRAL for trials that tested repeated pre- and postcoital use of hormonal drugs for
pregnancy prevention. We also searched for current trials via ClinicalTrials.gov and ICTRP.
SELECTION CRITERIA:
Published and unpublished studies in any language of repeated postcoital or immediately
precoital use of hormonal drugs for contraception with pregnancy as an outcome
DATA COLLECTION AND ANALYSIS:
Two authors independently confirmed the eligibility and extracted data from the included
studies. We calculated confidence intervals (CI) around individual study Pearl indices using a
Poisson distribution. We presented individual study estimates and pooled estimates and their
95% CI, where appropriate.
MAIN RESULTS:
We found 21 trials that evaluated pericoital use of LNG and other hormonal drugs on a regular
basis to prevent pregnancy. Pericoital levonorgestrel (LNG) was reasonably efficacious and safe.
The pooled Pearl Index for the 0.75 mg dose of LNG was 5.1 per 100 woman-years (WY) (95%
CI 3.8 to 6.7). The pooled Pearl Index for all doses of LNG was 4.9 per 100 WY (95% CI 4.3 to
5.5). Other hormonal drugs appeared promising but most of them were not studied extensively.
Most women liked the pericoital method in spite of frequent menstrual irregularities.
AUTHORS' CONCLUSIONS:
The studies of pericoital LNG regimens provided promising results but had a number of serious
methodological limitations. A pressing need exits to conduct a rigorous research to confirm the
efficacy and safety of pericoital use of LNG as a primary means of contraception among women
with infrequent intercourse. If the method is shown to be efficacious, safe and acceptable, the
results may warrant revision of the current WHO recommendations and marketing strategies.
PMID:
20091641
[PubMed - indexed for MEDLINE]
Publication Types, MeSH Terms, Substances
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Urol Clin North Am. 2014 Feb;41(1):145-61. doi: 10.1016/j.ucl.2013.08.012. Epub 2013 Sep 20.
Male contraception: history and
development.
Kogan P, Wald M.
Author information
Abstract
Although the twentieth century has seen great strides in the development of female
contraception, not a single new agent has been introduced as an approved method for common
use for male contraception. Condoms (considered uncomfortable by some) and vasectomy (a
permanent invasive procedure) are the only options provided to men, leaving an undue burden on
women to bear contraceptive responsibility. Significant developments have, however, been made
with regard to hormonal and nonhormonal contraception, and minor, reversible, procedural
contraception. This article reviews the currently available, soon to be available, and theoretically
possible methods of male contraception.
Copyright © 2014 Elsevier Inc. All rights reserved.
KEYWORDS:
Condoms, History, Male contraception, Testosterone, Vasectomy
PMID:
24286773
[PubMed - indexed for MEDLINE]
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J Clin Nurs. 2013 Nov 1. doi: 10.1111/jocn.12262. [Epub ahead of print]
Adult men's beliefs, values, attitudes and
experiences regarding contraceptives: a
systematic review of qualitative studies.
Hoga LA, Rodolpho JR, Sato PM, Nunes MC, Borges AL.
Author information
Abstract
AIMS AND OBJECTIVES:
To explore the men's beliefs, values, attitudes and experiences towards contraceptives.
BACKGROUND:
The promotion of male participation in contraceptive practices requires the knowledge and
consideration of the beliefs, values, attitudes and experiences involved. The systematic review of
the literature focusing on these themes can be useful for the evidence-based health care.
DESIGN:
A systematic review of qualitative studies.
METHODS:
Studies published between 1994 until 2011 (inclusive) were included. The participants included
men from all cultures, ethnic backgrounds and religions who have expressed their beliefs, values,
attitudes and experiences regarding male contraceptives. The databases CINAHL, PubMed,
PsycINFO, SciELO, LILACS and MedCarib were explored. The appraisal of primary studies,
carried out through the JBI-QARI (Qualitative Assessment and Review Instrument) resulted in
the inclusion of 16 studies in this systematic review.
RESULTS:
The set of statements of beliefs, values, attitudes and experiences regarding contraceptives
resulted in five synthesis: (1) contraceptive behaviour is influenced by religious, family and
social backgrounds; (2) gendered, male-centred values predominate in contraceptive behaviours;
(3) the sense of invulnerability influences contraceptive behaviours; (4) strong obstacles should
be overcome to use contraceptives; (5) behaviours, decision-making and experiences regarding
male contraceptives.
CONCLUSIONS:
The male beliefs and values regarding contraceptives are strongly influenced by religious, family
and social backgrounds, and their attitudes in this scope are male centred.
RELEVANCE TO CLINICAL PRACTICE:
A deeper male consciousness regarding contraceptive responsibility should be promoted. It
requires the knowledge of the men's personal backgrounds regarding contraceptives because they
can be diverse according to family, social and cultural contexts. The consideration of the men's
personal perspective is essential in the planning and implementation of reproductive health care.
These aspects are essential for the concretisation of the evidence-based health care, a current
challenge worldwide.
© 2013 John Wiley & Sons Ltd.
KEYWORDS:
contraception, family planning, men, meta-synthesis, reproductive health
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Bioorg Med Chem Lett. 2014 Jan 15;24(2):419-24. doi: 10.1016/j.bmcl.2013.12.004. Epub 2013
Dec 7.
Male contraception: Another holy grail.
Murdoch FE1, Goldberg E2.
Author information
Abstract
The idea that men should participate in family planning by playing an active role in
contraception has become more acceptable in recent years. Up to the present the condom and
vasectomy have been the main methods of male contraception. There have been and continue to
be efforts to develop an acceptable hormonal contraceptive involving testosterone (T)
suppression. However the off target affects, delivery of the analogs and the need for T
replacement have proven difficult obstacles to this technology. Research into the development of
non-hormonal contraception for men is progressing in several laboratories and this will be the
subject of the present review. A number of promising targets for the male pill are being
investigated. These involve disruption of spermatogenesis by compromising the integrity of the
germinal epithelium, interfering with sperm production at the level of meiosis, attacking specific
sperm proteins to disrupt fertilizing ability, or interfering with the assembly of seminal fluid
components required by ejaculated sperm for acquisition of motility. Blocking contractility of
the vas deferens smooth muscle vasculature to prevent ejaculation is a unique approach that
prevents sperm from reaching the egg. We shall note the lack of interest by big pharma with
most of the support for male contraception provided by the NIH.
Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.
KEYWORDS:
Blood-testis barrier, Contraception, Fertility, Isozymes, Sertoli cells, Spermatozoa, Testes
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Contraception. 2011 May;83(5):459-65. doi: 10.1016/j.contraception.2010.09.011. Epub 2010
Nov 13.
Contraceptive usage patterns in North
American medical students.
Rowen TS, Smith JF, Eisenberg ML, Breyer BN, Drey EA, Shindel AW.
Author information
Abstract
BACKGROUND:
Previous studies indicate that the sexual beliefs and mores of students in medical professions
may influence their capacity to care for patients' sexuality and contraception issues. Students also
represent a large sample of reproductive-age individuals. In this study, we examined
contraceptive usage patterns in North American medical students.
STUDY DESIGN:
Students using online medical student social and information networks enrolled in allopathic and
osteopathic medical schools in North America between February and July of 2008 were invited
to participate via email and published announcements in an Internet-based survey consisting of a
questionnaire that assessed ethnodemographic factors, year in school and sexual history. We also
collected information about current use of contraceptive and barrier methods. Descriptive
statistics and logistic regression were utilized to analyze responses.
RESULTS:
Among our 2269 complete responses, at least one form of contraception was being utilized by
71% of men and 76% of women. Condoms were the most popular form of contraceptive, utilized
by 1011 respondents (50% of men and 40% of women). Oral contraceptive pills were the
contraceptive of choice for 34% of men and 41% of women. Decreased rates of contraception
use were associated with being black or Asian, not being in a relationship and having more
sexual dysfunction in female respondents. Students who reported comfort discussing sexual
issues with patients were more likely to use effective contraceptive methods themselves. Ten
percent of this of sexually active medical students was not currently using contraception.
CONCLUSIONS:
There are significant differences in contraceptive use based on demographics, even at the highest
education levels. The personal contraception choices of medical students may influence their
ability to accurately convey information about contraception to their patients. In addition,
medical students may personally benefit from improved knowledge of effective contraceptive
practices.
Copyright © 2011 Elsevier Inc. All rights reserved.
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Volume 39, Number 4, December 2013
Consumer Perspectives on a Pericoital
Contraceptive Pill In India and Uganda
By Jane K. Cover, Jennifer Kidwell Drake, Imelda T. Kyamwanga, Eleanor Turyakira, Tanya
Dargan, Edward Kumakech and Claudia Harner-Jay
CONTEXT: Studies suggest that women in some countries have adopted emergency
contraceptive pills as a routine method of family planning. This practice indicates there may be
latent demand for a pericoital contraceptive pill taken only when a woman has sexual
intercourse, and labeled and marketed for use as a regular contraceptive method.
METHODS: To understand the appeal and potential market for a pericoital contraceptive pill,
39 focus groups and 23 in-depth interviews were conducted with women and men in Lucknow,
Uttar Pradesh, India, and Kampala, Uganda. A total of 281 individuals participated in this
qualitative study.
RESULTS: In general, women embraced the idea of a female-controlled method that would be
easier than taking a daily oral contraceptive pill and that could be taken either before or after
sexual intercourse; in Uganda, especially, women approved of the fact that the method could be
taken without a partner’s knowledge. Although we do not yet know the extent of side effects for
this method, women expressed some concerns about the level and nature of potential side effects.
CONCLUSIONS: The results suggest that a pericoital contraceptive pill would be well-received
by consumers in both country settings. If its efficacy and side effects are acceptable, a pericoital
contraceptive pill could fill a gap for female-controlled, discreet, coitus-related contraception,
particularly among women who do not have sex very frequently.
International Perspectives on Sexual and Reproductive Health, 2013, 39(4):195–204. doi:
10.1363/3919513
A substantial proportion of women in developing countries with an unmet need for family
planning cite infrequent sex as a reason for not practicing contraception: 6–39% of women with
unmet need in Sub-Saharan Africa and 14–35% in South and Southeast Asia.1 Notably, about
one in four adolescent women aged 15–19 with unmet need report that they are not using a
method because they do not have sex frequently.2 For women who have infrequent sex, an oral
contraceptive pill taken only at the time of intercourse may offer advantages in terms of
convenience and ease of use; because this method is discreet and female-controlled, it may
appeal to other women as well.
Pericoital contraceptive pills—also referred to as “on- demand” or “real-time” contraceptives—
are being considered as a way to address unmet need, especially among women who have sex no
more than six times a month. There is currently no oral contraceptive pill marketed for such use.
Women could take a pericoital contraceptive pill within 24 hours before or after intercourse,
rather than daily. Levonorgestrel, one compound being considered as the active component in a
pericoital pill, is a synthetic progestin that has been used as an active hormonal ingredient in
daily birth control pills for about 40 years. It is also the key ingredient in contraceptive implants,
hormone-releasing IUDs and emergency contraceptive pills. Levonorgestrel is off-patent and has
a good safety profile.3
Studies from a number of countries suggest that some women are already using emergency
contraception off- label as an on-demand pill, demonstrating latent demand for a pericoital
method.4–6 Women who do not have sex frequently are particularly likely to use emergency
contraception as their regular method.4 Moreover, a survey of women in urban Nigeria found that
those who reported having used emergency contraception had done so an average of five times in
a six-month period.7 Interviews with West African women using emergency contraception as a
regular method reveal a preference for the convenience of an “occasional pill” and for episodic,
rather than sustained, exposure to hormones (reflecting their safety concerns about hormones that
remain in the system).8 These studies show that in the absence of a coitus-related, femalecontrolled contraceptive method that does not interrupt sexual activity and is labeled and
marketed for routine use, women have adapted an existing method to meet that need.
There are obvious similarities between a potential pericoital contraceptive product and currently
available emergency contraception; for example, both are coitus-related methods, and the same
active ingredient may be used for both. That said, a dedicated pericoital pill would be labeled and
marketed for use within 24 hours before or after sex, as a routine contraceptive method. While
repeat use of levonorgestrel does not pose any known health risks, emergency contraception is
not currently labeled for routine use, nor for use prior to sexual intercourse.9 The appropriate or
recommended coital frequency for pericoital contraceptive users will depend on the efficacy and
side effects of the active ingredient; a current World Health Organization clinical trial of a
pericoital pill using 1.5 mg of levonorgestrel defines the appropriate coital frequency for study
participants as six or fewer times a month.
To understand better the appeal and potential market for a pericoital contraceptive pill, PATH
conducted a qualitative study of the perceptions of potential consumers in Lucknow, Uttar
Pradesh, India, and Kampala, Uganda. PATH assessed the general appeal of the method,
explored anticipated patterns of use and developed potential client profiles through focus group
discussions and in-depth interviews with potential consumers (241 women and 40 men).
METHODS
Country Contexts
To capture regional variation, we wanted to have study sites in both South or Southeast Asia and
Sub-Saharan Africa. India was chosen because of its vibrant commercial market for oral
contraceptives and emergency contraception, and because of the potential to form partnerships
with local manufacturers for production and distribution. Uganda was selected due to the
dominant role of the private sector in providing oral contraceptives and a recently renewed
commitment to family planning by government leaders.
The study focused on urban areas under the assumption that a pericoital pill would initially be
available for purchase in pharmacies and through social marketing in urban settings. This
assumption is based, at least in part, on the critical role the commercial sector has played in
making emergency contraception available in a variety of settings. Moreover, data on women
who use emergency contraception as a primary method tend to draw on urban populations.4,6,7
We selected Lucknow and Kampala as study sites because they represented urban settings that
were accessible to our study teams and that have family planning infrastructure and programs
that could facilitate eventual introduction of a new method.
In Lucknow district, according to the India Demographic and Health Survey (DHS), about one in
four married women of reproductive age have an unmet need for family planning (Table 1).10
Sterilization, used by 20% of married women aged 15–49, dominates the contraceptive method
mix, as it does for India as a whole; the next most commonly used methods are condoms (12%)
and traditional methods (10%). Indian women wishing to space births tend to rely on methods
that require male involvement (condoms, periodic abstinence and withdrawal). DHS reports do
not include data on current use of emergency contraception; however, nearly 30% of married
women in Lucknow reported knowing about the method and numerous brands of emergency
contraception are available in India. The strong commercial market for emergency contraception
products and substantial reliance on methods that require male involvement suggest a need and
demand for a female-controlled pericoital method.
In Kampala region, injectables (19%), oral contraceptives (10%) and traditional methods (8%)
dominate the contraceptive method mix.11 An estimated 32% of married women in Uganda, and
nearly 40% of sexually active unmarried women, know of emergency contraception, and it is
available in the private sector under the brand name Postinor 2. Although emergency
contraception is intended to be available by prescription only in Uganda, women are able to
procure it over the counter.
Uganda’s total fertility rate of about six children per woman is high, even compared with the
rates in other Sub-Saharan African countries.11 Ugandan men desire larger families than
Ugandan women do (about six children vs. five). This discord in fertility intentions may translate
into challenges for women who desire to use family planning. Moreover, it may create a demand
for short-term methods, like the injectable or the pericoital pill, that are female- controlled and
can be used surreptitiously.
Study Design and Analysis
Our analysis draws on qualitative data collected through focus group discussions and in-depth
interviews. We sampled participants purposefully and attempted to maximize diversity in order
to gather insights on potential consumers of pericoital contraception and solicit a wide variety of
viewpoints on the proposed method. Accordingly, we included married and unmarried women
and men aged 18–45 who were upper-middle, middle or working class and who were using
modern contraceptives, traditional methods or no method. This sampling strategy draws from
previous research showing that diverse characteristics can inform contraceptive use.12 In
addition, we recruited young, unmarried women who either were currently attending college or
had recently graduated, as well as a small sample of women who had used emergency
contraception in the past, assuming that the use dynamics of another coitus-related oral method
might provide insight on possible use of a pericoital pill.
To promote information sharing within focus group discussions, we designed each group to be
homogeneous in terms of participant characteristics. In Lucknow, a team of trained recruiters
identified participants through household visits and snowball sampling in a socioeconomically
diverse set of neighborhoods. In Kampala, our team worked with clinic staff, community
representatives, and college and other education officials in neighborhoods selected to represent
a variety of socioeconomic conditions to identify potential participants. Two of the college
groups were recruited through universities and one through a nursing school. In both countries,
women using permanent contraception (i.e., sterilization) were excluded from participating.
The Indian field team queried married female participants about their current contraceptive use
as a basis for assignment to specific focus groups; because of Ugandan women’s reluctance to
disclose current method use during recruitment, a mix of users and nonusers were recruited
though clinics and communities and participated in focus groups together. Likewise, because it
was difficult in Kampala to clearly define marriage and thus separate women by marital status,
all women in any form of union and those who clearly stated that they were in a relationship but
not married participated in the same focus groups. We conducted a total of 33 focus group
discussions with women: 15 with women in Lucknow (a total of 116 participants) and 18 in
Kampala (142 participants; Table 2).
Emergency contraception was discussed in in-depth interviews, rather than in focus groups, at
the recommendation of both country teams, who felt that women might not be comfortable
talking about their emergency contraception use in a group setting because of the stigma
sometimes attached to this method. In Kampala, emergency contraception users were recruited
through clinics and by following up with any focus group participants who mentioned having
used the method. In Lucknow, we were able to recruit emergency contraception users the same
way we recruited focus group participants. We conducted a total of 15 interviews with
emergency contraception users (eight in Lucknow and seven in Kampala).
We recruited men because of their influence on a couple’s decisions about whether to use family
planning and what kind of method to use. The sample of men was designed to maximize
variation in socioeconomic status, age and marital status. Men using permanent contraception
were not eligible to participate. We recruited men for focus group discussions and in-depth
interviews using methods similar to those described above for recruiting women in each setting.
In Lucknow, we conducted six focus group discussions with a total of 30 men—three with
unmarried men and three with married men. In Uganda, we used individual interviews only,
because our team felt that men would not be comfortable discussing family planning in a group
context. We conducted 10 in-depth interviews with men of varied marital status (single, married
but living apart, or married and living together), socioeconomic status (by years of education)
and age (18–29 and 30–45).
We developed the discussion and interview guides to be consistent across the two settings, but
revised them to be context-appropriate following pretesting with six groups in Uganda and five
in India. Specifically, we reordered the questions to improve the flow of the discussion or
interview, added additional information explaining pericoital contraception and reworded some
questions to improve comprehension. While some questions varied across country context, the
instruments addressed the same themes regarding influences on contraceptive decision making,
including knowledge of contraceptive methods, family planning decision making, perceptions
about methods and method characteristics, reaction to the concept of pericoital contraception,
intent to use pericoital contraception, willingness to pay for the method, and preferred price and
source of supply.12
Consumer perceptions of the proposed pericoital method were elicited by the following:
“Suppose there was a pill that a woman would take up to 24 hours before or after she has sex—
so this pill is taken only on days when a woman has sex, instead of every day. For example, a
woman could take it 24 hours before sex, or 10 hours before sex, or one hour before sex, or up to
24 hours after sex. It would be intended for women/couples who are not having very frequent
sex. What is your impression of that method?” Once participants had shared their impressions of
the method and its perceived advantages, they were asked to voice any concerns, questions or
perceived method disadvantages. After expressing any reservations, they were prompted to
discuss three specific issues: irregular bleeding (given that levonorgestrel is associated with this
side effect), method effectiveness (based on currently available data3) and HIV prevention. First,
participants were asked, “If this method caused spotting or irregular bleeding, would women still
consider using this? Why or why not?” As a probe for consumers’ concerns about method
effectiveness, participants were asked, “Considering that this product may be more effective than
condoms and less effective than regular birth control pills at preventing pregnancy, how likely
are women to consider using this method?” Participants were also asked, “If the method only
prevented pregnancy but did not protect against HIV, would women still consider using it? Why
or why not?”
In both Lucknow and Kampala, each focus group discussion and interview was conducted by
two moderators of the same gender as the participants. In Lucknow, all moderators were Indian
and were fluent in both Hindi and English. Moderators in Kampala were fluent in Luganda.
Focus group discussions and interviews were conducted in the language (English, Hindi or
Luganda) preferred by participants.
Field teams were trained on the purpose of the study, research ethics and use of the guides, and
each moderator demonstrated mastery of interviewing, facilitating and note-taking skills prior to
data collection. After confirming participants’ eligibility, the moderators explained the study
purpose and obtained written consent. They stressed the voluntary and confidential nature of the
assessment at the time of recruitment and again at the start of each focus group discussion or
interview. No name identifiers were recorded during data collection.
The focus group discussions and interviews were audio-recorded and lasted 1–2 hours; each
focus group comprised 5–10 individuals. In Lucknow, all focus group discussions and interviews
took place in private rented spaces in the community. In Kampala, focus group discussions and
interviews with women took place in private settings, usually in a closed room in a family
planning clinic or a rented space in the community. Interviews with men in Kampala mainly took
place in their home, at the preference of participants; again, privacy was assured.
Data analysis approaches were slightly different across the field teams. In India, the team
transcribed the audio files and translated them from the local language, read the transcripts and
sorted the information by topic. Once transcripts were compiled, researchers developed themes
by identifying similarities and differences among groups. In Uganda, all interviews and focus
group discussions conducted in the local language were translated into English. According to the
preferences of the highly experienced female moderators in Uganda, notes and audio recordings
from women’s focus groups and interviews were used to develop expanded field notes, which
were used as the basis for analysis; men’s interviews were transcribed verbatim. All teams
compared data from each focus group discussion and interview with findings from the other
discussions to identify themes that resonated across similar groups or among similar individuals,
or that were distinct to a particular individual or group. Information coding followed an inductive
approach in which codes and themes evolved organically from the transcripts and notes. Teams
carried out multiple iterations of data synthesis, interpretation and summarization in both
settings, and they implemented quality control procedures during data analysis. Specifically,
researchers in the United States independently analyzed transcripts from three focus group
discussions in each setting and then compared the findings with those of the field teams in each
country to ensure a systematic and replicable approach to data analysis.
The Lucknow Ethics Committee in India, the Institutional Review Boards at Makerere
University in Uganda and the Ugandan National Council for Science and Technology granted
research ethics approval for the study.
RESULTS
Perceptions of Pericoital Contraception
Across population segments and in both country settings, many participants viewed the product
favorably, including a large majority in India and a majority in Uganda (especially among young,
unmarried women). Positive attributes and advantages of this potential method that emerged in
both countries included the convenience of not having to take a daily pill, flexible timing for
taking the pill (although perceptions of this varied somewhat by study location and
subpopulation), and the potential for discreet use, which was especially appreciated in Uganda.
The most prominent concerns that emerged about this method had to do with safety and side
effects; in Uganda especially, participants had concerns about the potential effects of the
proposed pill—and of hormonal methods generally—on future fertility. Many women did not see
potential for irregular bleeding, predicted lower effectiveness relative to oral contraceptives, or
lack of HIV protection as likely to discourage their use of the method. Proportionately more men
than women in both countries expressed concern about these three issues.
Freedom from a Daily Pill
Participants from all categories commented on the convenience of not having to take a daily pill.
In nearly every focus group or interview in both countries, women pointed out that pericoital
contraception would reduce the daily burden of regular pill use.
“We only have to take this when we have intercourse, not every day. If we take this four times in
a month there is no harm.”—Married woman, age-group 30–45, Lucknow
“It is so demanding and a burden to take pills day by day, even if you may only expect to have
your partner about [nearby] next month. It is so inconveniencing. You feel it is a burden. So you
take that [pericoital contraception] to ease your way of life.”—Female college student, Kampala
In discussing the convenience of the proposed peri-coital pill, a few men and women observed
that taking one pill around the time of intercourse would be easier to remember than taking a pill
each day, and the connection between the pill and sexual intercourse may serve as a memory
trigger.
“You will not forget. When you are going to do the action, you take it.”—Married man, aged 49,
Kampala
“I would rather take one pill when I know I am going to have sex…than take a pill every day.
The other pills you take them every day…this [pericoital contraception] is better. It is like
solving forgetfulness…. If you forget, you can take it after.”—Female college student, Kampala
“This is good, because we have to take Mala-D [common brand of oral contraceptives in India]
daily and this we have to take it once. Because females are very busy, they can forget to take, so
this is good.”—Female college student, Lucknow
For a few men interviewed in Uganda, the advantage of an occasional pill appeared to be less
about convenience than about the improved efficacy associated with better compliance. Because
a pericoital pill is less burdensome and easier to remember than regular oral contraceptives, men
thought that women would be less likely to miss pills and therefore better protected from
pregnancy.
“When you miss [a dose] in the previous type of pills [oral contraceptives], there are chances that
you will get pregnant. I think for this one, you may also miss, but it may not occur frequently
like the previous one. I do not know how to put it. It is something easy to deal with. The people
using it may be more compliant.”—Married man, aged 37, Kampala
Flexibility and Timing
Another advantage that emerged from all groups of women and men in India, and from some in
Uganda, is the flexible timing of taking the pericoital pill. The concept of taking a pill after sex
to prevent pregnancy was a novel idea to some women older than 30 in Uganda who had not
used emergency contraception.
“Ehh, that [pericoital] pill is a very good one. You might forget and have sex but later you
remember… It is very good because I do not think that for these other pills [oral contraceptives],
you can have sex and then have her take it afterwards.”—Unmarried man, aged 30, Kampala
“Good it does not have a fixed time of taking it. You can take anytime, even after having sex.”—
Woman, age-group 30–45, Kampala
The novelty and advantage of taking the pill before sex was a stronger theme in India than in
Uganda; participant remarks suggested greater awareness of and familiarity with emergency
contraception. The ability to take a pill before sex was perceived by participants to be
advantageous, reducing the tension associated with unprotected intercourse.
“It is good because other tablets [emergency contraception] you have to take if you have any
doubt about pregnancy, but this tablet you can take before 24 hours or after 24 hours of sex, so it
is better than those [emergency contraception].”—Female college student, Lucknow
One woman interviewed in Uganda was familiar with the idea of a pill taken before sex, as she
takes emergency contraception in anticipation of sexual intercourse:
“Those pills work nicely, they can do whatever you want… Me, most times I use emergency
contraception for my part-time [casual partner]. I know I am going to meet the person. Many
times I have been using it before, the day before I meet my person.”—Emergency contraception
user, Kampala
By contrast, the limit on the number of times pericoital pills should be taken within a given
month emerged as a theme of concern among many Ugandan women, especially married
women. They noted that married women are generally not at liberty to negotiate the number of
times they engage in intercourse with their husband. A few Ugandan women also expressed
concern about the shorter time frame for using pericoital contraception, relative to the 72-hour
window for using emergency contraception.
“The pill will work for people who are just in relationships but for marrieds, I don’t think you are
going to tell your husband, ‘four times only!’ Maybe for people in relationships who know, ‘I am
going to check on [see] him the other weekend.’ Not the one who is going to stay with the person
day after day and you are going to tell him, ‘my dear, I am on the [pericoital] pill, and you know
it has to be four times only and we have finished our four times of the month.’ It might work for
these other people but not for marrieds.”—Woman, age-group 20–29, Kampala
“The time limit is also little. The emergency contraception pill gives you at least three days so
that you remember your sins. This one is just one day.”—Woman, age-group 20–29, Kampala
Many married women in Uganda noted that because they often cannot predict when sexual
activity will occur, the pill would be taken more often after sex, rather than in anticipation of sex.
One of the men interviewed echoed this reasoning:
“This should be after sex that a woman can take the pill. Because on most occasions, I do not
stay with my wife. When I am going home to meet her, I cannot even raise her [call her] to tell
her, ‘now I am coming, remember to take those pills.’ At times I can call her and her phone is
off. It should be after sex.”—Married man aged 27, Kampala
Most female college students and recent graduates in Uganda, however, seemed to feel able to
anticipate when they might need pericoital contraception and valued being able to take it before
sex. College women in India were not as forthcoming in discussing sexual activity, seldom
speaking from a personal perspective.
“I am talking about college girls. You go to visit your boyfriend or whatever, because in most
cases when you go you know things will happen, you go prepared. Instead of you being there
already, and then after, sometimes you remember… It helps you prepare.”—Female college
student, Kampala
Discreet Use
Many women in Kampala remarked that they could take pericoital contraception without the
knowledge of their spouse or partner; discretion and the ability to hide method use was also
mentioned by a few women in Lucknow. Many Kampala participants felt that since pericoital
contraception would consist of only a single dose, they could easily hide it from a spouse who
does not support family planning, and they valued being able to use a method surreptitiously.
“It is a secret weapon. For pills, he can easily check because the thing is there. He can easily
check in your bag and find the pill there. However this one, you swallow it in the bathroom and
clear everything.”—Female college student, Kampala
“There are some husbands who do not want family planning; they want you to produce and
produce until you are old. This pill you can hide and take after sex without your husband’s
knowledge.”—Woman, age-group 20–29, Kampala
Safety, Side Effects and Future Fertility
Across subgroups and country settings, many participants (both male and female) spontaneously
expressed concern over method safety and possible side effects.
“Won’t it destroy our eggs? Won’t our children lose sexual appetite? Won’t we lose weight?
Won’t we bleed a lot with huge clots of blood? Won’t we grow excessively fat? All family
planning methods have side effects.”—Woman, age-group 30–45, Kampala
Many women in Uganda, and a few participants in India, voiced unprompted the specific
concern that a pericoital pill should not limit one’s ability to conceive in the future. Participants
also raised fears of compromised fertility related to hormonal method use generally.
“It shouldn’t happen that the lady can’t get pregnant in future; no side effects like this should be
there.”—Married woman, age-group 30–45, Lucknow
“Can it affect her chances in the future for producing [reproducing] as a result of overusing
it?”—Married man aged 28, Kampala
Irregular Bleeding
Most married women in India and Uganda expressed minimal concern about irregular bleeding,
and some said that bleeding between menstrual cycles was a common side effect of family
planning and not problematic. Some also noted that receiving information about this side effect
from providers before starting the method would help allay potential concerns about bleeding.
“As it is, the menses get irregular sometimes, so no problem. It happens even if we do not take
anything, so we will take it.”—Married woman, age-group 20–29, Lucknow
“Bleeding cannot affect use [of a pericoital contraceptive product]…provided the woman is
counseled and is aware of this side effect.”—Woman, age-group 30–45, Kampala
Young, unmarried women were more concerned about menstrual spotting than married women
in Uganda and India, but for different reasons. In India, a few college women observed that if a
pericoital pill were to trigger excessive bleeding, the stigma of premarital sexual activity would
inhibit girls from seeking advice and limit method appeal.
“If there is much bleeding, girls will get scared. They cannot ask their mother [about the
bleeding].”—Female college student, Lucknow
In Uganda, a few women thought that intermittent bleeding could limit method appeal because
an irregular menstrual cycle is inconvenient.
“It disorganizes you for those three, four, five days. So that grace period where you are resting
and having your nice time, and then this thing [irregular bleeding] comes, it would just disturb
you… Period is bad enough. Now something coming in the middle is just not funny. So if it
[pericoital contraception] ever had that side effect, people would think twice before using it.”—
Female college student, Kampala
About half of the Ugandan men interviewed, and most married men in India, also found irregular
menstrual bleeding to be undesirable because it would interfere with sexual activity or cause
health concerns.
“Most people will lose hope because as I said, oral pills also cause bleeding and abnormal ones
[periods]. To me, a man, that one [pericoital contraception] is very inconveniencing because you
cannot stay with a woman in the house when she is bleeding. So people will not welcome that
one.”—Married man aged 27, Kampala
Potential Effectiveness
Participants were somewhat divided on the importance of method effectiveness. For some Indian
women and a few Ugandan women, their willingness to continue with the method may be tied
closely to its effectiveness. For some men in India and most of the men interviewed in Uganda,
the lower expected effectiveness of a pericoital pill relative to oral contraceptives is a
disincentive to use.
“So then it is better to take daily pill, because there will be doubt that it [pericoital contraception]
is safe.”—Married man, Lucknow
“If it fails, I think they will not like it because it will cause confusion in the family first of all. I
know you have taken the pill and you come and tell me you are pregnant. ‘No, you are lying.
That is not my son. That is not my pregnancy. I am not responsible for that.’ It will end up
causing family havoc. Men will not like that. Even a woman would not like that to happen in her
family.”—Unmarried man aged 30, Kampala
In one of the focus group discussions, female college students in India considered low
effectiveness to be a significant disincentive, remarking that a pericoital pill would be a better
method for married women due to the stigma of pregnancy among unmarried women.
“Only married women can take this pill, because even if she becomes pregnant there is no fear.
Unmarried cannot take it.”—Female college student, Lucknow
Some older women and emergency contraception users in Uganda also expressed concerns about
effectiveness.
“If I want to protect myself and I take it, [but] it does not do what it is supposed to do, I end up
disappointed. Effectiveness is very important, because it is the real thing you want it to do for
you.”—Emergency contraception user, Kampala
However, in the Ugandan context, most women were not unduly worried about the effectiveness
of pericoital contraception. Most did not strongly indicate that they would refuse to use a pill that
was less effective than regular oral contraceptives. Some seemed more excited about the other
advantages of the single pill and were willing to try it if it did not have side effects.
“If it is less effective, some people would reject it… If it has not worked for one, then that person
may tell others not to use it. But it would not stop people from using it…. Methods can fail, so
what matters is convenience. All we need as women is a method that can work and with less side
effects and more convenient. Convenience matters.”—Woman, age-group 30–45, Kampala
Lack of Dual Protection
Most participants in both countries did not consider lack of HIV protection a barrier to method
acceptance and felt it would only be problematic if one were to have multiple partners. Women
in Uganda noted that people have been sensitized about HIV and would minimize their risk of
infection in other ways (e.g., by knowing their partners’ HIV status and choosing appropriate
protection). Some Ugandan women observed that women are more concerned about pregnancy
than HIV infection. Especially in India, many women and men noted that most currently
available modern contraceptives also do not offer protection from HIV.
“You test, and when you find you are both negative, you can use this kind of pill.”—Female
college student, Kampala
“If you do not know the status of the woman, you have to use [condoms]. But if you know [her
status] and you know yours, you can’t use condoms. I know my companion is negative and I am
negative, there is no need for condoms anymore as long as this method is there.”—Unmarried
man aged 30, Kampala
However, many men in both countries, especially unmarried men in India, as well as a few
unmarried women in India, were concerned about the lack of HIV protection. A few women and
men in Uganda expressed concerns about the possibility of pericoital pill use replacing condom
use and facilitating the spread of HIV. Four in 10 Ugandan men volunteered that they would
prefer peri- coital contraception over condoms if it were available.
“The rate of AIDS will increase a bit instead of decreasing because people will not practice this
protected sex [with condoms]. Most ladies in Uganda, I know they fear pregnancy more than
AIDS.”—Unmarried man aged 30, Kampala
“The truth is that if this pill is effective, then there is no reason as to why I should wear condoms.
This is because I do not feel as good when having sex with my partner when I use condoms. I do
not enjoy much.”—Married man aged 28, Kampala
A number of the Ugandan men interviewed described contextualized method use in which they
would continue using condoms with partners they do not know well or trust, while using
pericoital contraception with their spouse or regular partner.
“It is better that we use it [pericoital contraception] with our partners in our homes and not with
the extramarital partners because we need to wear condoms for those we meet outside
marriage.”—Married man aged 25, Kampala
Potential Users
Participants’ perspectives on the appropriate clients for this method varied somewhat across the
two country settings. In Uganda, most participants thought that young, unmarried, sexually
active women have lifestyles that would align well with pericoital contraceptive use, given that
they are motivated to avoid pregnancy and that their coital frequency would likely be appropriate
for the method. Many college students readily identified themselves as potential users.
“Unmarried women—school girls—because they may meet their boyfriends once a month…they
do not want to become pregnant…they will like it very much.”—Woman, age-group 30–45,
Kampala
“I think it will suit them because most university girls are not married. So in most cases when
you are to have sex, I do not think it is on a daily basis, so I think it is suitable.”—Female college
student, Kampala
In India, diverse potential target audiences for pericoital contraception were identified, including
working women, educated women, those aged 25 or older who are not using permanent
contraception, women who do not reside with their husbands and unmarried women.
DISCUSSION
Our qualitative study suggests that in both settings, many women embraced the idea of a femalecontrolled method that would be easier than taking a daily pill, would offer flexibility in timing
and could be taken without a partner’s knowledge. A theme that the team heard repeatedly and
resoundingly was that the daily dosage schedule for oral contraceptives is challenging and feels
bothersome. At the same time, many of the participants who were receptive to the proposed
method also raised concerns about it, specifically, about the nature and severity of potential side
effects and, for married Ugandan women in particular, use among those unable to negotiate
sexual frequency.
Key differences emerged between the two settings that reflect broader differences in terms of
family planning and cultural norms. Injectable contraception is the most popular contraceptive
method in Uganda;11 use of this method is easily hidden from partners who may be opposed to
contraception. Therefore, it is perhaps not surprising that discretion emerged as an especially
prominent advantage of pericoital contraception among our female sample in Uganda. By
contrast, effectiveness emerged as a greater concern for women in Lucknow, a setting in which
sterilization dominates the method mix10 and where unintended pregnancy among unmarried
women may have serious social consequences.
Pericoital contraception was particularly appealing to young, unmarried female participants in
Uganda. Premarital sexual activity is fairly common in Uganda, with about one in four
adolescent women aged 15–19 and nearly half (45%) of adolescent men reporting that they are
sexually active but not yet married.13 Many unmarried women feel inhibited to seek family
planning from clinics and tend to use contraceptives inconsistently.14
Unmarried women were also identified as a possible audience in India, but premarital sexual
activity remains highly stigmatized there, and it is therefore difficult to estimate the share of
unmarried women needing contraceptive services. Though there have been very few studies of
premarital sexual activity in India, a recent survey in Pune District found that 10% of young
women were sexually active before marriage.15 A relatively small share of young Indian women
may be exposed to pregnancy risk, but for those who are sexually active, condom use is quite
rare—a recent study found that only 7% of sexually active young women reported that they had
ever used a condom.16 Because of the stigma associated with premarital sexual activity, offering
pericoital contraception via pharmacies may provide a reasonable alternative for young women
who find clinic-based family planning services unreceptive and do not feel comfortable
purchasing condoms or insisting on condom use by their partners. Moreover, studies suggest that
the daily schedule for oral contraceptives is challenging for adolescent women.13,17 Pericoital
contraception may be appropriate for young unmarried women who have periodic sex and
struggle with the daily oral contraceptive schedule.
Unmarried women are not the only potential targets for this method. There is a large population
of women for whom a pericoital pill could be appropriate, based on coital frequency. An
estimated 63% of currently married women in Uttar Pradesh, India, and 45% of married and
sexually experienced unmarried women in Uganda have sex about six times or less in a given
month and more than twice in six months.18 A recent study from the United States found that
among married women aged 30–49, more than two-thirds had sex at least a few times in a year,
but no more often than once a week; the same was true among 59% of women aged 25–29.19 For
women who are having sex once a week or once a month, taking a daily pill may feel impractical
and burdensome. Analyses to identify the extent to which women who have sex infrequently use
contraceptive methods, the methods they use, and whether they are using them effectively and
consistently should inform the introduction of pericoital contraception. Subsequent research
should also provide further information on the appeal of a pericoital pill among women having
more frequent sex and their potential use of the method.
The receptivity of Ugandan and Indian consumers to pericoital contraception suggests that many
of the features of this method align with women’s contraceptive preferences. Receptivity toward
the method among women in our sample is consistent with the results of a recent study that
found pericoital pills are rated very favorably, relative to other methods, when methods are
compared on the basis of their characteristics.20 The authors found that an over-the-counter
pericoital pill has 68% of the method features that women consider extremely important and is a
closer match to women’s preferences than any existing method, except for over-the-counter oral
contraceptives, which have 71% of desired features. Naturally, methods that reflect women’s
expressed preferences for what they value most should be given high priority as new
contraceptive technologies are developed.
Most married women in our sample did not perceive that intermittent bleeding would prevent
them from using pericoital contraception, but a few younger, unmarried women, as well as men,
expressed reservations. Studies of adolescents’ experiences with oral contraceptives have found
that breakthrough bleeding or amenorrhea is a key cause of discontinuation because irregularity
is inconvenient and provokes anxiety about pregnancy and future fertility.21 Breakthrough
bleeding may also create challenges for pregnancy detection, particularly for women using
pericoital contraceptives multiple times during the menstrual cycle. Moreover, dual use of a
pericoital pill with periodic abstinence would not be feasible because intermittent bleeding would
make identifying the fertile period difficult.
Few women in either setting reported that they would be discouraged from using pericoital
contraception due to the lack of HIV protection. The opinions of men were more variable; some
indicated a preference for pericoital contraception over condoms, while others indicated an
intention to continue condom use with new or extramarital partners. Some men anticipated that
preference for peri- coital contraception over condoms (depending on the partner) might make
the proposed method problematic from a public health standpoint, but it may also simply reflect
a general reluctance among men to use condoms. Nonetheless, particularly in places where HIV
infection rates are high, reinforcing messages about HIV risk for pericoital pill users, as well as
for users of other hormonal methods and IUDs, will be important.
The perspective of potential consumers is but half the dynamic in assessing the appeal of and
potential demand for a new method. Efforts to introduce pericoital contraception should also be
guided by the views of family planning providers and policymakers to identify enabling and
inhibiting factors for method introduction.12
Study Limitations
This study is limited in several ways. The sample was purposive, and the opinions of participants
may not be representative. In particular, the small samples of emergency contraception users and
men limit what we can conclude about the views of these groups. There were also a number of
country-specific challenges. In India, the stigma associated with premarital sexual activity
seemed to hinder young women from discussing contraception in a small group. In Uganda, the
field team faced difficulty identifying emergency contraception users and higher-income women
for inclusion in the study. They were also unable to select participants according to family
planning use patterns, which may have created less homogeneous groups than would have been
desirable. In both countries, we presented pericoital contraception to participants as intended for
women who have infrequent sex, given the high level of unmet need in this population. By doing
so, we may have created another study limitation: Respondents may have been unduly concerned
that some women might use the method more frequently. Finally, this study queried consumers
about how women and men expect to use a hypothetical method; research has shown that
perceived method appeal may differ from actual practice and perceptions.12
REFERENCES
1. Sedgh G et al., Women with an unmet need for contraception in developing countries and their
reasons for not using a method, Occasional Report, New York: Guttmacher Institute, 2007, No.
37.
2. Darroch JE, Sedgh G and Ball H, Contraceptive Technologies: Responding to Women’s
Needs, New York: Guttmacher Institute, 2011.
3. Halpern V, Raymond EG and Lopez LM, Repeated use of pre- and postcoital hormonal
contraception for prevention of pregnancy, Cochrane Database of Systematic Reviews, 2010,
Issue 1, No. CD007595.
4. Keesbury J, Morgan G and Owino B, Is repeat use of emergency contraception common
among pharmacy clients? Evidence from Kenya, Contraception, 2011, 83(4):346–351.
5. Lerkiatbundit S and Reanmongkol W, Use of 0.75 mg levonorgestrel for postcoital
contraception in Thailand, Journal of Clinical Pharmacy and Therapeutics, 2000, 25(3):185–
190.
6. Opoku B, Contraceptive use among “at-risk” women in a metropolitan area in Ghana, Acta
Obstetricia et Gynecologica Scandinavica, 2010, 89(8):1105–1107.
7. Chin-Quee D, Repeat use of emergency contraceptive pills: a study of urban women in Kenya
and Nigeria, paper presented at the annual meeting of the American Public Health Association,
San Francisco, CA, USA, Oct. 27–31, 2012.
8. Teixeira M et al., Representations and uses of emergency contraception in West Africa. A
social anthropological reading of a northern medicinal product, Social Science & Medicine,
2012, 75(1):148–155.
9. World Health Organization (WHO), Fact sheet on the safety of levonorgestrel-alone
emergency contraceptive pills, Geneva: WHO, 2010.
10. International Institute for Population Sciences (IIPS), District Level Household and Facility
Survey (DLHS-3), 2007–08: India, Mumbai: IIPS, 2010.
11. Uganda Bureau of Statistics (UBOS) and ICF International, Uganda Demographic and
Health Survey 2011, Kampala, Uganda: UBOS; and Calverton, MD, USA: ICF International,
2012.
12. Heise L, Beyond acceptability: reorienting research on contraceptive choice, in: Sundari
Ravindran TK, Berer M and Cottingham J, eds., Beyond Acceptability: Users’ Perspective on
Contraception, London: Reproductive Health Matters, 1997, pp. 6–14.
13. Darabi L et al., Protecting the Next Generation in Uganda: New Evidence on Adolescent
Sexual and Reproductive Health Needs, New York: Guttmacher Institute, 2008.
14. Nalwadda G et al., Persistent high fertility in Uganda: young people recount obstacles and
enabling factors to use of contraceptives, BMC Public Health, 2010, doi: 10.1186/1471-2458-10530, accessed Nov. 3, 2013.
15. Alexander M et al., Romance and sex: pre-marital partnership formation among young
women and men, Pune district, India, Reproductive Health Matters, 2006, 14(28):144–155.
16. Santhya KG, Acharya R and Jejeebhoy SJ, Condom use before marriage and its correlates:
evidence from India, International Perspectives on Sexual and Reproductive Health, 2011,
37(4):170–180.
17. Woods JL et al., Patterns of oral contraceptive pill-taking and condom use among adolescent
contraceptive pill users, Journal of Adolescent Health, 2006, 39(3):381–387.
18. Winfrey B, Futures Institute, special tabulations of data from the Uttar Pradesh and Uganda
Demographic and Health Surveys.
19. Herbenick D et al., Sexual behavior in the United States: results from a national probability
sample of men and women ages 14–94, Journal of Sexual Medicine, 2010, 7(Suppl. 5):255–265.
20. Lessard LN et al., Contraceptive features preferred by women at high risk of unintended
pregnancy, Perspectives on Sexual and Reproductive Health, 2012, 44(3):194–200.
21. Clark LR, Will the pill make me sterile? Addressing reproductive health concerns and
strategies to improve adherence to hormonal contraceptive regimens in adolescent girls, Journal
of Pediatric and Adolescent Gynecology, 2001, 14(4):153–162.
RESUMEN
Contexto: Hay estudios que sugieren que, en algunos países, las mujeres han adoptado las
píldoras de anticoncepción de emergencia como método rutinario de planificación familiar. Esta
práctica indica que puede haber una demanda latente para una píldora anticonceptiva pericoital,
etiquetada y comercializada para su uso como método anticonceptivo habitual, que se tome
solamente cuando una mujer tenga una relación sexual.
Métodos: Para comprender el atractivo y el mercado potencial de una píldora anticonceptiva
pericoital, se condujeron 39 grupos focales y 23 entrevistas en profundidad con mujeres y
hombres en Kampala (Uganda) y Lucknow (Uttar Pradesh, India). Un total de 281 individuos
participaron en este estudio cualitativo.
Resultados: En general, las mujeres apoyaron la idea de un método controlado por la mujer, más
fácil usar que una píldora anticonceptiva oral diaria, y que podría tomarse tanto antes como
después de la relación sexual. En Uganda, especialmente, las mujeres aprobaron que el método
pueda tomarse sin el conocimiento de la pareja. Aunque todavía no se conoce cuáles son los
efectos secundarios de este método, las mujeres expresaron preocupaciones sobre el grado y la
naturaleza de los efectos secundarios potenciales.
Conclusiones: Los resultados sugieren que una píldora anticonceptiva pericoital sería bien
recibida por las consumidoras de los dos países estudiados. Si su eficacia y los efectos
secundarios son aceptables, una píldora anticonceptiva pericoital podría responder a la demanda
de un método anticonceptivo controlado por la mujer, discreto, relacionado con la relación
sexual, especialmente entre las mujeres que no tienen relaciones sexuales con mucha frecuencia.
RÉSUMÉ
Contexte: Les études laissent entendre que les femmes de certains pays ont adopté la
contraception d’urgence comme méthode régulière de planification familiale. Cette pratique est
peut-être signe d’une demande latente d’une pilule péricoïtale, que la femme ne prendrait qu’en
cas de rapports sexuels et qui serait étiquetée et commercialisée comme méthode contraceptive
ordinaire.
Méthodes: Dans le but de cerner l’attrait et le marché potentiel d’une pilule contraceptive
péricoïtale, 39 groupes de discussion et 23 entretiens en profondeur ont été organisés avec des
femmes et des hommes de Kampala (Ouganda) et de Lucknow (Uttar Pradesh, Inde). Au total,
281 personnes ont participé à cette étude qualitative.
Résultats: De manière générale, les femmes embrassent l’idée d’une méthode féminine plus
simple que la pilule journalière et qui pourrait être prise avant ou après les rapports sexuels. Les
Ougandaises en particulier approuvent le fait que la méthode pourrait être pratiquée à l’insu du
partenaire. Bien que l’étendue des effets secondaires de cette méthode ne soit pas encore connue,
les femmes expriment certaines réserves quant au niveau et à la nature des effets secondaires
potentiels.
Conclusions: Les résultats laissent entendre qu’une pilule contraceptive péricoïtale serait bien
reçue sur le marché des deux contextes considérés. Si son efficacité et ses effets secondaires sont
acceptables, la pilule péricoïtale pourrait combler une lacune en termes de contraception
féminine discrète dépendante de l’acte sexuel, en particulier pour les femmes dont l’activité
sexuelle n’est guère fréquente.
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AUTHOR AFFILIATIONS
Jane Cover and Jennifer Kidwell Drake are program officers, and Claudia Harner-Jay is senior
commercialization officer, all at PATH, Seattle, WA, USA. Imelda Kyamwanga and Eleanor
Turyakira are professors at Mbarara University of Science and Technology, Kampala, Uganda.
Tanya Dargan is consultant, New Delhi, India. Edward Kumakech is program officer, PATH,
Kampala, Uganda.
© copyright 1996-2014, Guttmacher Institute
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AIDS Patient Care STDS. 2010 Nov;24(11):713-7. doi: 10.1089/apc.2010.0178. Epub 2010 Oct
23.
Factors associated with sexually transmitted
infection testing among men who utilize an
internet-based men who have sex with men
community.
Stupiansky NW, Rosenberger JG, Schick V, Herbenick D, Novak DS, Reece M.
Author information
Abstract
Public health messaging encourages men who have sex with men (MSM) to be tested for
sexually transmitted infections (STI) and HIV at least yearly, and more frequently depending on
sexual behaviors. However, despite engaging in a range of sexual behaviors, many MSM do not
participate in regular STI testing. The objective of this study was to understand factors associated
with STI testing among a nonclinic-based population of men accessing an Internet-based social
and sexual networking site. We asked 25,736 men to complete a comprehensive behavioral and
health assessment after being recruited from an Internet site popular among men seeking social
or sexual interactions with other men. Analyses were performed using multivariate logistic
regression with effects significant at p < 0.05. Two separate predictive models were assessed:
STI diagnosis within the past 2 years and STI testing within the past year. Regarding previous
STI diagnosis, men who used a condom some of the time or never during both insertive (odds
ratio [OR] = 1.72) and receptive (OR = 1.41) anal sex were significantly more likely to have had
an STI in the past 2 years. For STI testing, men who never used condoms during receptive anal
sex were more likely to have had an STI test within the past year (OR = 1.31), but men who had
a STI history were less likely to have been tested (O = 0.24). Public health efforts directed
toward MSM should continue to emphasize screening for STI other than HIV, particularly
among those men prioritized during condom promotion campaigns. In addition to the benefits of
learning one's STI status, the STI screening and treatment environment itself may provide an
important venue for encouraging a range of sexual health promoting behaviors.
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AIDS Care. 2012;24(8):1028-38. doi: 10.1080/09540121.2012.668285. Epub 2012 Apr 23.
Condom use problems during anal sex among
men who have sex with men (MSM): findings
from the Safe in the City study.
D'Anna LH, Margolis AD, Warner L, Korosteleva OA, O'Donnell L, Rietmeijer CA, Klausner
JD, Nomura W, Malotte CK; Safe City Study Group.
Author information
Abstract
Our research aims were to: (1) assess the prevalence of two condom use problems: breakage or
slippage and partial use (delayed application or early removal) among men who have sex with
men (MSM) seeking services in urban US STD clinics; and (2) examine the association between
these condom use problems and participant, partner and partnership characteristics. Analysis was
restricted to HIV-negative MSM who reported having anal sex at least once in the preceding 3
months and who completed both the baseline and 3 month follow-up assessments. Two models
were fitted using the generalized estimating equations (GEE) approach. A total of 263 MSM
(median age=32 years) reported 990 partnerships. Partnerships with no condom use 422 (42.6%)
were excluded. Thus, 207 MSM and 568 partnerships were included. Among condom users,
100% use was reported within 454 partnerships (79.9%) and <100% within 114 (20.1%), and
21(3.7%) reported both condom use problems, 25 (4.4%) reported only breakage, 67 (11.8%)
reported only partial use, and 455 (80.1%) reported no errors. The breakage or slippage and
partial use rates per condom used were 3.4% and 11.2%, respectively. A significantly higher rate
of breakage or slippage occurred among non-main partnerships. Characteristics associated with
increased odds for condom breakage or slippage were: lower education level (OR=2.78; CI: 1.17.5), non-main partner status (OR=4.1; CI: 1.5-11.7), and drunk or high during sex (OR=2.0; CI:
1.1-3.8), and for partial use: lower education level (OR=2.6; CI: 1.0-6.6), perceived partner
sexually transmitted infections (STI) risk (OR=2.4; CI: 1.3-4.2), and inconsistent condom use
(OR=3.7; CI: 2.0-6.6). A high percentage of MSM partnerships reported no condom use and
among condom users, a sizable proportion did not use them consistently or correctly. MSM may
benefit from interventions designed to increase proficiency for condom use with a particular
focus on the behaviors of inconsistent and partial condom use.
PMID:
22519680
[PubMed - indexed for MEDLINE]
PMCID:
PMC3389178
Free PMC Article
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Endocr Metab Immune Disord Drug Targets. 2010 Jun;10(2):179-87.
How close are we in achieving safe,
affordable and reversible male
contraceptives?
Tulsiani DR, Abou-Haila A.
Author information
Abstract
The world population, currently estimated to be over six billions, is expected to double in the
next forty years. The projected growth will cause severe over crowding that will have an adverse
effect on the ecological health of the planet. A recent survey by the United Nations found that a
majority of men in many countries are willing to participate in family planning by taking full
control of their fertility. However, the available contraceptives for men have either higher failure
rates or they are irreversible. Thus, the contraceptive needs of tens of millions of men go unmet
every day resulting in millions of unwanted pregnancies, and hundreds of thousands of abortions.
Since the introduction of oral contraceptive (pill) for women over five decades ago, there have
been numerous collaborative efforts by scientists and pharmaceutical companies to improve the
effectiveness and delivery of contraceptives to women who wish to safely regulate their
reproductive physiology. However, the contraceptive options available to men have not changed
in several decades and are still limited to the use of condoms and timely withdrawal (coitus
interruptus) or under going a minor surgical procedure (vasectomy) that prevents the release of
spermatozoa during ejaculation. The first two methods have relatively higher typical-use failure
rates, whereas the last approach is largely irreversible and not suitable for younger men. Despite
non-stop efforts worldwide, we may still be several years away from providing safe, effective
and affordable male contraceptives which will allow both men and women to participate fully in
family planning. In this article, we will discuss various contraceptives currently available to
regulate male fertility. In addition, we will summarize potentially new contraceptives for men
that are at various stages of research and development. Finally, our intention is to discuss details
of two safe, reversible and affordable male contraceptive approaches that are inching closure to
being approved for use by the masses in India and China, the world's two most populous nations.
PMID:
20350290
[PubMed - indexed for MEDLINE]
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Sex Transm Infect. 2010 Aug;86(4):263-70. doi: 10.1136/sti.2009.038752.
Prevalence of Chlamydia trachomatis: results
from the first national population-based
survey in France.
Goulet V, de Barbeyrac B, Raherison S, Prudhomme M, Semaille C, Warszawski J; CSF group.
Collaborators (13)
Author information
Abstract
BACKGROUND:
Few studies have estimated Chlamydia trachomatis (CT) prevalence in the general population,
most prevalence studies being based on people already attending healthcare settings.
OBJECTIVES:
To estimate the prevalence of CT in France, assess the feasibility of home sampling without any
face-to-face intervention and identify risk factors associated with CT infection using data from
the Contexte de la Sexualité (CSF) survey on sexual behaviour; a national population-based
survey, carried out by telephone in 2006.
METHODS:
A random subsample of sexually experienced people aged 18-44 (N=4957) were invited to
participate in a CT home-sampling study (NatChla study). Participants' samples were tested for
CT by PCR. Percentages were weighted for unequal selection probabilities and post-stratified
based on French population census data. Independent risk factors were identified by logistic
regression.
RESULTS:
CT prevalence in people aged 18-44 was estimated at 1.4% (95% CI 0.8% to 2.6%) for men, and
1.6% (95% CI 1.0% to 2.5%) for women. Increased rates were found in subjects aged 18-29:
2.5% (95% CI 1.2% to 5.0%) for men and 3.2% (95% CI 2.0% to 5.3%) for women. CT
infection was associated, for both genders, with having their last sexual intercourse with a casual
partner. Other risk factors were for men, having last intercourse with a new partner, living in the
Paris area, and for women, multiple partners during the previous year, same sex partners and a
low level of education.
CONCLUSIONS:
CT prevalence in France is similar to that in other developed countries. Home sampling proved
feasible and useful to reach members of the population with limited access to traditional care.
PMID:
20660590
[PubMed - indexed for MEDLINE]
=
Sex Transm Infect. 2010 Aug;86(4):263-70. doi: 10.1136/sti.2009.038752.
Prevalence of Chlamydia trachomatis: results
from the first national population-based
survey in France.
Goulet V, de Barbeyrac B, Raherison S, Prudhomme M, Semaille C, Warszawski J; CSF group.
Collaborators (13)
Author information
Abstract
BACKGROUND:
Few studies have estimated Chlamydia trachomatis (CT) prevalence in the general population,
most prevalence studies being based on people already attending healthcare settings.
OBJECTIVES:
To estimate the prevalence of CT in France, assess the feasibility of home sampling without any
face-to-face intervention and identify risk factors associated with CT infection using data from
the Contexte de la Sexualité (CSF) survey on sexual behaviour; a national population-based
survey, carried out by telephone in 2006.
METHODS:
A random subsample of sexually experienced people aged 18-44 (N=4957) were invited to
participate in a CT home-sampling study (NatChla study). Participants' samples were tested for
CT by PCR. Percentages were weighted for unequal selection probabilities and post-stratified
based on French population census data. Independent risk factors were identified by logistic
regression.
RESULTS:
CT prevalence in people aged 18-44 was estimated at 1.4% (95% CI 0.8% to 2.6%) for men, and
1.6% (95% CI 1.0% to 2.5%) for women. Increased rates were found in subjects aged 18-29:
2.5% (95% CI 1.2% to 5.0%) for men and 3.2% (95% CI 2.0% to 5.3%) for women. CT
infection was associated, for both genders, with having their last sexual intercourse with a casual
partner. Other risk factors were for men, having last intercourse with a new partner, living in the
Paris area, and for women, multiple partners during the previous year, same sex partners and a
low level of education.
CONCLUSIONS:
CT prevalence in France is similar to that in other developed countries. Home sampling proved
feasible and useful to reach members of the population with limited access to traditional care.
==
Sex Transm Infect. 2010 Aug;86(4):263-70. doi: 10.1136/sti.2009.038752.
Prevalence of Chlamydia trachomatis: results
from the first national population-based
survey in France.
Goulet V, de Barbeyrac B, Raherison S, Prudhomme M, Semaille C, Warszawski J; CSF group.
Collaborators (13)
Author information
Abstract
BACKGROUND:
Few studies have estimated Chlamydia trachomatis (CT) prevalence in the general population,
most prevalence studies being based on people already attending healthcare settings.
OBJECTIVES:
To estimate the prevalence of CT in France, assess the feasibility of home sampling without any
face-to-face intervention and identify risk factors associated with CT infection using data from
the Contexte de la Sexualité (CSF) survey on sexual behaviour; a national population-based
survey, carried out by telephone in 2006.
METHODS:
A random subsample of sexually experienced people aged 18-44 (N=4957) were invited to
participate in a CT home-sampling study (NatChla study). Participants' samples were tested for
CT by PCR. Percentages were weighted for unequal selection probabilities and post-stratified
based on French population census data. Independent risk factors were identified by logistic
regression.
RESULTS:
CT prevalence in people aged 18-44 was estimated at 1.4% (95% CI 0.8% to 2.6%) for men, and
1.6% (95% CI 1.0% to 2.5%) for women. Increased rates were found in subjects aged 18-29:
2.5% (95% CI 1.2% to 5.0%) for men and 3.2% (95% CI 2.0% to 5.3%) for women. CT
infection was associated, for both genders, with having their last sexual intercourse with a casual
partner. Other risk factors were for men, having last intercourse with a new partner, living in the
Paris area, and for women, multiple partners during the previous year, same sex partners and a
low level of education.
CONCLUSIONS:
CT prevalence in France is similar to that in other developed countries. Home sampling proved
feasible and useful to reach members of the population with limited access to traditional care.
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BMC Infect Dis. 2013 Aug 22;13:388. doi: 10.1186/1471-2334-13-388.
Prevalence of genital Chlamydia trachomatis
infection among young men and women in
Spain.
Fernández-Benítez C, Mejuto-López P, Otero-Guerra L, Margolles-Martins MJ, Suárez-Leiva P,
Vazquez F; Chlamydial Primary Care Group.
Collaborators (13)
Author information
Abstract
BACKGROUND:
There are no accurate data regarding the real prevalence of Chlamydia trachomatis infection in
Spain. Our aim was to determine the prevalence of C. trachomatis infections and the risk factors
for acquiring them among 1,048 young (15-24 years old) inhabitants of Laviana.
METHODS:
The study was completed in the period between 1st November 2010 and 31st December 2011.
We conducted a capture strategy in the whole population, instead of only in a sample group, with
a capture conducted in schools, in the local health centre, by post and by phone as a last resort.
The design was based on the model used by Shafer to increase screening rates. C. trachomatis
was identified by RT-PCR in urine samples.
RESULTS:
A total of 487 sexually active people underwent the test, which implies a response rate of 59.8%
of the sexually active people (target population). The prevalence was 4.1% (CI 95%: 3.1-5.8):
women: 4% ( CI 95%; 2.8-6.4) and men: 4.3% (CI 95%: 2.9-7.2). The circulating genotype was
the E genotype. There was an increase in the risk of C. trachomatis infection when barrier
contraceptives were not routinely used OR: 4.76 (CI 95%:1.30-17.36) p<0.05.
CONCLUSIONS:
In our study the prevalence in women resembles those found in other countries in Europe and the
prevalence in men is similar to that in women. Screening for C. trachomatis infection in women
would be cost-effective in Spain given the prevalence of C. trachomatis measured by this study.
The use of a condom is the best preventative measure for avoiding STIs in sexually active
people.
PMID:
23968487
[PubMed - in process]
PMCID:
PMC3765329
Free PMC Article
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Int J Impot Res. 2010 May-Jun;22(3):159-70. doi: 10.1038/ijir.2010.2. Epub 2010 Mar 25.
Update on male hormonal contraception: is
the vasectomy in jeopardy?
Manetti GJ, Honig SC.
Author information
Abstract
Traditionally, male contraception has consisted of either barrier methods, such as condoms, or
vasectomy. However, in recent years, we have made great strides in the basic science and clinical
medicine to better understand the feedback mechanisms and physiology of the male reproductive
system. These advances have enabled the development of several nonsurgical, hormonal,
reversible, well-tolerated alternatives for male contraception. Men are more likely now than ever
to participate in the choice of contraceptive techniques. This review will discuss the current
status and recent developments in nonsurgical hormonal male contraception, a field that has been
historically limited by social, financial and physiological challenges.
PMID:
20336073
[PubMed - indexed for MEDLINE]
Publication Types, MeSH Terms, Substances
LinkOut - more resources
=
Int J Impot Res. 2010 May-Jun;22(3):159-70. doi: 10.1038/ijir.2010.2. Epub 2010 Mar 25.
Update on male hormonal contraception: is
the vasectomy in jeopardy?
Manetti GJ, Honig SC.
Author information
Abstract
Traditionally, male contraception has consisted of either barrier methods, such as condoms, or
vasectomy. However, in recent years, we have made great strides in the basic science and clinical
medicine to better understand the feedback mechanisms and physiology of the male reproductive
system. These advances have enabled the development of several nonsurgical, hormonal,
reversible, well-tolerated alternatives for male contraception. Men are more likely now than ever
to participate in the choice of contraceptive techniques. This review will discuss the current
status and recent developments in nonsurgical hormonal male contraception, a field that has been
historically limited by social, financial and physiological challenges.
PMID:
20336073
[PubMed - indexed for MEDLINE]
Publication Types, MeSH Terms, Substances
LinkOut - more resources
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Int Nurs Rev. 2008 Mar;55(1):103-9. doi: 10.1111/j.1466-7657.2007.00572.x.
Contraceptive methods with male
participation: a perspective of Brazilian
couples.
Marchi NM, de Alvarenga AT, Osis MJ, Bahamondes L.
Author information
Abstract
OBJECTIVE:
To assess the perspectives of couples who requested vasectomy in a public health service on the
use of male participation contraceptive methods available in Brazil: male condoms, natural
family planning/calendar, coitus interruptus and vasectomy.
METHODS:
A qualitative study with semi-structured interviews was held with 20 couples who had requested
vasectomy at the Human Reproduction Unit of the Universidade Estadual de Campinas, Brazil.
Data analysis was carried out through thematic content analysis.
FINDINGS:
The couples did not, in general, know any effective contraceptive options for use by men and/or
participating in their use, except for vasectomy. The few methods with male participation that
they knew of were perceived to interfere in spontaneity and in pleasure of intercourse. Men
accepted that condom use in extra-conjugal relations offered them protection from sexually
transmitted diseases; that their wives might also participate in extra-marital relationships was not
considered.
DISCUSSION:
The few contraceptive options with male participation lead to difficulty in sharing
responsibilities between men and women. On the basis of perceived gender roles, women took
the responsibility for contraception until the moment when the situation became untenable, and
they faced the unavoidable necessity of sterilization.
CONCLUSIONS:
Specific actions are necessary for men to achieve integral participation in relation to reproductive
sexual health. These include education and discussions on gender roles, leading to greater
awareness in men of the realities of sexual and reproductive health.
PMID:
18275543
[PubMed - indexed for MEDLINE]
=
Indian J Community Med. 2010 Jan;35(1):40-5. doi: 10.4103/0970-0218.62552.
Male behavior toward reproductive
responsibilities in sikkim.
Chankapa YD, Pal R, Tsering D.
Author information
Abstract
BACKGROUND:
Failure to assess the impact of men's perceptions on reproductive health decisions has weakened
reproductive health care programmes.
OBJECTIVES:
We evaluated husbands' knowledge and practices with regard to the use of conventional
contraceptives as manifested through reproductive health and sexual decisions.
MATERIALS AND METHODS:
A population-based cross-sectional study was conducted in a rural setting of Sang PHC and
Pakyong PHC area in Sikkim, India. Five hundred and ninety-six currently married men whose
names were included in the eligible couple registers were selected by multistage random
sampling. Information regarding knowledge and practice of contraceptive use was obtained from
the participants by interview.
RESULTS:
Out of the 596 male participants, the majority (55.87%) opined that they were in favor of using a
contraceptive method after one child. Most participants (55.54%) said that their main source of
information on contraceptive methods were the government health staff, while 24.84%
acknowledged that most of their information came from the mass media. Eighty-two percent
reported currently using some kind of the contraceptive method. Condom was used as a
temporary method by only 16.27% of the responders, with the permanent method of vasectomy
being opted for by only 4.87%. The method most widely used by their partners was the oral
contraceptive pill (43.41%), followed by tubectomy (15.77%) and IUD (4.19%).
CONCLUSIONS:
This research found that awareness and prevalence of contraceptive use among married men in a
rural community in the East District of Sikkim were quite high. Nevertheless, female
contraceptive methods continue to be the dominant method used in the community. Researchers
and health care providers often ignore the sociodemographic significance of men and their role in
the acceptance of contraceptive practices in the community.
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Cult Health Sex. 2007 Jan-Feb;9(1):1-14.
'A shot of his own': the acceptability of a
male hormonal contraceptive in Indonesia.
[Article in English, French, Spanish]
Solomon H, Yount KM, Mbizvo MT.
Author information
Abstract
Male hormonal contraception has been shown to confer reversible infertility for at least one year;
however, while clinical trials refine hormonal regimens, their acceptability, cultural meanings,
and implications for study of men's sexualities remain under examined. This paper presents
findings from interviews conducted with men and their female partners in a male hormonal
contraception clinical trial in Jakarta and Palembang, Indonesia, and describes the ideas
expressed about this new contraceptive technology. Fourteen men and their partners in Jakarta
and ten men and their partners in Palembang were interviewed about their motivations to
participate in the trial and their perceptions of the injection's physical, psychological and social
effects. Concerns such as excess fertility and attendant economic liability shaped one quarter of
motivations reported by men, while many women highlighted how a male method could help
them prevent pregnancy without physical complications. Intimacy and sexual relations between
couples were key themes within interpretations of contraceptive acceptability. Taken together,
the narratives presented in this study call attention to the need for more nuanced analyses of
contraceptive acceptability, as well as to the importance of studies of new male contraceptives
for the understanding of masculinities.
PMID:
17364710
[PubMed - indexed for MEDLINE]
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Sex Health. 2008 Dec;5(4):321-30.
Relationships between condoms, hormonal
methods, and sexual pleasure and
satisfaction: an exploratory analysis from the
Women's Well-Being and Sexuality Study.
Higgins JA, Hoffman S, Graham CA, Sanders SA.
Author information
Abstract
BACKGROUND:
Little is known about how condoms and other contraceptives influence women's sexual
enjoyment, which could shape use patterns.
METHODS:
Data from an online study of women's sexual health and functioning were used to examine how
three categories of contraceptive use - hormonal method only, condoms primarily, and dual use could help predict decreased sexual pleasure associated with contraceptive method and overall
sexual satisfaction in the past 4 weeks.
RESULTS:
In analyses controlling for age, relationship length, and other variables, male condoms were most
strongly associated with decreased pleasure, whether used alone or in conjunction with hormonal
methods. Women who used hormonal methods alone were least likely to report decreased
pleasure, but they also had significantly lower overall scores of sexual satisfaction compared
with the other two groups. Dual users, or women who used both condoms and a hormonal
method, reported the highest sexual satisfaction scores.
CONCLUSIONS:
Because male condoms were viewed by many of these women as decreasing sexual pleasure,
sexual risk practices are likely to be affected. Although hormonal only users were highly
unlikely to report decreased pleasure, they reported lower sexual satisfaction compared with the
other two groups. Dual users, who had the highest sexual satisfaction scores, may have been the
most sexually satisfied because they felt more fully protected against unwanted pregnancy and
sexually transmissible infections - consistent with previous qualitative documentation of
'eroticising safety.' This exploratory study suggests that different contraceptives affect sexuality
in various ways, warranting further research into these sexual dimensions and how they influence
contraceptive practices.
PMID:
19061551
[PubMed - indexed for MEDLINE]
PMCID:
PMC2746830
Free PMC Article
=
Womens Health Issues. 2007 Jan-Feb;17(1):29-36.
Attitudes toward contraceptive methods
among African-American men and women:
similarities and differences.
Thorburn S.
Author information
Abstract
PURPOSE:
Men's attitudes toward contraceptives are an understudied area, even though many men
participate in contraceptive decision making. The purpose of this study was to examine attitudes
and perceptions regarding a selection of contraceptive methods among a national sample of
African Americans, with a particular focus on gender differences.
METHODS:
Data come from a telephone survey of African Americans (aged 15-44 years) living in the
contiguous United States. For the present analyses, the sample was restricted to 152 men and 281
women who reported having had a sexual partner of the opposite gender at some point in their
lives. Bivariate analyses compared men and women's ratings of birth control pills, male
condoms, female condoms, Norplant, Depo Provera, female sterilization, and male sterilization
along several dimensions: bad/good, harmful/beneficial, difficult/easy, dangerous/safe,
immoral/moral, and effectiveness. Multiple logistic regressions were performed to determine the
association between gender and contraceptive attitudes, adjusting for sociodemographic
variables.
RESULTS:
Male condoms were given the most favorable ratings along most dimensions by both AfricanAmerican men and women. In general, ratings of male condoms, female condoms, and Norplant
did not significantly differ by gender. African-American men did, however, give female and
male sterilization, birth control pills, and Depo Provera significantly poorer ratings than did
African-American women.
CONCLUSION:
African-American men had less favorable evaluations of some contraceptive methods than did
African-American women. Further research is needed to examine how such gender differences
may play a role in contraceptive decisions.
PMID:
17321945
[PubMed - indexed for MEDLINE]
PMCID:
PMC1853268
Free PMC Article
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Womens Health Issues. 2007 Jan-Feb;17(1):29-36.
Attitudes toward contraceptive methods
among African-American men and women:
similarities and differences.
Thorburn S.
Author information

Department of Public Health at Oregon State University, Corvallis, Oregon 97331-6406,
USA. Sheryl.Thorburn@oregonstate.edu
Abstract
PURPOSE:
Men's attitudes toward contraceptives are an understudied area, even though many men
participate in contraceptive decision making. The purpose of this study was to examine attitudes
and perceptions regarding a selection of contraceptive methods among a national sample of
African Americans, with a particular focus on gender differences.
METHODS:
Data come from a telephone survey of African Americans (aged 15-44 years) living in the
contiguous United States. For the present analyses, the sample was restricted to 152 men and 281
women who reported having had a sexual partner of the opposite gender at some point in their
lives. Bivariate analyses compared men and women's ratings of birth control pills, male
condoms, female condoms, Norplant, Depo Provera, female sterilization, and male sterilization
along several dimensions: bad/good, harmful/beneficial, difficult/easy, dangerous/safe,
immoral/moral, and effectiveness. Multiple logistic regressions were performed to determine the
association between gender and contraceptive attitudes, adjusting for sociodemographic
variables.
RESULTS:
Male condoms were given the most favorable ratings along most dimensions by both AfricanAmerican men and women. In general, ratings of male condoms, female condoms, and Norplant
did not significantly differ by gender. African-American men did, however, give female and
male sterilization, birth control pills, and Depo Provera significantly poorer ratings than did
African-American women.
CONCLUSION:
African-American men had less favorable evaluations of some contraceptive methods than did
African-American women. Further research is needed to examine how such gender differences
may play a role in contraceptive decisions.
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J Fam Plann Reprod Health Care. 2002 Oct;28(4):196-200.
A study on the knowledge and practice of
contraception among men in the United Arab
Emirates.
Ghazal-Aswad S, Zaib-Un-Nisa S, Rizk DE, Badrinath P, Shaheen H, Osman N.
Author information

Department of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences,
United Arab Emirates (UAE) University, Al-Ain, UAE. saad.ghazal-Aswad@uaeu.ac.ae
Abstract
OBJECTIVE:
To determine the knowledge and practice of contraception among United Arab Emirates (UAE)
men.
DESIGN:
Cross-sectional survey.
PARTICIPANTS:
Four hundred UAE monogamously married men with children.
METHOD:
The participants were randomly selected from the community and interviewed about knowledge
and practice of contraception using a structured questionnaire.
RESULTS:
A total of 348 men (87%) gave consent to participate in the study. Two hundred and ninety-four
participants (84.5%) were aware of the availability of male contraceptive methods but only 94
(27%) were currently using these methods; 39 (41.5%) used condoms, 30 (31.9%) practised
coitus interruptus, 24 (25.5%) practised the rhythm method and only one (1.1%) had been
sterilised. Male contraception was accepted by 116 (33.3%) subjects of the total study
population. The reasons for the objections were: religious 133 (57.3%), cultural barriers 47
(20.3%), personal beliefs 29 (12.5%), medical disorders 18 (7.8%) and economical factors five
(2.2%). Of 54 users of condoms and coitus interruptus, 16 (29.6%) reported to have experienced
adverse effects that included testicular pain in six (37.5%), decreased libido in six (37.5%) and
diminished orgasm in four (25%). There were significant associations between using male
contraception and levels of education of the partners (male p < 0.007, female p < 0.01), low
family size (p = 0.0001) and family income (p < 0.05). Fifty-seven subjects (19.4%) thought that
a 'male contraceptive pill' is available and 44 (15.0%) believed that a monthly injection is
available for men.
CONCLUSIONS:
The level of awareness of contraception among men attending primary care in UAE is moderate.
Two-thirds of the study subjects objected to the use of contraception by their wives and less than
20% practise contraception themselves. This is partly due to sociocultural traditions, religious
beliefs and poor knowledge.
PMID:
12419060
[PubMed - indexed for MEDLINE]
Free full text
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Endocr Rev. 2008 Jun;29(4):465-93. doi: 10.1210/er.2007-0041. Epub 2008 Apr 24.
Advances in male contraception.
Page ST, Amory JK, Bremner WJ.
Author information
Abstract
Despite significant advances in contraceptive options for women over the last 50 yr, world
population continues to grow rapidly. Scientists and activists alike point to the devastating
environmental impacts that population pressures have caused, including global warming from the
developed world and hunger and disease in less developed areas. Moreover, almost half of all
pregnancies are still unwanted or unplanned. Clearly, there is a need for expanded, reversible,
contraceptive options. Multicultural surveys demonstrate the willingness of men to participate in
contraception and their female partners to trust them to do so. Notwithstanding their paucity of
options, male methods including vasectomy and condoms account for almost one third of
contraceptive use in the United States and other countries. Recent international clinical research
efforts have demonstrated high efficacy rates (90-95%) for hormonally based male
contraceptives. Current barriers to expanded use include limited delivery methods and perceived
regulatory obstacles, which stymie introduction to the marketplace. However, advances in oral
and injectable androgen delivery are cause for optimism that these hurdles may be overcome.
Nonhormonal methods, such as compounds that target sperm motility, are attractive in their
theoretical promise of specificity for the reproductive tract. Gene and protein array technologies
continue to identify potential targets for this approach. Such nonhormonal agents will likely
reach clinical trials in the near future. Great strides have been made in understanding male
reproductive physiology; the combined efforts of scientists, clinicians, industry and
governmental funding agencies could make an effective, reversible, male contraceptive an option
for family planning over the next decade.
===
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J Biosoc Sci. 2002 Oct;34(4):497-510.
Factors affecting ever-married men's
contraceptive knowledge and use in Nigeria.
Oyediran KA, Ishola GP, Feyisetan BJ.
Author information
Abstract
African men play important roles in the decisions about family life, including fertility and family
planning. However, fertility and family planning research and programmes have ignored their
roles in the past, focusing only on women's behaviours. Since the 1994 International Conference
on Population and Development (ICPD), interest in men's involvement in reproductive health has
increased. Unfortunately, data on their knowledge and use of contraception are generally scanty.
This paper examines knowledge and use of contraception among ever-married men in Nigeria. A
total of 1451 ever-married men aged 18-55 were interviewed in Imo and Ondo States, Nigeria.
The findings reveal that men's level of contraceptive knowledge is high in the study areas. About
90% knew at least one method of family planning. Furthermore, the level of contraceptive use
among married men is such that men could participate in family planning activities if there were
adequate programmes to involve them. Men in the sample areas were found not only to support
their spouses' use of contraceptives, but were actually using condoms to delay or prevent
pregnancy. Age, education, place of residence, number of living children and being counselled
for family planning were identified as key factors determining contraceptive knowledge and use
among married men in the study areas. To ensure increased participation of men in family
planning, programmes must be designed to educate them on the need for family size limitation
and involve them in service delivery, even if only to their male counterparts.
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Endocr Rev
PMC2528850
Endocr Rev. 2008 June; 29(4): 465–493.
doi: 10.1210/er.2007-0041
PMCID: PMC2528850
Advances in Male Contraception
Stephanie T. Page, John K. Amory, and William J. Bremner
Author information ► Article notes ► Copyright and License information ►
This article has been cited by other articles in PMC.
Go to:
Abstract
Despite significant advances in contraceptive options for women over the last 50 yr, world
population continues to grow rapidly. Scientists and activists alike point to the devastating
environmental impacts that population pressures have caused, including global warming from the
developed world and hunger and disease in less developed areas. Moreover, almost half of all
pregnancies are still unwanted or unplanned. Clearly, there is a need for expanded, reversible,
contraceptive options. Multicultural surveys demonstrate the willingness of men to participate in
contraception and their female partners to trust them to do so. Notwithstanding their paucity of
options, male methods including vasectomy and condoms account for almost one third of
contraceptive use in the United States and other countries. Recent international clinical research
efforts have demonstrated high efficacy rates (90–95%) for hormonally based male
contraceptives. Current barriers to expanded use include limited delivery methods and perceived
regulatory obstacles, which stymie introduction to the marketplace. However, advances in oral
and injectable androgen delivery are cause for optimism that these hurdles may be overcome.
Nonhormonal methods, such as compounds that target sperm motility, are attractive in their
theoretical promise of specificity for the reproductive tract. Gene and protein array technologies
continue to identify potential targets for this approach. Such nonhormonal agents will likely
reach clinical trials in the near future. Great strides have been made in understanding male
reproductive physiology; the combined efforts of scientists, clinicians, industry and
governmental funding agencies could make an effective, reversible, male contraceptive an option
for family planning over the next decade.
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I. Introduction
II. Acceptability of Male Contraception
III. Currently Available Male Contraceptive Methods
o A. Condoms
o B. Vasectomy
IV. Regulation of Testicular Function and Spermatogenesis
o A. The hypothalamic-pituitary axis: control of gonadotropin secretion
o B. Testosterone production and androgen action
o C. Spermatogenesis
o
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D. The epididymis
V. Male Hormonal Contraception Methods
o A. Hormonal contraceptive efficacy
o B. Testosterone alone
o C. Testosterone-progestin combinations
o D. Adding GnRH analogs to hormonal contraceptive regimens
o E. Oral male hormonal contraceptive development
o F. Reversibility of male hormonal contraception
o G. Side effects of male hormonal contraceptives
o H. Selective androgen receptor modulators for male contraception
o I. Why doesn’t hormonal contraception work for all men?
VI. Nonhormonal Methods
o A. Testicular targets
o B. Epdidymal targets
o C. Targeting sperm motility or sperm-egg fusion
o D. Immunological approaches to contraception
VII. Conclusions
Go to:
I. Introduction
DESPITE CURRENTLY AVAILABLE contraceptives, the world’s population exceeds 6.5
billion and is increasing by 75 million yearly (1), and overpopulation continues to be a
significant contributor to environmental degradation and human suffering worldwide. Much of
our current global population growth is unintended. It is estimated that half of all conceptions are
unplanned and half of the resulting pregnancies are undesired (2). In the United States,
approximately half of unintended pregnancies are attributable to a failure to use contraception,
and the other half to difficulties with contraceptive use or method failure (3). Moreover, in
developing countries contraception use is further limited by restricted access to many available
methods, both economically and culturally. The contraceptive shortfall results in over 20% of
pregnancies ending in abortion (3,4). In addition, undesired pregnancies result in unwanted
children who suffer disproportionately from poverty and neglect (5,6). Therefore, there is a great
need for better access and education regarding existing contraceptives and more contraceptive
options.
Women have a wide range of contraceptive choices. Research and family planning organizations
have traditionally focused upon female methods of contraception because women bear a
disproportionate portion of the health and economic consequences of childbearing and rearing.
Consequently, women have many contraceptive choices, ranging from daily oral medications to
intrauterine devices implanted every 5 yr to sterilization. In the current era, there are only two
forms of male contraception available, condoms and vasectomy, with only the former being
reliably reversible. In fact, no new, reversible, male-based methods have become commercially
available since the condom was introduced more than 300 yr ago. However, despite few
available options, male methods account for approximately 14% of contraception worldwide,
with prevalence significantly higher in the more developed world where male-directed methods
account for more than 30% of contraception.
Funding for the development of male contraceptives has faltered since this topic was last
reviewed (7). Although support from some public agencies has continued, albeit at reduced
levels, the pharmaceutical industry has largely abandoned this potential market. Three major
international pharmaceutical companies have cancelled their programs in male contraception
over the last 5 yr, citing corporate changes in direction as the motivating force. However, it is
difficult to imagine that other forces have not influenced these decisions, including the
perception that the safety standards for regulatory approval of such products would require
studies of such numbers and length as to be financially infeasible or lacking in incentive for
profit. In addition, despite the environmental and health consequences of the ongoing but largely
forgotten population crisis, large nonprofits such as the Bill and Melinda Gates Foundation have
focused their resources on other global health concerns. Without the support of these
organizations in the long run, progress in the development of effective and available male
contraceptives is difficult to imagine.
In this article, we will review the mechanism of action and recent advances in male
contraception, with particular emphasis on newer regimens that may be nearing introduction to
clinical practice. First, however, we will discuss the important question of acceptability, because
only a contraceptive that men, and their female partners, will reliably use represents a true
advance in the field. We will discuss the physiological challenges of male contraceptive
development, hormonal methods of contraception, which likely offer the prospect of reaching the
market first, and nonhormonal methods, including immune-based products.
Go to:
II. Acceptability of Male Contraception
It has been suggested that development of male-based contraceptive methods represents a
misdirection of resources (8) because contraception is ultimately in the domain of female
reproductive health. However, the appeal of a male contraceptive to both men and women is
great. In surveys spanning four continents, a majority of men indicate a willingness to use a male
contraceptive if one were available (9,10). Additional multinational and multiethnic studies of
potential hormonally based male contraceptives demonstrate that most men (11), and their
female partners (12), would be willing to use such a method of contraception. In fact, 98% of
women in stable relationships would be willing to rely on their male partner to use male
contraception (12). Acceptability of male-based contraceptive methods is, however, influenced
by economic, cultural, religious, and relationship status. For example, higher income and
education status are associated with a great willingness to use male contraception (10). Other
studies demonstrate marked cultural differences. For example, men in predominantly Muslim
Indonesia were less willing to use a male contraceptive and cited religious beliefs as a major
objection (10). Male Australian immigrants were less receptive to the notion of male
contraception than those born in Australia (13). Among women with current partners in Hong
Kong, only 14% felt that they would rely a male-based method in the future if it were available,
whereas in Shanghai 71% of these female respondents would use a male-based method were it
available (12). Interestingly, more than 70% of women in both locales thought male
contraception was a “good idea” (12).
Clearly, mode of delivery is an important factor in the acceptability of male contraceptive
regimens. In large surveys, oral forms of contraceptive delivery are favored by most male
respondents (10,14). Depending on their country of origin, women felt their partners were most
likely to use a daily pill or monthly injection (12). Injection-based hormonal regimens, the most
clinically studied experimental contraceptive method to date, are acceptable to the majority of
participants in male contraceptive studies (15,16). However, whether the injections are once a
month (16) or as far apart as every 12 wk (15), participants find the injection schedule and
associated discomfort as the biggest disadvantage to these regimens, and 35–40% cite
dissatisfaction with the method as a result (15,16). A combination of a daily transdermal gel with
every 3-month injections was slightly less acceptable to participants, with 45% stating they
would use such a regimen if it were commercially available but one third citing that the daily gel
interfered with their daily routine, making it less acceptable (17).
In summary, most men and their female partners are receptive to the notion, and in fact the
practice, of male contraception. Overall, a majority of men feel that the responsibility of
contraception falls too much on women (11) and are receptive to male-based methods (10), while
71–97% of women believe male hormonal contraception is a “good idea” (12). The time is ripe,
therefore, for introduction of new methods to the marketplace.
Go to:
III. Currently Available Male Contraceptive Methods
A. Condoms
Barrier methods have been used to prevent pregnancy since ancient times, but sheath-like
condoms, originally made from animal intestines, were developed 300–400 yr ago. Today,
barrier methods, including the female as well as male condom, are the only effective means,
besides abstinence and lifelong mutual monogamy, of preventing sexually transmitted disease
transmission. In particular, although male circumcision has recently been shown to significantly
reduce male transmission of HIV (18), the condom remains the most effective way of preventing
HIV transmission during sexual contact.
Condoms are currently used by approximately 20% of couples using contraception in the United
States (19,20), although the United Nations reports that only 5% of reproductive age women
worldwide rely on male condoms for contraception (21). Condoms are associated with few
adverse side effects; however, they have a marginal contraceptive efficacy. This is mainly due to
improper or inconsistent usage, as demonstrated by comparison of pregnancy rates for “typical
use” (15%) vs. “perfect use” (2%) for couples using condoms for contraception (22,23). A
significant drawback to condoms is their poor long-term compliance, with more than half of
users reporting inconsistent use with every act of intercourse (24). In addition, many men dislike
condoms because they feel condoms diminish sexual pleasure (25), again hampering consistent
usage. However, even when used correctly, condom breakage and slippage are not infrequent,
occurring in up to 2–8% of cases (26,27,28,29,30).
Since 1920, most condoms have been made of latex rubber; however, latex condom use has been
associated with development of latex allergies in both men and women, which can cause skin
irritation and even death (31,32). As a result of latex allergies, polyurethane condoms have been
more recently developed and entered the market in the 1990s. Clinical studies with these
condoms have demonstrated a slightly higher rate of condom breakage and slippage when
compared with latex condoms (26,29,30,33). In addition, some users have greater difficulty with
putting on (33) or unrolling (30) polyurethane condoms compared with latex condoms. Most
importantly, however, in general polyurethane and latex condoms have similar efficacy rates
(26,28), with the exception of one study reporting slightly greater efficacy with the latex condom
(29). Therefore, despite their increased breakage, polyurethane condoms are an important
alternative to latex condoms for couples, particularly those with latex allergies.
B. Vasectomy
Vasectomy is a safe, simple, outpatient surgery performed under local anesthesia in which the
ductus deferens is severed and the ends ligated through a small scrotal incision. Approximately
500,000 vasectomies are performed yearly in the United States (34), where approximately 10%
of couples using contraception rely on this method (19,20). Worldwide over 40 million men have
undergone the procedure (35), accounting for about 5% of active contraception (21).
Vasectomies are highly effective, with a failure rate of less than 1% and a low incidence of
complications (36,37,38). The “no scalpel technique” was introduced in the early 1990s after
development in the Sichuan province in China (39). This technique utilizes a single, midline
puncture in the scrotal raphe made with scissors, and in experienced hands it is superior to
previous procedures because it minimizes blood loss and risk of infection (40,41,42). The major
drawbacks to vasectomy are a delay in the onset of azoospermia of several months and the lack
of complete reversibility. Acute pain, blood loss, and surgical site infections are very rare,
particularly with the no-scalpel technique (41). However, whereas postoperative pain usually
resolves quickly, 6–15% of men experience some degree of postvasectomy chronic testicular
discomfort (43,44,45). In one study of such men, the majority had relief of their symptoms with
reversal of the vasectomy (46).
Three to 5% of men with vasectomies eventually request reversal, usually due to remarriage
(47,48). Vasectomy reversal, or vasovasostomy, has the potential to restore fertility; however,
rates of pregnancy vary from 30–60% (45). Factors that impact postreversal pregnancy rates
include microsurgical technique used and the length of time between the vasectomy and the
reversal procedure (45,49). In 20–30% of men, vasovasostomy is unable to restore patency of the
vas if more than 8 yr have elapsed since the original vasectomy (49), and pregnancy rates fall to
less than 50%. In fact, 20–40% of all couples remain infertile after vasectomy reversal despite
restored patency of the vas (as documented by imaging techniques), possibly due to the presence
of antisperm antibodies (50,51). The type of antibody response may be a key factor. One study
found that the presence of IgA antisperm antibodies greatly increased rates of fertility failure
after vasovasostomy (52). In summary, for these reasons, vasectomy cannot be considered to be
a truly reversible method of male contraception and is most appropriate for men who no longer
wish to father children.
Vasectomy appears to be safe in regard to overall male health. Earlier reports of associations
between vasectomy and cardiovascular disease have proven incorrect (53), and more recent
concerns about vasectomy and prostate cancer risk have not been substantiated
(35,43,45,54,55,56). In summary, vasectomy is highly effective and safe. The major drawbacks
of vasectomy are a risk of chronic testicular discomfort, the inability of surgery to reliably
restore fertility when desired, and economic constraints in developing countries.
Go to:
IV. Regulation of Testicular Function and Spermatogenesis
The purpose of this section is to introduce the physiological basis of male fertility, with
particular attention to potential contraceptive targets. It is not meant to be a comprehensive
review of all factors involved in this process. Developmental aspects of the male reproductive
tract have been reviewed recently (57).
A. The hypothalamic-pituitary axis: control of gonadotropin secretion
The hypothalamic-pituitary-testicular axis is a classic endocrine loop, with negative feedback of
downstream products playing the pivotal regulatory role in maintaining homeostasis. Testicular
production of both hormones and sperm is exquisitely regulated by gonadotropins produced by
the pituitary, whereas gonadotropin production is under the direct control of pulsatile GnRH
secretion from the hypothalamus (Fig. 11).). In turn, steroid and peptide hormones produced in
the testes provide inhibitory signals to the pituitary and hypothalamus.
Figure 1
The endocrinology of spermatogenesis and male hormonal contraception. Open arrows denote
promotion of spermatogenesis; dashed lines denote inhibition of spermatogenesis and hormone
production. A, Diagram of the naturally occurring, normal state. B, Diagram ...
It has been known for over 25 yr that both temporal and quantitative changes in GnRH secretion
disrupt testicular function (58). GnRH secretion from the hypothalamus is directly related to
pulsatile release of LH and FSH in the peripheral circulation (59,60); thus disrupters of GnRH
secretion and action are potential contraceptive targets. Over the last 5 yr there have been rapid
advances in understanding of the neuroendocrine control of reproduction upstream of GnRH, and
these too represent potential new contraceptive targets that have yet to be tested. Initially, studies
into the genetics of familial hypogonadotropic hypogonadism revealed the critical role of the
then orphan G protein receptor GPR54 in gonadotropin secretion (61,62). Previous studies had
demonstrated that the 54-amino acid peptide kisspeptin-54 (also called metastin) is the ligand for
GPR54 (63,64,65). Subsequent investigations have demonstrated that: 1) kisspeptin is expressed
in the arcuate, periventricular, and anteroventral periventricular nuclei of the forebrain; 2)
GPR54 receptors located on GnRH-secreting neurons in the brain respond to kisspeptin; 3)
kisspeptin administration in the brain results in GnRH and gonadotropin secretion in animal
models; 4) gonadotropin responses to kisspeptin administration in animals are blocked by
administration of a GnRH antagonist; and 5) kisspeptin appears to have direct inhibitory effects
on pituitary gonadotropin release through interaction with GPR54 expressed on pituitary
gonadotropes (reviewed in Ref. 66). Moreover, the negative feedback of testosterone and
estradiol on GnRH secretion is mediated via inhibition of kisspeptin production in the arcuate
nucleus of the hypothalamus (67,68). Most recently, in contrast to acute administration of
kisspeptin, which stimulates gonadotropin and testosterone release, chronic administration of
kisspeptin lowers serum LH levels in monkeys (69) and leads to testicular atrophy in adult male
rats similar to that seen with chronic GnRH infusions (70). Together, these studies directly link
kisspeptin-GPR54 to male reproduction and demonstrate the importance of this pathway in
upstream regulation of testicular function and sex steroid homeostasis (Fig. 11).). Similar to
GnRH, the kisspeptin-GPR54 neuroendocrine pathway could be exploited for contraception.
Inhibitors of kisspeptin, and/or GPR54 agonists and antagonists, in combination with
testosterone, are a theoretically viable contraceptive strategy yet to be tested.
Negative feedback to the pituitary and hypothalamus is critical to maintain endocrine
homeostasis in the male (Fig. 11).). Testosterone is the main testicular steroid, but significant
aromatase activity in the testicle and peripheral tissues results in production of estradiol as well.
Testosterone clearly inhibits kisspeptin transcription (67) and GnRH and gonadotropin secretion
(71,72,73,74). Some of this inhibition is estrogen independent (75,76,77,78), but estradiol seems
to play an important role in steroid negative feedback in the male, particularly by decreasing LH
production (79,80,81,82,83). Aromatase inhibition results in significant increases in LH and FSH
secretion in normal men (80); normal levels can be restored with estradiol supplementation in a
nonlinear fashion, with higher estradiol levels having increasingly less effect on circulating
gonadotropin and testosterone levels (81). Moreover, both aromatase inhibition and medical
castration result in similar increases in FSH, despite markedly decreased testosterone levels with
medical castration compared with aromatase inhibition; this suggests that, at least acutely, FSH
regulation is more dependent on estradiol than testosterone (84,85). In contrast,
dihydrotestosterone (DHT), a nonaromatizable androgen, is a poor inhibitor of gonadotropin
production in the male when given at or near physiological doses (83,86), and 5α-reductase
blockade with finasteride or dutasteride, which lowers serum DHT concentration by as much as
95%, fails to alter gonadotropin levels (87). However, with chronic administration and
supraphysiological dosing, exogenous DHT inhibits both LH and FSH secretion despite
concomitant suppression of testosterone and estradiol (88,89), demonstrating that aromatization
is not an absolute requirement for negative feedback.
Like other sex steroids, progesterone is expressed in the male as well as the female, albeit at
lower levels (90). The precise role of progesterone in normal male physiology is unknown, but
progesterone receptors have been demonstrated in the male hypothalamus, pituitary, and
reproductive tract (91,92,93). Mature male progesterone receptor-deficient mice have normal
reproductive phenotype, normal serum LH, and mildly decreased FSH levels compared with
wild-type animals (94), results which suggest that the physiological role of progestins in the male
hypothalamic-pituitary axis is minimal, at least in the rodent. However, progestins enhance male
hormonal contraceptive efficacy when combined with androgens (95), an effect attributed to
increased hypothalamic-pituitary suppression of gonadotropin secretion either directly or through
the androgen receptor. Brady et al. (96) compared the effects of progesterone and the synthetic
progestin, desogestrel, on gonadotropin secretion and GnRH responsiveness in normal men.
Although both progestins decreased LH and FSH secretion, only progesterone decreased the LH
response to GnRH. These results demonstrate that progesterone affects gonadotropin secretion
through progesterone receptors and provide evidence for such inhibition at both the
hypothalamic and pituitary levels. However, the effects of exogenous progestins on
spermatogenesis are greater than can be accounted for by enhanced suppression of gonadotropins
alone (97). Therefore, it has been suggested that progestins may act directly on the testes. There
is recent evidence directly supporting this hypothesis. First, both membrane-bound and
intracellular progesterone receptors have been demonstrated in the human testes (98). Second,
Walton et al. (99) recently demonstrated that the exogenous progestin desogestrel, when
combined with testosterone and a GnRH antagonist, mediates a direct effect on testicular gene
expression. In this context, progestins influenced expression of genes involved in
steroidogenesis, Sertoli cell function, and spermatogenesis. Together these data strongly support
an effect of progestins on male reproduction independent of their gonadotropin effects.
Exploitation of testicular progestin action is an additional mechanism whereby specific
progestins could be formulated as male contraceptives.
Finally, the nonsteroidal testicular product inhibin B contributes to hormonal feedback in the
male. Inhibin B is a dimeric molecule consisting of α and β subunits and a member of the TGF-β
family. Inhibin B is predominantly produced by Sertoli cells (100), and inhibin B levels correlate
with Sertoli cell number (101). However recent observations in boys with constitutively active
LH-receptor mutations resulting in familial male-limited precocious puberty suggest that Leydig
cells may produce some inhibin B (102). Indeed, although inhibin B levels rise acutely with FSH
administration (103), chronic FSH and spermatogenic suppression results in only a 25% decline
in levels, suggesting FSH-independent inhibin B production (104). Similarly, inhibin B levels are
low, but detectable, in rare individuals with FSH and FSH receptor mutations (105,106,107).
Negative feedback by inhibin B on FSH production has been demonstrated in 1) normal men,
where inhibin B and FSH exhibit an inverse relationship (108,109); 2) castrate men with very
high FSH levels compared with normal men rendered medically castrate (109); 3) men with
testicular disorders (103,110); and 4) male infertility (111) where low inhibin B levels are
associated with increased levels of FSH. Together, these data establish the role for inhibin B as a
testicular regulator of FSH, as hypothesized by McCullagh (112) over 75 yr ago. Aside from its
role in regulating FSH production and as an indicator of Sertoli cell function, no clear role for
inhibin B in testicular physiology or spermatogenesis has been established. Theoretically,
exogenous inhibin B in conjunction with androgens might further suppress FSH and be an
adjunct in a male hormonal contraceptive regimen (Fig. 11).). However, to date recombinant
inhibin B has not been available for clinical studies, and recent investigations suggest that
incomplete FSH suppression may not be pivotal to persistent spermatogenesis in men undergoing
male hormonal contraceptive treatment (see Ref. 97 and Section IV.D).
B. Testosterone production and androgen action
Testosterone is produced by the Leydig cells of the testes, primarily in response to LH
stimulation. However, there is increasing evidence that there may be non-LH-dependent
production of testosterone, which may be critical in maintaining spermatogenesis under
conditions of LH inhibition, such as with the hormonal approach to male contraception. LHreceptor (LHR −/−) knockout mice have low, but detectable levels of circulating testosterone
(113,114). Despite being infertile, a detailed histological examination of testicular tissue from
mature LHR −/− mice revealed low level spermatogenesis that was completely blocked by
treatment with an androgen receptor antagonist (113). These results are consistent with low
levels of testosterone observed in rodents after hypophysectomy (115,116). Regulation of nongonadotropin-dependent testosterone production in men, if it is similar to that in rodents, may be
a critical aspect in the development of a universally effective hormonal method of male
contraception because this approach relies on blockade of gonadotropin secretion for efficacy.
Under normal physiological conditions in young men, 4–6 mg of testosterone is secreted by the
testes daily (117,118,119) with a circadian rhythm; the highest level of secretion is in the early
morning, and lower levels are found in the circulation during midafternoon (120,121,122). This
pattern is blunted with age, likely due to impairment at multiple levels of the hypothalamicpituitary-testicular axis (123,124,125,126). A small percentage of testosterone (<1%) is
converted to DHT within the testes and elsewhere by the isoenzymes 5α-reductase I and II,
resulting in circulating DHT levels in the 1–3 nmol/liter range in normal men. DHT is thought to
be a considerably more potent androgen than testosterone, due to its 10-fold greater affinity for
the androgen receptor, but its role in spermatogenesis is not known. Significant reductions in
serum DHT appear to have a marginal impact on sperm production in normal men (87). In
addition, testosterone can be aromatized to estradiol within the testes. The role of estradiol in
spermatogenesis is unclear, but increasing evidence suggests that it may play a role. Men with
aromatase deficiency or mutations in the estrogen receptor have impaired spermatogenesis
despite otherwise normal secondary sexual development (127,128,129,130). Moreover, estrogen
receptors are expressed in the testes and perhaps on human male germ cells themselves
(131,132,133). Both testosterone and its active metabolites therefore appear to be important in
qualitatively and quantitatively normal spermatogenesis.
Because testicular Leydig cells are the site of testosterone synthesis and secretion under the
control of LH, intratesticular testosterone concentrations are 100-fold those of serum
(134,135,136,137,138), but the relative importance of this high-androgen environment for
spermatogenesis is not well understood. Experimental suppression of LH and FSH levels
profoundly decreases testosterone production (137,139,140) and dramatically reduces
spermatogenesis in men (141,142). However, results from LH receptor-deficient mice suggest
that even markedly reduced levels of androgen can support spermatogenesis (113,114), although
complete blockade of residual androgen action with androgen receptor antagonist flutamide
abolished spermatogenesis (113). In addition, using the very effective combination of
testosterone enanthate (TE) + cyproterone acetate, higher levels of serum testosterone were
associated with a lesser degree of spermatogenic suppression (143). These findings have led to
the proposal that high levels of exogenous androgens or residual androgen production after
gonadotropin withdrawal may be sufficient to support spermatogenesis and result in
contraceptive failure (117,138,144,145). However, two recent studies have called this into
question (140,146). In contrast to a rodent model (147), no significant relationship between
sperm concentration and intratesticular androgen concentrations was observed in men after
prolonged gonadotropin withdrawal in these small studies. Moreover, although it has been
suggested that the active metabolite of testosterone, DHT, a more potent androgen, may play a
pivotal role in maintaining spermatogenesis during male hormonal contraceptive treatment
(117,138), intratesticular DHT levels did not explain persistent spermatogenesis in these studies.
These results are consistent with data in humans where the addition of a 5α-reductase inhibitor to
a male hormonal contraceptive regimen was not shown to increase the effectiveness of
spermatogenic suppression (148,149). Further investigation into the precise regulation and role
of intratesticular androgens in supporting spermatogenesis in men is clearly needed, because
targeted disruption of residual androgen production and/or action might be an adjunct to increase
effectiveness of current hormonal methods.
Classically, androgen action results from ligand binding to the androgen receptor and
translocation of the bound, dimerized receptor-ligand complex to the nucleus where it directs
androgen-regulated gene transcription via interaction with androgen-response-elements (150).
Androgen receptor is expressed in multiple cell types within the testes including Sertoli, Leydig,
peritubular myoid, and vascular smooth muscle cells, and on germ cells during the early stages
of spermatogenesis (151). Mice completely devoid of androgen receptor throughout development
have feminized genitalia, cryptorchid testes, and azoospermia with arrested spermatogenesis at
the pachytene spermatocyte stage (152). Due to the role of androgen receptor signaling in the
development of both the external and internal male phenotype, tissue-specific knockouts were
required to further delineate the role of androgen receptor in supporting spermatogenesis in
specific testicular cell types. Normal fertility is preserved in mice lacking androgen receptor in
either germ cells (153) or peritubular myoid cells (154), although in the latter case reduced germ
cell numbers, particularly within the epididymis, were noted. In contrast, both Leydig cell and
Sertoli cell-specific androgen receptor knockouts are infertile (153,155,156,157) and have small
testes. Interestingly, the level of serum testosterone found in various Sertoli-cell only knockouts
varies from low to supraphysiological for unclear reasons (155,156,157). These differences
aside, these studies emphasize the critical importance of paracrine actions of androgens within
the testes, but the precise mechanism whereby androgen receptor signaling in Leydig and Sertoli
cells supports germ cell maturation is not yet clear. Three recent studies examining the
transcriptional targets of androgen receptor using Sertoli-cell only androgen receptor knockouts
suggest potential targets, but further functional analyses of these will be required (158,159,160).
In theory, these models suggest that androgen receptor disrupters that could be targeted to
specific cell types such as the Sertoli cell might make excellent contraceptives but such
compounds have yet to be developed.
Data from animals with disrupted androgen receptor and mice treated with androgen receptor
blockade with the antagonist flutamide (161) demonstrate that signaling through the androgen
receptor is required for spermatogenesis. Modulators of androgen action include tissue-specific
expression of coactivators and corepressors as well as genomic variation in the androgen
receptor itself. Molecules that bind the androgen receptor yet prohibit or enhance binding of
tissue-specific coactivators or corepressors could act as selective androgen receptor modulators
(SARMs). Recently, a second, nongenotropic sex steroid receptor-mediated signaling pathway
has been proposed that may allow for a second, tissue-specific mechanism for androgen receptor
signaling (162,163,164). Activators of nongenomic estrogen-like signaling, or “ANGELS”
(164,165), are thought to act predominantly through the MAPK kinase signaling cascade,
although their exact mechanism of action and degree of tissue selectivity remain controversial
(166). Either SARMs or ANGELS could be employed as part of a hormonal approach to male
contraception, allowing for tissue-specific androgen replacement in the setting of reduced
gonadotropin and endogenous testosterone production. However, such approaches have yet to be
tested in human trials.
In addition, naturally occurring variations in the androgen receptor structure could be exploited
in the design of such “designer” androgens. For example, exon 1 of the androgen receptor
contains a trinucleotide CAG repeat of variable number, encoding a polymorphic polyglutamine
tract and a downstream GGN repeat encoding a polyglycine region (167). The number of CAG
repeats is inversely associated with the transcriptional response to androgens in vitro (168,169)
and in vivo (170,171,172). Impairments in spermatogenesis have been associated with increased
CAG repeat length (173,174), although this is not a consistent finding (175,176). Expanded
GGN repeats are also thought to decrease androgen receptor signaling, but increased repeats
were not associated with impaired spermatogenesis (177) unless found in conjunction with
longer CAG repeats (178). The crystal structure of the androgen receptor with expanded exon 1
repeats has not been published to date, so the exact impact of these changes on the ligand binding
domain is not known. However, given the subtle androgen effects of CAG and GGN repeats
observed clinically, exploitation of naturally occurring variations in androgen receptor is unlikely
to prove an effective strategy for contraceptive drug design.
Over the last few years, a number of testosterone formulations have become available, including
long-acting depot injections, implants, transdermal gels, transdermal patches, and buccal
formulations (Table 11).). Each of these has its own particular pharmacokinetics (179). Using a
hormonal approach to contraception, testosterone is administered in part to block gonadotropin
secretion but also to maintain nongonadal androgen-dependent functions such as sexual drive
and muscle mass. The importance of mimicking normal physiological testosterone secretion
patterns in maintaining both nongonadal androgenicity and contraceptive efficacy using a
hormonal approach is not known (180), because head to head trials comparing different forms of
testosterone delivery are lacking. Long-acting injections, which are currently being tested as part
of a large contraceptive efficacy trial, are associated with peaks and troughs, even after multiple
injections (181). Although the transdermal preparations have the most physiological
pharmacokinetic profiles, patches have been universally disappointing in contraceptive trials
(182,183,184), probably due to low levels of serum testosterone. The only large study using
transdermal testosterone gel to date, although highly effective, achieved testosterone levels in the
slightly supraphysiological range (185). Significant supraphysiological dosing of testosterone
can be associated with side effects including high-density lipoprotein (HDL) suppression, acne,
and increased hemoglobin concentrations (186,187) that would not be desirable in a regimen
designed for long-term use, although these are not consistent findings (188). Therefore, the goal
of most hormonal regimens under study is to maintain serum testosterone levels within the
normal range, delivering approximately 5 mg/d of testosterone.
Table 1
Androgen formulations available for possible incorporation into a male hormonal contraceptive
regimen
C. Spermatogenesis
Male contraceptive strategies may generally be divided into approaches that disrupt
spermatogenesis, which are largely hormonally based, and those that disrupt sperm-egg
interactions by disrupting either sperm motility or processes involved in fertilization. These latter
approaches are nonhormonal. Although this is not meant to be a comprehensive review of our
current understanding of spermatogenesis, we provide a brief overview of sperm maturation here
to put these strategies into context. In particular, there have been substantial developments in
delineating the markers and potential of germ cell stem cells recently, and we refer the reader to
recent reviews of this field (189,190).
During spermatogenesis, spermatogonia, through multiple mitotic and meiotic divisions, develop
into mature spermatozoa. In brief, this process may be divided into four stages (191). First, type
A spermatogonia undergo mitosis, resulting in renewal of germline stem cells as well as type B
spermatogonia that continue to undergo differentiation. Second, type B spermatogonia undergo
meiosis, generating haploid round spermatids. Next, spermiogenesis occurs, wherein round
spermatids mature to motile spermatozoa without undergoing further cell division.
Spermiogenesis includes formation of the acrosome, nuclear condensation, and extensive cellular
reorganization including sperm tail development. Finally, interactions with the Sertoli cell
mediate the process of spermiation, wherein cytoplasmic material from the spermatid is removed
and the mature sperm is released into the lumen of the seminiferous tubule. This entire process is
under strict endocrine regulation, and there is potential for contraceptives to target all or part of
this process.
Although the role of FSH in human spermatogenesis has been debated, it is clear that both FSH
and LH are required for quantitatively and qualitatively normal spermatogenesis in men. This has
been demonstrated in a series of human studies wherein gonadotropin production and
spermatogenesis were suppressed in men using exogenous testosterone and either LH [in the
form of human chorionic gonadotropin (hCG)] or FSH were given back in a selective fashion
(192,193,194,195). Although either gonadotropin alone can reinitiate spermatogenesis, both LH
and FSH are required to achieve normal semen parameters. Matthiesson et al. (196) recently
expanded upon this work with detailed examination of the relative stages of spermatogenesis
affected by selective gonadotropin supplementation using exogenous testosterone plus
depomedroxyprogesterone (DMPA) to suppress endogenous testosterone and spermatogenesis.
Data from both rodents and monkeys suggested that FSH is more important than LH for
spermatogonial maturation, whereas LH and/or intratesticular androgens are needed for normal
completion of meiosis and spermiogenesis/spermiation (197,198,199,200). Surprisingly, after 6
wk of selective LH or FSH withdrawal, only pachytene sperm differed among men lacking FSH
(treated with testosterone + DMPA + hCG) compared with untreated, control individuals; men
lacking LH showed no differences compared with untreated men. Moreover, this was despite a
100-fold reduction in intratesticular testosterone in men treated with testosterone + DMPA +
FSH compared with control and hCG-treated men (196). Although the interpretation of these
results is limited by the length of treatment and small numbers of individuals studied, they
suggest that either FSH or LH/intratesticular androgens are sufficient to support all stages of
spermatogenesis, including spermatogonial maturation, meiosis, spermiogenesis, and
spermiation. These data emphasize the need for hormonally based male contraceptive strategies
to maximally suppress both LH and FSH to optimize spermatogenic suppression.
D. The epididymis
Once spermatogenesis is complete, sperm are released from the Sertoli cells into the lumen of the
seminiferous tubules and move through the epididymis before ejaculation. These processes
involve additional, as yet poorly characterized events that might provide further targets for
contraception. Both FSH and testosterone are thought to play a role in spermiation (201), the
release of the spermatid into the tubule lumen, perhaps through regulation of proteins involved in
germ-Sertoli cell adherence (197). In rodents, this multiprotein junctional complex appears to
involve N-cadherin and a number of other integrins and kinases and is sensitive to
phosphorylation (202). Failure of spermiation results in sperm retention and phagocytosis by the
Sertoli cell. Therefore, the molecules in these Sertoli-germ cell complexes are attractive
contraceptive targets if testes specificity could be demonstrated and appropriate agents
developed (203).
Within the epididymis, sperm undergo further maturation steps allowing for maximal motility
and fertilization capacity, as exemplified by the improved fertility rates when recovered
spermatozoa are injected intracytoplasmically into the egg or when spermatozoa from further
down the cauda are used for in vitro fertilization (204). There have been a number of detailed
analyses of the transcriptional profiles of the rodent epididymis, including detailed segmental
analyses (205,206,207). It is possible that in the future such analyses will provide novel
contraceptive targets, but at this point these data remain largely descriptive and functional
analyses of these novel transcripts are required. Similar analyses using proteomics have begun,
again perhaps providing novel, organ-specific targets for intervention (208). Suzuki et al. (209)
have recently identified an epididymis-specific promoter from the Lipocalin 5 that may be of use
in contrasting animal models to assess these targets. Finally, as they travel through the
epididymis, maturing sperm encounter an increasingly hyperosmolar environment, yet upon
arrival in the female tract these sperm must adopt to the local, hyposmolar environment to
remain motile and competent. This requires significant, regulated volume decreases via ion
channels acquired during epididymal maturation that might be targets for contraception in either
the male or female (210,211).
Go to:
V. Male Hormonal Contraceptive Methods
It has been known for almost 70 yr that the chronic administration of testosterone to a man
suppresses sperm production (212). Because the administration of testosterone alone fails to
completely suppress sperm production in some men, progestogens or GnRH antagonists have
been combined with testosterone to further suppress pituitary gonadotropins and improve its
contraceptive efficacy. These hormonal contraceptive regimens inhibit sperm production and do
not incapacitate existing sperm. Because spermatogenesis takes place over 72 d, there is a 2- to
3-month delay in the onset of full contraceptive effect associated with the use of male hormonal
contraceptives, a delay that is similar to that seen with vasectomy, but longer than the period of
time required for female oral contraceptives to be effective. In addition, there are ethnic
differences in the response of sperm concentrations to male contraceptive regimens. For
example, study volunteers in Asia exhibit rates of azoospermia in the 90–100% range on
testosterone-alone regimens, whereas Caucasian men have rates of azoospermia closer to 60%
with the same treatment (142,213,214,216). The explanation for this difference is unknown,
although it is unlikely to be due to different rates of metabolic clearance of testosterone (122),
and it complicates extrapolation of rates of suppression of sperm concentrations between
populations.
A. Hormonal contraceptive efficacy
The best test of a contraceptive is to study the method in couples who use it as a sole means of
contraception. Although the efficacy of condoms and vasectomy is well studied, the only
experimental male contraceptive methods to date to undergo efficacy testing are hormonal
regimens. Four such male hormonal contraceptive efficacy trials have been published
(141,142,217,218), and a fifth multicenter study was recently completed. The first of these tested
only the fertility of men who became azoospermic with exogenous testosterone administration
(141) and demonstrated that the contraceptive efficacy of testosterone-induced azoospermia is
almost perfect. However, this study cannot be used to determine the overall efficacy of
testosterone alone as a contraceptive because men who did not achieve azoospermia were not
allowed to enter the efficacy phase.
The three more recent trials have examined the outcomes of all subjects enrolled and allowed
men who suppressed below a threshold sperm concentration (<1 to 5 million sperm/ml) to use
the method as a sole means of birth control. Analysis of these studies reveals that male hormonal
contraception has an overall efficacy of approximately 95%, even when men who do not
completely suppress sperm production are included (Table 22).). This overall figure is only
slightly inferior to the efficacy of female hormonal contraceptives. In these studies, a sperm
concentration at or below 1 million sperm/ml of ejaculate—severe oligospermia—is associated
with a risk of pregnancy of approximately 1% (142). Therefore, uniform suppression of all
subjects to a sperm concentration no greater than 1 million sperm/ml is thought to be a
reasonable short-term goal for male hormonal contraceptive development (219). Aside from
those studies mentioned above, male hormonal contraceptive studies examine the impact of
exogenous hormones on sperm production, with effectiveness measured as rates of azoospermia
(0 sperm/ml), severe oligospermia (≤1 million sperm/ml), or oligospermia (<3 million sperm/ml)
among users.
Table 2
Male hormonal contraceptive efficacy trials
B. Testosterone alone
1. Testosterone enanthate (TE).
As mentioned above, the World Health Organization (WHO) conducted two seminal,
multicenter, male hormonal contraceptive efficacy studies. These trials used the injectable
testosterone ester, TE, as a single agent for male contraception. The first study enrolled 271
Asian and Caucasian men who were administered 200 mg TE by weekly injection for 6 months
(141). Sixty-five percent of the men became azoospermic using this regimen after a mean of 4
months, and 75% of the remaining men became oligospermic (<3 million sperm/ml). The
fertility of 119 of the azoospermic men was then evaluated in a 12-month efficacy phase. In
these couples, who used TE as their sole means of contraception during this year, only one
pregnancy occurred, corresponding to a pregnancy rate of 0.8 pregnancies per 100 person-years
and an efficacy rate of over 99%.
The second WHO study tested the fertility of men who became either azoospermic or
oligospermic (less than 3–5 million sperm/ml) on 200 mg of TE weekly (142). The study
enrolled 399 men, all but eight (2%) of whom became azoospermic or oligospermic and met
criteria for entry into the efficacy phase of the study. In this phase, there were no pregnancies
fathered by the men who became azoospermic. In men whose sperm concentration was
suppressed to less than 3–5 million/ml, fertility was reduced to 8.1 pregnancies per 100 personyears. The fertility rate for all men who suppressed enough to enter the efficacy phase was 1.4
per 100 person-years, and the overall failure rate (including the eight men who failed to suppress
to less than 5 million sperm/ml) was 5.3%, for an overall contraceptive efficacy of 94.7% (Table
22).
These two seminal studies demonstrated that a regimen of weekly TE injections is a reversible
and effective contraceptive in the large majority of men and is safe over the 18 months of
treatment. The main drawbacks to this approach are the delay in onset of full contraceptive
action of 3–4 months, the fact that 2% of men fail to suppress below 3 million sperm/ml and
therefore remain potentially fertile, and the potential safety concerns associated with long-term,
supraphysiological levels of serum testosterone, the long-term consequences of which are not
known. Side effects from weekly injections of 200 mg of TE in healthy men include weight gain,
a reversible 25% reduction in testicular volume, a 6% increase in hemoglobin, and a 10–15%
decrease in serum HDL cholesterol (142,187,220). Importantly, these effects appear to be doserelated (186). There was no evidence that exogenous testosterone administration, despite
increasing estradiol levels, increases the risk of blood clotting, which could increase the risk of
heart attack or stroke. Indeed, one study suggests that the administration of exogenous
testosterone in a male contraceptive regimen may exhibit antithrombotic and antiinflammatory
effects (221,222). Quality of life, sexual function, and well-being are maintained or slightly
improved with TE-based male contraceptive regimens (220,223). Overall, the TE regimen was
rated better than expected by a majority of men in these studies (224). However, the use of
weekly im injections in this regimen led to discontinuation by a small number of men. Although
useful as a proof of principle, these landmark studies demonstrated that use of weekly TE alone
for contraception is limited by side effects, a 2% failure to adequately suppress spermatogenesis,
and the impracticality of weekly injections, and suggested that additional agents would be
necessary to improve the hormonal approach to male hormonal contraception.
2. Testosterone undecanoate (TU).
TU is a long-chain ester that can be administered orally or by injection (225,226). In
testosterone-deficient men, a single injection maintains serum testosterone levels in the normal
range for 6–12 wk (226,227). Oral administration requires dosing two or three times daily,
making it less practical (225), and explaining perhaps the somewhat disappointing results of the
only (pilot) male hormonal contraceptive study using oral TU (228). Three small trials using TU
injections in normal men for male contraception were initially conducted. In the first study,
conducted in China, volunteers received monthly doses of 500 or 1000 mg TU. Eleven of the 12
men in the 500-mg group and all 12 in the 1000-mg group became azoospermic, with the 1000mg group achieving azoospermia more quickly (229). In the two other pilot studies, conducted in
Germany, TU was used alone or in combination with a progestin (see Section V.C) (230,231). In
the arms of these studies in which subjects received only TU, eight of 14 men who were
administered 1000 mg TU every 6 wk achieved azoospermia, with four of the remaining six
suppressing their sperm concentrations below 3 million sperm/ml. Although the regimens and
formulations of TU were slightly different than that used in China, it appears that, as was the
case with TE, it remains more difficult to suppress sperm concentrations in non-Asian
populations even with long-acting androgens such as TU.
Subsequently, a large Chinese efficacy trial studied 308 men treated with monthly injections of
500 mg TU after a 1000-mg loading dose (217). Forty-three percent of men suppressed to
azoospermia on this regimen, but only nine (3%) of the men failed to suppress to sperm
concentrations below 3 million sperm/ml, the criteria for entering the efficacy phase of the study.
During the subsequent 12-month contraceptive efficacy phase, 296 couples used the TU
injections as a sole means of contraception. Of these, six men had partial return of sperm
production, and there was one pregnancy attributed to the reappearance of sperm while on TU
therapy. Overall, this regimen has a 96.7% contraceptive efficacy in Chinese men (Table 22).).
As with TE, injections of TU at this dosing interval resulted in supraphysiological levels of
serum testosterone in some men, and nadir testosterone levels were 31% greater than baseline
testosterone levels. Similar to TE, injectable TU was associated with weight gain, a 9% increase
in hemoglobin, and a 14% decrease in HDL. However, there were no serious adverse events
during treatment, and these changes were reversible. Moreover, most participants found the
regimen acceptable (16). A phase III trial of contraceptive efficacy with TU in tea seed oil
involving 1000 Chinese couples is currently nearing completion, which will add much to the
field.
3. Transdermal testosterone.
Scrotal transdermal testosterone patches were introduced in the late 1980s (232). Although
testosterone patches are useful for the treatment of male hypogonadism, they have not been
effective for male contraception, presumably because the serum testosterone levels are
insufficient to completely suppress gonadotropin secretion from the pituitary, even with the
addition of a progestin. For example, one study combining a testosterone patch with the
progestin levonorgestrel resulted in azoospermia in only two of 11 men and counts below 3
million sperm/ml in three others (182). In a second study, testosterone patches were combined
with oral levonorgestrel, but less than 50% of subjects achieved azoospermia (183). Skin
reactions to the patch are also a problem. In a third testosterone-patch study, which combined
testosterone patches with the progestin desogestrel, only 41% of the subjects achieved
azoospermia, and 24% of participants withdrew from the study because of skin irritation
attributable to the patches (184).
Recently, transdermal testosterone gels have been introduced into the marketplace for the
treatment of male hypogonadism (233,234). We recently reported that, in contrast to the
testosterone patch, the combination of testosterone gel plus a long-acting injectable progestin,
DMPA, resulted in levels of azo- and oligospermia comparable to previous studies with im
testosterone (185). These gels hold promise for contraceptive development because they achieve
higher serum testosterone levels and are associated with less irritation of the skin than
testosterone patches (233). It is possible that in the future, these gels could be combined with a
progestin gel as an “all-gel” approach to male contraception.
C. Testosterone-progestin combinations
Because progestins inhibit the secretion of gonadotropins from the pituitary, several progestins
have been combined with testosterone to improve its contraceptive effect by augmenting
suppression of gonadotropins. In addition, it has been hypothesized that progestins might also
have a direct inhibitory effect on spermatogenesis, although a recent study in nonhuman primates
failed to demonstrate such an effect for the progestin norethisterone (235).
Testosterone/progestin regimens were first tested for male hormonal contraception in the 1970s
(236). One early case report suggested that the contraceptive efficacy of the early combinations
was not ideal, with nine of 100 couples conceiving while on treatment, despite instructions to
simultaneously use other methods of contraception and sperm concentrations under 10 million
sperm/ml (237). Over the following 35 yr, efficacy of testosterone-progestin-based regimens has
greatly improved. However, the use of progestins in men can be associated with side effects such
as weight gain, additive suppression of serum HDL cholesterol, and perhaps increases in
proinflammatory cytokines associated with increased cardiovascular risk (222); thus current
protocols aim to minimize these adverse effects (see Section V.G).
Early studies of progestins focused on demonstrating improved sperm suppression compared
with testosterone alone, while subsequent studies have aimed at minimizing the doses involved
or optimizing the delivery strategy. A randomized, controlled trial of 0.5 mg of oral
levonorgestrel with 100 mg of weekly TE showed that the combination was superior to TE alone
in achieving azoospermia (67 vs. 33%) by 6 months in Caucasian men (238). Furthermore, the
proportion of subjects achieving a sperm concentration of less than 3 million/ml was 94% in the
combination group compared with 61% in the TE-alone group. However, the combination
regimen resulted in greater weight gain and further decreases in HDL cholesterol when
compared with the TE-alone group, side effects which have been minimized without
compromising effectiveness by lowering the dose of levonorgestrel in subsequent studies
(239,240). Recently, the combination of a long-acting levonorgestrel implant and 1000 mg of TU
every 8 wk resulted in azoospermia in 90% of Chinese men, with all subjects suppressing to
concentrations fewer than 3 million sperm/ml (241). Another oral progestin, desogestrel, has
been tested in male contraceptive regimens with injectable TE (242,243) or testosterone pellets
(400 mg implanted every 12 wk) (244,245) with overall rates of azoospermia in the 80–90%
range in mostly Caucasian populations. The active metabolite of desogestrel is etonogestrel. Oral
etonogestrel has been studied in combination with im injections at 4- or 6-wk intervals of the
testosterone ester, testosterone decanoate (TD). In a study of 112 subjects, 111 achieved sperm
concentrations of less than 1 million sperm/ml (246). Suppression was more rapid in the group
receiving TD injections every 4 wk, and side effects were minor.
Based upon these results, enthusiasm for the combination of injectable testosterone and a
progestin led to two studies combining etonogestrel implants with testosterone. In the first, one
or two implanted etonogestrel rods were combined with testosterone pellets and resulted in
azoospermia in nine of 14 men in the higher dose etonogestrel group, with 13 of 14 men having
sperm counts less than 0.1 million sperm/ml after 24 wk (247). Importantly, there were no
significant reductions in HDL cholesterol when the progestin was administered via implant,
implying that nonoral administration may be preferable for long-term administration of these
compounds. The results from this pilot study were promising enough for a large pharmaceutical
company to sponsor a multicenter phase II study of the combination of etonogestrel implants
with TD given by im injection every 4–6 wk (248). This combination achieved rates of
azoospermia in the 80–90% range, with overall high acceptability and a low incidence of side
effects. A follow-up trial of etonogestrel implants combined with TU (which exhibits a half-life
superior to that of TD) and involving more than 300 subjects has recently been completed in
Europe; these results are not yet published. Success from this trial could in theory result in the
first marketed male hormonal contraceptive, although the industry sponsors of this trial (Organon
Biosciences and Schering Corporation) may be discontinuing their programs in male
contraceptive development.
Some progestins such as cyproterone acetate have antiandrogenic properties (249). The
antiandrogenic effect of cyproterone may allow it to interfere with testosterone-mediated
spermatogenesis in the testis in addition to its progestogenic inhibition of FSH and LH secretion
from the pituitary. In one small trial combining oral cyproterone acetate with 100 mg TE weekly,
all men receiving the combination became azoospermic, whereas only three of five in the TEalone group attained azoospermia (250). In addition, the time required to achieve azoospermia
was markedly less in the cyproterone + TE groups compared with the testosterone-alone group
(49 vs. 98 d). This group went on to evaluate lower doses of cyproterone acetate (251), which
was also effective, and a completely oral male contraceptive regimen combining cyproterone
with twice daily oral TU (228). In the study of the oral regimen, four of eight men suppressed
their sperm concentrations below 1 million sperm/ml, with the four remaining subjects
suppressing to 1.2–6 million sperm/ml (228). Cyproterone is not currently available in some
countries (including the United States). Additionally, a similar “antiandrogenic” progestogen,
dienogest, may be a promising progestin for future clinical trials in male contraception (252).
The long-acting injectable progestogen, norethisterone enanthate, has also been tested in male
hormonal contraceptive trials (253). In one study, 13 of 14 men who received the combination of
1000 mg TU and 200 mg norethisterone every 6 wk achieved azoospermia after 32 wk of
treatment, with HDL suppression and mild weight gain in line with prior studies of
testosterone/progestin combinations (231). It has subsequently been demonstrated that high rates
of azoospermia (90%) can be maintained when TU and norethisterone enanthate are
administered at 8-wk intervals, but not when they are dosed every 12 wk (254). Furthermore,
although there is some accumulation of serum testosterone with every 8-wk dosing, the
pharmacokinetics of TU are not altered by coadministration of norethisterone (181). This
approach, employing an every 8-wk injection schedule, is a significant improvement over the
requirement for weekly injections of TE in most prior studies. Alternatively, norethisterone
enanthate can also be administered orally in combination with injectable TU (255).
Similar to norethisterone enanthate, medroxyprogesterone acetate can be delivered by depot
injection (DMPA). Doses identical to those widely used by women for contraception as DepoProvera (300 mg every 3 months) have been tested in three recent male contraceptive studies.
The first was an Australian study combining DMPA with testosterone pellets administered by
implantation every 4–6 months (218). In this study, 53 of 55 men achieved sperm concentrations
of less than 1 million sperm/ml and entered a 12-month efficacy phase in which no pregnancies
were observed (Table 22).). This important trial was the first testosterone/progestin efficacy
study and confirms that the high rate of pregnancy prevention observed in the original
testosterone-only WHO studies extends to testosterone/progestin combinations. Weight gain and
HDL suppression were also very limited in this study. Additionally, a trial of TU at a dose of
1000 mg every 8 wk with DMPA was conducted in China and demonstrated uniform
azoospermia in subjects receiving the combination, but not in those receiving TU alone (256).
Finally, DMPA injected every 3 months combined with daily transdermal testosterone gel
effectively suppressed 19 of 21 participants to sperm concentrations less than 1 million/ml after 6
months of administration (185). This combination of testosterone plus DMPA is therefore an
attractive candidate for larger efficacy studies.
In summary, the contraceptive effect of most of the progestins is fairly similar, although smaller
doses may be more efficacious for some progestins compared with others and their side effect
profiles likely vary (see Section V.G). Combinations of im TU or testosterone pellets and
levonorgestrel, etonogestrel, norethindrone, or medroxyprogesterone all result in azoospermia
rates of almost 90%. As a result, many researchers now feel that one of these combinations is the
most likely to result in a clinically useful contraceptive method. However, larger-scale phase III
studies of efficacy at pregnancy prevention will need to be carried out with these regimens
before they can be marketed. Suggested guidelines for such a study have been recently outlined
(219), and a focus on both pre- and postmarketing side effect profiles is warranted, given the
importance of minimizing these in delivery of a long-term medication to a healthy population.
D. Adding GnRH analogs to hormonal contraceptive regimens
GnRH agonists (such as leuprolide) are not effective when used with testosterone for male
hormonal contraception (257), perhaps because these agonists tend to allow the continued
production of FSH even after chronic administration (257). In contrast to agonists, GnRH
antagonists can suppress FSH and LH production within hours of administration and inhibit
gonadotropin secretion more completely than agonists.
Several trials have investigated the effects of both short- and longer-acting GnRH antagonists as
adjuncts in male hormonal contraceptive treatment. Initial very small trials investigated the
GnRH antagonist Nal-Glu, administered by daily sc injection, in combination with testosterone
to maintain peripheral androgenicity. In the first two trials, 14 of 16 subjects achieved
azoospermia by 6–10 wk of treatment (258,259). But a third small, randomized trial
demonstrated no difference in azoospermia with TE plus Nal-Glu compared with TE alone, at
least at the doses given (260). Moreover, daily sc injections required for the use of Nal-Glu were
not considered to be a feasible part of a long-term contraceptive regimen. It was suggested,
therefore, that GnRH antagonists might have a useful role in the induction of azoospermia with
maintenance by a combination of hormonal agents. This was demonstrated with Nal-Glu, which
induced azoospermia when administered with TE for 12 wk, which was then maintained by TE
alone for 20 additional weeks (261). In contrast, the GnRH antagonist cetrorelix, also given by
daily injection, combined with the androgen 19-nortestosterone resulted in azoospermia by 12
wk in all six subjects tested; however, azoospermia could not be maintained after the cetrorelix
was discontinued (262). It is possible that failure to maintain azoospermia in the second study
stemmed from the use of 19-nortestosterone that cannot be aromatized to estrogen, because
estrogen may play a role in the feedback suppression of gonadotropin secretion at the pituitary.
Indeed, increased gonadotropin levels were seen associated with spermatogenesis after cessation
of cetrorelix in this study (262).
Longer-acting GnRH antagonists have recently been developed. A depot formulation of the
GnRH antagonist abarelix results in effective gonadotropin suppression for periods up to 1
month (263), but case reports of allergic reactions to this agent may limit its clinical utility. The
GnRH antagonist acyline can markedly suppress gonadotropins for up to 2 wk after a single sc
administration without significant side effects (264). In a small trial, 12 wk of acyline combined
with DMPA and testosterone gel did not demonstrably augment sperm suppression, or the
rapidity of sperm suppression, compared with testosterone and DMPA alone (185). These results
were surprising because preliminary data demonstrated that administration of acyline in
combination with testosterone injections resulted in more rapid gonadotropin suppression than
testosterone alone or testosterone plus a progestin (Fig. 22,, A. D. Coviello and W. J. Bremner,
unpublished data). Additional GnRH antagonists are in development, including orally
administered peptide and nonpeptide antagonists (265,266) and a long-acting (>2 yr) GnRH
agonist implant that has recently been introduced to the market for treatment of prostate cancer
(267). These remain interesting prospects for future contraceptive trials because in theory they
could be combined with similarly delivered testosterone formulations without the need for a
progestin, perhaps minimizing nonreproductive side effects. In conclusion, while theoretically
appealing, GnRH antagonists have been relatively understudied compared with testosteroneprogestin combinations; however, improved methods of delivery may allow for their
incorporation into future contraceptive regimens.
Figure 2
Rate and extent of gonadotropin suppression with various hormonal interventions. Normal
healthy men ages 18–55 given TE alone (100 mg im every week), TE plus oral levonorgestrel
(LNG, 125 mg oral, daily), TE + acyline (300 μg/kg ...
E. Oral male hormonal contraceptive development
Although implant and injection-based hormonal contraceptive regimens have been well studied,
many men would prefer an oral formulation for contraception (10). The only orally available
testosterone replacement products currently approved for use in the United States are alkylated
testosterone derivatives such as methyltestosterone, which can cause liver injury and have been
associated with hepatomas (268) and thus are not safe for contraceptive use. The testosterone
ester TU is an oral testosterone available in many countries and is not associated with the liver
injury seen with methyltestosterone. However, the bioavailability of TU is significantly
dependent upon the simultaneous ingestion of a fatty meal (269), and it must be dosed two or
three times per day to achieve normal serum testosterone levels, thus making it a poor choice for
contraceptive purposes.
Oral administration of crystalline testosterone does not greatly increase serum testosterone levels
due to extensive hepatic first-pass metabolism and low bioavailability (225,270,271,272).
However, we recently demonstrated that the addition of a 5α-reductase inhibitor to orally
administered testosterone in an oil emulsion improved the bioavailability of testosterone
compared with oral testosterone alone (273,274). In these studies, serum testosterone levels
within the normal range were achieved for 10 h in normal men with reversible, medically
induced hypogonadism when a single dose of testosterone was administered orally in oil together
with a 5α-reductase inhibitor. Although longer-term studies will be required to demonstrate its
safety and efficacy, this form of oral testosterone delivery, in combination with an oral progestin
and/or GnRH antagonist raises the possibility of a “male pill” in the future.
An additional orally available androgen that holds promise for hormonal contraception has been
reported recently. Attardi et al. (275) demonstrated that the 19-nortestosterone derivative
dimethandrolone is active in vivo in a rodent model, causing suppression of LH in castrate rats.
Moreover, dimethandrolone has both androgenic and progestational activity, at least in vitro,
which might increase its potency as a single agent for contraception (275). Such a strategy
remains to be tested in men. Similarly, some steroidal and nonsteroidal SARMs, which have
some tissue selectivity for androgen action (see Section V.H) (276), are orally active and
represent potentially attractive agents for long-term oral use alone or combined with a progestin.
F. Reversibility of male hormonal contraception
A contraceptive for men must be not only efficacious but also fully reversible. Liu et al. (277)
recently published a comprehensive analysis of spermatogenic recovery after experimental male
hormonal contraceptive treatment including androgens or an androgen plus a progestin for a
minimum of 3 months. Data from 1549 men enrolled in 30 studies was examined. Recovery was
defined as attaining a sperm concentration of more than 20 million sperm/ml, consistent with
WHO guidelines for normal semen analyses and normal fertility (278). Importantly, in no case
did a subject fail to recover. Median time to recovery was 3.4 months. Increased length of
recovery time was associated with longer treatment periods and the use of longer-acting
testosterone compounds. Prolonged recovery was not, however, associated with inclusion of a
progestin in the regimen. Although the additional recovery data provided by two recently
completed multicenter trials will be important to increase the absolute numbers of individuals
examined, this analysis provides significant reassurance that the hormonal contraceptive
approach is truly reversible in men.
G. Side effects of male hormonal contraceptives
Male hormonal contraceptive regimens can have small but significant effects on a number of
nonreproductive parameters, and these need to be examined carefully because such regimens are
designed for long-term use in large numbers of men. The extent to which these nonreproductive
systems are affected appears to be mediated, at least in part, by differences in the progestin
component of the regimen and perhaps by the mode of hormonal delivery (injection vs. oral vs.
transdermal). Direct comparisons between regimens have, however, rarely been performed, and
it is difficult to extrapolate the relative differences between studies performed at various centers.
Since efficacy has been established, at least in small studies, dose-reduction and delivery systems
designed to minimize the extragonadal effects of male hormonal contraceptive regimens will be
an important aspect of drug development over the next decade.
It is possible that, analogous to female oral contraceptives that reduce the incidence of some
hormone-dependent cancers (279), male hormonal contraceptives could have health benefits for
men. In healthy young men, exogenous androgens increase lean body mass and decrease fat mass
in a dose-dependent manner (280), whereas androgen replacement in hypogonadal men results in
similar improvements in body composition in addition to increasing bone mineral density
(281,282). It is possible that such benefits could occur in men using hormonal contraception over
the long term, although these changes may be modulated by the necessary addition of a progestin
(283) or other agent. Increases in lean body mass and decreases in fat mass might be beneficial in
reducing the incidence of the metabolic syndrome or cardiovascular disease or in maintaining
physical function as men age. Moreover, increases in bone mineral density could decrease
fracture risk. Long-term trials and data collection will be required to ascertain whether such
benefits are conferred when exogenous androgens are given to healthy men.
Little is known about the cardiovascular effects of exogenous androgen-based contraceptive
regimens, but weight gain and HDL suppression have been consistent findings. However, total
cholesterol and the proatherogenic lipid particle low-density lipoprotein are also suppressed by
androgens. High doses of testosterone can cause some of these effects, as in the second WHO
efficacy trial of high-dosage im TE (200 mg im/wk), where HDL levels declined by 13% and
weight increased by 4 kg (142). More physiological dosages of testosterone alone cause
significantly less HDL suppression and weight gain but are not as effective at suppressing sperm
production and thus have limited clinical utility as a contraceptive (183,238). The mechanism
through which androgens alter serum lipids is not fully understood, but likely is a combination of
changes in body fat distribution and stimulation of hepatic lipase activity resulting in decreased
lipid particle size and increased lipid density (283). Whereas combining physiological doses of
testosterone with a progestin dramatically improves sperm suppression, HDL and weight are also
adversely affected (183,238). At least in the case of some regimens, HDL and weight effects
have been clearly shown to be related to the progestin dose (238,239,240,242). Together, these
data suggest that the progestin component of androgen-progestin-based male hormonal
contraceptive regimens may negatively affect metabolic parameters in men.
Very little is known about the effects of progestins on cardiovascular risk factors in men. In a
small study of men (283) and a large study of women (284), progestins were associated with
increased total body and abdominal fat and insulin resistance. The route of administration of the
progestin may modulate these metabolic effects, because oral administration is associated with
first-pass metabolism in the liver, a critical site for cholesterol metabolism and glucose
homeostasis. For example, testosterone combined with oral northethisterone and testosterone
plus im northethisterone were equally effective in inducing uniform severe oligospermia, but
testosterone plus oral northethisterone induced significantly greater HDL suppression (17%) than
testosterone plus im northethisterone (10–12%) (255). Similarly, oral desogestrel significantly
suppresses HDL (by ∼20%), but in a separate trial its active metabolite etonogestrel, delivered
by implant, did not cause significant HDL suppression (although HDL levels decline by 7–22%
in dosages that effectively induce severe oligospermia) (242,245,246,247,285).
Inflammation has been implicated in the development of cardiovascular disease, and a number of
inflammatory markers including IL-6 and its product, C-reactive protein, are linked to the
development of heart disease. In women, exogenous progestins can increase inflammatory
markers (284), but there are little data on the inflammatory effects of progestins in men. In a
recent study, norethisterone enanthate administered im in combination with testosterone was
associated with an increase in proinflammatory IL-6, whereas testosterone alone resulted in
decreased IL-6 (222).
Perhaps the most worrisome potential drawback to androgen administration in men is inducing
or stimulating prostate diseases including benign prostatic hypertrophy or prostate cancer, both
major causes of morbidity and mortality in men. The relationship between circulating androgens
and the development of prostate disease in men is controversial. Some epidemiological data
correlate high serum testosterone levels with prostate cancer risk (286), although these studies
have been conflicting (reviewed in Ref. 287). In contrast, other studies have found a relationship
between low serum testosterone levels and occult, aggressive prostate cancer (288,289).
Prostate assessments in previous trials of male hormonal contraception and of androgen therapy
in testosterone-deficient men, while reassuring, have been limited to measurement of serum
prostate-specific antigen (PSA), and in some cases, prostate volume (217,218,256,285). Limited
data in young men acutely administered im TE at doses as high as 500 mg weekly (five times the
physiological dose) for 20 wk did not demonstrate significant elevations in PSA (290), but no
other measures of prostate function or morphology were assessed. Given the high prevalence of
prostate disease in the developed world, even small changes in disease prevalence associated
with exogenous androgen administration in young men could be associated with significant
harm. Thus, understanding the long-term effects of exogenous but physiologically dosed
androgens on prostate health is a key component to hormonal contraceptive development.
Moreover, novel combinations such as a GnRH antagonist plus low-dose androgens with or
without a 5α-reductase inhibitor might minimize prostate stimulation and deserve further clinical
evaluation.
H. Selective androgen receptor modulators for male contraception
There has been recent interest in the development of SARMs that provide tissue-selective
androgen action (276). Although development is targeted to hypogonadal men, “prostatesparing” androgens that inhibit gonadotropin secretion and spermatogenesis while supporting
sexual function and maintaining lean body and bone mass would be attractive for long-term
contraceptive use. One approach that might achieve these goals is combining testosterone with a
5α-reductase inhibitor. 5α-Reductase type II is highly expressed in the prostate and is responsible
for the conversion of testosterone to the more potent androgen DHT, resulting in tissue-specific
amplification of androgen signaling. In older, hypogonadal men, the combination of TE plus
finasteride, a specific inhibitor of 5α-reductase type II, maintains the beneficial effects of
testosterone on bone mineral density (291), strength, physical performance, lipids, and body
composition (292) without precipitating the increases in prostate size or PSA noted with
administration of TE alone (291). Moreover, results from the Prostate Cancer Prevention Trial
(293) suggest that 5α-reductase inhibition may have long-term benefits for men by reducing
prostate cancer incidence. In addition, it is possible that the addition of a potent 5α-reductase
inhibitor to testosterone might improve contraceptive efficacy by inhibition of 5α-reductase
activity in the testes because persistent intratesticular DHT levels have been suggested to
contribute to the failure to reach azoospermia in some male hormonal contraceptive studies
(99,117,138). However, contraceptive trials have yet to demonstrate that the addition of a 5αreductase inhibitor to testosterone plus a progestin further blocks spermatogenesis (140,148).
The compound 7α-methyl-19-nortestosterone (MENT) is the first steroidal SARM to be tested as
part of a male hormonal contraceptive regimen. The 7-methylation of this compound prevents
5α-reduction, effectively minimizing the prostatic activity of MENT (294) and perhaps other
androgenic side effects attributed to DHT such as male pattern baldness. Such noncontraceptive
benefits could significantly improve the appeal of a male hormonal contraceptive to men. In a
study in castrated monkeys, MENT showed a 10-fold greater potency (vs. testosterone) for LH
inhibition, but only 2-fold greater potency at stimulating prostate growth (295). In men, MENT
has a short half-life, probably due to the fact that MENT does not appear to bind to SHBG (296).
Therefore, MENT implants have been synthesized to allow for sustained delivery. These
implants suppress gonadotropins and androgens by 80–90% in men (297); as a contraceptive,
MENT as a single agent resulted in azoospermia in 73% of those individuals who received four
implants (298). Recently, MENT implants have been combined with a progestin for
contraception (299). Disappointingly, effective sperm suppression was not maintained beyond 12
wk with combined, implantable MENT plus etonogestrel, likely due to the low levels of MENT
in the circulation. Future studies with more sustained delivery of MENT or perhaps other
selective steroidal SARMS, combined with a progestin or GnRH antagonist, are still a promising
approach to contraceptive development.
Like MENT, some anabolic steroids have been recently demonstrated in vitro and in animal
models to have some degree of tissue selectivity. These studies come predominantly from efforts
aimed at understanding the physiological effects of substances that merit banning in professional
sport. Some of these have been shown to have tissue-selective androgen action that may make
them candidates both for androgen replacement therapy and as part of a contraceptive regimen.
For example, desoxymethyltestosterone appears to be significantly more potent for levator ani
muscle than at the prostate (300) in a castrate rat model. Similarly, tetrahydrogestinone is less
potent than DHT on the rat prostate at doses capable of maintaining muscle mass (301). Both
tetrahydrogestinone (302) and dimethandrolone (275) appear to have significant interaction with
both the androgen and progestin receptors. Such properties might provide the benefits of
increased gonadotropin and spermatogenic suppression, which characterize combined androgenprogestin regimens. Some of these steroids, particularly dimethandrolone that can be
administered orally, warrant further testing in humans as part of a contraceptive strategy.
Recently, a number of nonsteroidal small molecule SARMs, which may be compatible with oral
administration, have been described (276,303,304,305). In order for these compounds to act as
hormonal contraceptives, they must be potent at the pituitary, muscle, and bone while sparing the
prostate. One such compound suppressed spermatogenesis in rats by 75% after 10 wk of
treatment (306), and another has been shown to maintain bone density and muscle mass while
suppressing LH in castrate rats (307). Some of these compounds are currently undergoing
clinical evaluation in humans. Nonsteroidal SARMs are particularly appealing because they
might allow for oral administration of the androgen component of future male contraceptive
regimens and could, in theory, minimize any adverse effects on the prostate. However, their
development as contraceptive agents will require a significant effort on the part of the
pharmaceutical industry.
I. Why doesn’t hormonal contraception work for all men?
A major mystery in the field of male hormonal contraceptive research is why some men fail to
sufficiently suppress their sperm counts despite inhibition of serum gonadotropin secretion to
extremely low levels. There are no apparent differences in the gonadotropin levels among men
who suppress to azoospermia and those who do not; thus the degree of gonadotropin suppression
itself is unlikely to be the explanation for these differences (97,308,309). As discussed above, an
alternative hypothesis has been that persistent intratesticular DHT levels may support ongoing
spermatogenesis in this setting (99,117,138); however clinical trials do not support an additional
contraceptive benefit with the addition of 5α-reductase inhibitors to contraceptive regimens
(140,148). Similarly, “residual” intratesticular testosterone production in some men despite
maximal gonadotropin suppression might support spermatogenesis in those men deemed
treatment “failures.” Indeed, work in the LH-receptor knockout mouse supports the concept of
basal, non-LH dependent testosterone production capable of supporting low levels of
spermatogenesis (113,310). However, in two small studies we found no relationship between
residual intratesticular testosterone levels and sperm production in men undergoing hormonal
contraceptive treatment (134,146). Larger studies are required to confirm these results, but it is
possible that, in contrast to studies in rodents, persistent intratesticular androgen levels after
hormonal contraceptive treatment do not explain treatment “failures” and alternative
explanations should be pursued.
Clinically, it would be of great use if one could predict treatment failures based upon serum
markers, either before or during treatment. Although examined in almost every male
contraceptive study, baseline sex steroids, gonadotropins, and sperm concentrations do not
appear to be predictive of those men who will achieve adequate sperm suppression with
hormonal contraceptive treatment. Insulin-like factor 3 (INSL3) is a recently described protein
secreted by the testes and found in abundance in the serum (311). INSL3 secretion is regulated,
at least in part, by LH, and may be a marker of Leydig cell function (311,312). Although the
physiological role of INSL3 is not completely understood, some data suggest that INSL3 may
play a role in germ cell survival (313). Male hormonal contraceptive treatment results in a
significant decrease in circulating INSL3 (311,312). In a retrospective analysis, we recently
showed that higher end-of-treatment INSL3 concentrations after male hormonal contraceptive
treatment correlated with persistent spermatogenesis and failure to achieve azoospermia (314).
Although these results require further confirmation in a prospective fashion, this is the first
demonstration of a serum marker that may be associated with persistent spermatogenesis.
Exploring a possible functional role for INSL3 in spermatogenesis will be the subject of future
studies in this important area.
Genetic polymorphisms may explain the difference between men who suppress to azoospermia
and those who do not. No such polymorphisms have been identified to date, although three have
been examined. Androgen receptor action is influenced, in part, by two trinucleotide repeats
located in exon 1. Increased numbers of CAG repeats are associated with decreased androgen
activity, whereas the effects of GGN repeats are less clear. One study found that a CAG repeat
number of greater than 22 was associated with an increased chance of azoospermia in the setting
of incompletely suppressed gonadotropins after hormonal contraceptive treatment (315).
However, a second study found that the number of neither CAG nor GGN repeats in the
androgen receptor appeared to influence individual responsiveness to hormonal suppression of
spermatogenesis (316). These authors went on to examine polymorphisms in the CYP3A4 gene,
which encodes an important enzyme in the metabolism of testosterone, and again found no
relationship between a known polymorphism in CYP3A4 and sperm suppression (316). Clearly,
further investigation will be needed to understand the innate differences in the intratesticular
environment that allow some men to continue to produce sperm in the extremely low
gonadotropin environment of a male contraceptive regimen. These efforts will likely require a
coordinated effort among research centers to yield significant results, due to the relatively small,
but critical, numbers of men who fall into the category of hormonal contraceptive treatment
“failures.”
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VI. Nonhormonal Methods
Nonhormonal approaches to male contraception can target either sperm production (testicular
targets) or sperm motility. These are attractive targets because, theoretically, agents targeted to
these processes might be very specific, thus lacking the systemic side effects that plague
hormonal methods. In addition, it is possible that such agents could have a much more rapid
onset of action. However, development in this area has been slow, and only one of these
approaches has reached phase II trials in men (gossypol). Both reversibility and efficacy in
animal models continues to be an issue for these approaches, but with advances in genetic and
proteomic array approaches, new potential targets will continue to emerge.
A. Testicular targets
Two plant extracts, gossypol, a phenolic compound derived from the cotton plant, and triptolide,
derived from the Chinese herbal medicine Trypterigium wilfordii, were promising nonhormonal
agents evaluated in the 1980s and 1990s in China. Unfortunately, both agents were found to
result in significant, serious side effects and in some cases irreversible infertility, and their
development as contraceptives has been abandoned. Gossypol affects both spermatogenesis and
sperm motility. Of more than 8000 Chinese men treated with oral gossypol, more than 90%
achieved sperm concentrations of less than 1 million/ml (317,318); however, in 20% of cases this
effect was not reversible (319). In addition, hypokalemia was a frequent side effect, in some
cases resulting in periodic paralysis (320). A subsequent study suggested that these adverse
effects of gossypol may be dose-dependent, but reversible infertility still resulted when lower
doses were used (321). However, these side effects caused a reevaluation of the preclinical
criteria for contraceptive development (320). T. wilfordii, an herbal medicine with
immunosuppressive properties, impairs sperm motility and density when given to rats and men
(322). Purification of the active component of T. wilfordii, triptolide, followed (323).
Unfortunately, administration of triptolide to rodents resulted in irreversible infertility (324,325).
Moreover, the immunosuppressive effects of triptolide would likely have prohibited its
development as a contraceptive.
Mild elevations in scrotal temperature, just above that of the body core, can cause germ cell
apoptosis (326,327). Rodent germ cells appear to be particularly susceptible to testicular heat
(328,329). Although exogenous heat alone is not an effective, long-term contraceptive strategy in
men (330), it is possible that heat may decrease the time to low sperm concentration when used
in combination with hormonal or nonhormonal contraceptive methods (331). In a recent study,
heat using a scrotal water bath at 43 C (30 min/d for 6 consecutive days) in combination with
exogenous testosterone decreased sperm count and motility and increased germ cell apoptosis
during the first 12 wk of treatment compared with testosterone alone (331). However, in contrast
to testosterone plus a progestin, most men using heat plus testosterone failed to achieve sperm
concentrations below 1 million/ml after 18 wk of treatment. Therefore, heat plus hormone-based
regimens are unlikely to be clinically useful at this point.
An alternative strategy to nonhormonal contraception is to target nongerm cells critical for
spermatogenesis. In theory, this could be either the Leydig or Sertoli cell, however interruption
with Leydig cell function would likely result in systemic hypogonadism requiring the addition of
exogenous testosterone. Indenopyridines, serendipitously found to have antifertility effects
during toxicology screening for new antihistamines, appear to target both Sertoli cells and germ
cells (332,333,334). One such indenopyridine, CDB-4022, when used in combination with a
GnRH antagonist, induced reversible infertility in male rats (335). Recently, the l-enantiomer of
CDB-4022 was tested in adult cynomolgus monkeys (332). Seven days of oral treatment with lCDB-4022 resulted in severe oligospermia in all four monkeys treated 17 d after initial
administration and remained as such for 6 wk total. Reversibility was demonstrated by wk 16, at
which time sperm counts were equivalent to vehicle-treated animals. Gonadotropin and sex
steroid concentrations were unaffected, and there were no overt toxicities associated with drug
administration. Although l-CDB-4022 clearly affected developing spermatocytes, its precise
mechanism of action in the monkey is unclear (332). Given that some studies have demonstrated
irreversible testicular effects of CDB-4022 administration in rodents, longer-term studies of lCDB-4022 in nonhuman primates will likely be necessary before testing in humans. However,
these are promising preclinical data for a potential oral, nonhormonal male contraceptive.
During their development in the seminiferous tubules, spermatids adhere tightly to Sertoli cells
via anchoring proteins in junctions known as apical ectoplasmic specializations (apical ES). Oral
administration of 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide (adjudin) to rats has
been shown to disrupt the interaction of spermatid-Sertoli cells by interacting with specific
proteins in the apical ES and to result in reversible infertility (336,337,338). However, in some
animals, nonreproductive side effects including liver inflammation and muscle atrophy were
noted with adjudin administration. These side effects appear to be overcome by directing adjudin
delivery to the testes (339). Mruk et al. (339) developed a mutated FSH molecule, lacking three
critical glycosylation sites, and conjugated it to adjudin, allowing for significantly less overall
drug exposure for the animals and with consistent achievement of reversible infertility.
Moreover, endogenous FSH activity appeared to be maintained. Not only adjudin, but also this
novel approach to directing agents to the testes is an exciting new area in contraceptive
development; however, caution will be required due to the possibility of developing anti-FSH
autoantibodies that might compromise reversibility with long-term use.
B. Epididymal targets
During transit through the epididymis, before ejaculation, spermatozoa undergo maturation; thus
the epididymis provides another possibly unique contraceptive target. Murine genetic knockout
models have provided a number of putative epididymal targets; however, none have reached
clinical testing in humans or nonhuman primates. Epididymal-specific proteins could provide
points for pharmaceutical intervention. For example, the G-coupled protein receptor HE6
appears to have epididymal duct-specific expression, and HE6-deficient mice are infertile but
otherwise phenotypically normal (340,341). HE6 appears to be critical to fluid resorption in the
efferent epididymal ductules, but its precise mechanism of action is not well known.
Nevertheless, G-coupled protein receptors can be excellent targets for drug development.
Similarly, CRISP-1, a member of the cystiene-rich secretory protein family, appears to have
epididymal-specific expression. CRISP-1 appears to be secreted into the lumen of the epididymis
where it is postulated to interact with spermatozoa, preventing the initiation of capacitation
during sperm transit and storage (342,343). Pursuit of these, and other, epididymal proteins as
contraceptive targets, however, is still a number of years from clinical use because not only do
appropriate inhibitors need to be identified, but their specificity and concentration in the
reproductive tract will need to be confirmed.
C. Targeting sperm motility or sperm-egg fusion
Recently, several investigators have focused on inhibition of sperm motility as a promising target
for male contraceptive development. Ascent of sperm in the female reproductive tract is
dependent on initiation of sperm flagellar beating during ejaculation. Sperm progress between 1
and 3 mm/min propelled by their flagella, which whip three-dimensionally in an elliptical cone
(344). Before fertilization, sperm dramatically increase the frequency and force of their flagellar
beating, a process termed “hyperactivation,” to reach and penetrate the ovum. Blocking sperm
motility, hyperactivation, or both has great appeal as a male contraceptive. A drug targeting
motility or hyperactivation may not need to cross the “blood-testes” barrier as long as the drug
partitioned into seminal fluid and was ejaculated with the sperm. In addition, such drugs might
have a very rapid onset of action, perhaps allowing for administration immediately before
intercourse.
Unfortunately, agents that interfere with sperm motility may not always be effective across
species. Glycosphingolipids are abundant in sperm, and mice deficient in enzymes involved in
glycosphingolipid biosynthesis and metabolism have significantly compromised fertility
(345,346,347). Gaucher disease is a rare autosomal recessive glycogen storage disease caused by
a deficiency in glycosphingolipid metabolism that can be treated, in part, by an inhibitor of
glycosphingolipid synthesis, miglustat (N-butyldeoxynojirimycin) (348,349,350). Administration
of miglustat to normal mice resulted in reversible infertility by markedly affecting sperm motility
and acrosome morphology (351). However, we recently demonstrated that, in contrast to the
initial findings in mice, administration of daily, oral miglustat to healthy men for 6 wk, at doses
similar to that used to treat Gaucher disease, had no effect on sperm motility, morphology, or the
acrosome reaction (352). In addition, the initial findings in mice were not reproducible among
different strains (353), suggesting that genetic variance plays a key role in spermatic sensitivity
to miglustat.
One approach to blocking sperm motility—and sperm hyperactivation in particular—has focused
on a group of four novel sperm-specific transmembrane proteins termed “CatSpers” (354). These
transmembrane proteins assemble, likely as a tetramer in conjunction with the transmembrane
protein CatSperbeta (355), and allow for calcium entry into the sperm tail through a bicarbonateactivated, voltage-sensitive channel. The rise in intracellular calcium mediated by the CatSpers is
directly responsible for the increase in flagellar beat frequency that characterizes sperm
hyperactivation. All four CatSpers are critical for fertility, and mice rendered deficient in even a
single CatSper are infertile (354,356) but otherwise phenotypically normal. Thus, CatSpers are
promising targets for male contraceptive development because they are highly specific for
sperm. However, antagonists for these channels have not yet been reported in the literature and
thus are a long way from clinical use.
Potassium chloride cotransporters and ion-specific channels are also thought to play an important
role in sperm motility. To maintain their motility, ejaculated sperm undergo regulated volume
decrease wherein ions and organic osmolytes are effluxed from the sperm in a regulated fashion
to prevent cytoplasmic swelling after exposure to the relatively hyposmolar female reproductive
tract (211). The nonselective ion channel blocker quinine maximally inhibits regulated volume
decrease (357,358), but sperm-specific potassium and chloride channels, and effective inhibitors,
for human sperm have yet to be identified and may not be equivalent to those in the mouse (357).
Additional potential targets for inhibiting sperm motility are the proteins of the principal piece of
the flagellum. A recent study used mass spectrometry proteomic analyses of isolated human
fibrous sheaths to identify several proteins that colocalize to the fibrous sheath of the flagellum
(359). Most of the isolated proteins were known glycolytic enzymes, but the authors also
identified a unique adenine nucleotide translocase. This protein, called sperm flagellar energy
carrier [SFEC, also termed ADP-ATP carrier protein 4 (AAC4)], appears to participate in the
transport of ATP within the principal piece. The authors hypothesize that once SFEC has moved
ATP to the flagellum core, dynein ATPases allow the microtubules of the flagellum to slide
across one another and generate flagellar movement. Structural modeling suggests that SFEC
possesses a unique protein motif at the entrance to the nucleotide-binding pocket that might be
an attractive drug target. Similarly, the sperm-specific glyceraldehydes 3-phosphate
dehydrogenase-S (GAPDS) is bound to the flagellar cytoskeleton and plays a critical role in
sperm glycolysis in the mouse (360). GAPDS-deficient male mice are completely infertile,
despite normal sperm counts, due to severely impaired motility (360). The human homolog of
GAPDS, GAPD2, also appears to be sperm-specific (361). If this is the case, if enzyme-specific
inhibitors can be developed that do not interfere with extraspermatic sites of glycosylation,
GAPD2 may be an intriguing contraceptive target.
Two final intriguing targets for male contraceptive motility research are the unique “soluble”
adenylate cyclase (sAC) and sodium-hydrogen exchanger (sNHE) found in sperm. Increased
intracellular cAMP is essential for preparing sperm for fertilization, a process known as
“capacitation.” sAC lacks a transmembrane anchor and produces cAMP in the cytoplasm of the
sperm. sAC activity is potentiated by bicarbonate and calcium, known triggers of sperm
hyperactivation (362). Therefore, an inhibitor of sAC could utilize two mechanisms to impair
fertility: 1) inhibiting sperm motility and hyperactivation; and 2) impairing capacitation. Mice
lacking sAC are infertile, and their sperm are immotile due to defects in cAMP production
(363,364). Furthermore, recent work with KH7, a specific inhibitor of sAC, demonstrated that
sAC inhibition markedly impairs the ability of mouse sperm to undergo capacitation, achieve a
hyperactivated state, and ultimately, fertilize oocytes in vitro (365). Analogous to sAC-null mice,
male mice deficient in sNHE are infertile due to immotile sperm (366), and this defect can be
overcome in vitro with the addition of cAMP. Wang et al. (367) recently demonstrated that
sNHE is required for the full expression of sAC at the protein level and that these two proteins
colocalize and form a complex critical for sperm motility. Future work to develop specific
inhibitors of sAC and/or sNHE is an intriguing prospect for male contraception.
A sperm-specific membrane protein with structural homology to Ig, Izumo, has been recently
identified. Data suggest that Izumo is required for sperm-egg fusion (368). Male knockout mice
with homozygous Izumo deficiency appear phenotypically normal, with normal sperm numbers,
morphology, and motility, yet are infertile. Sperm from Izumo-deficient animals could penetrate
the zona pellucida of eggs in vitro but could not complete fertilization. However, when
intracytoplasmic sperm injection was used to inject Izumo-deficient sperm into normal eggs in
vitro, the defect was overcome. Its apparent specificity for this critical prefertilization step makes
Izumo an attractive target of contraceptive development; however, pharmacological inhibitors of
Izumo have yet to be identified.
Finally, over the last two decades researchers in India have been developing an injectable intravas compound that has been tested in small phase I and II trials (369,370). RISUG is a polymer
of styrene maleic anhydride dissolved in the vehicle dimethylsulfoxide that is injected into the
lumen of the vas deferens using a no-scalpel technique. In the phase II study of 12 men,
sustained azoospermia was achieved between 5 and 106 d after the procedure, with the exception
of one individual who did not reach azoospermia until d 243, although 100% of his remaining
sperm from d 39 onward were nonmotile (370). No pregnancies in the 12 couples studied were
reported over the following 12-month period, wherein after the initial 2 months of condom use
couples relied only upon the RISUG for contraception. Unfortunately, although RISUG denotes
“reversible inhibition of sperm under guidance,” to date both preclinical and clinical studies have
failed to demonstrate reversibility, and the mechanism whereby this might be achieved is not
clear. More recent reports from this group have suggested that exposure to the styrene maleic
anhydride-dimethylsulfoxide combination within the vas deferens results in irreversible
alterations of the sperm membrane via changing the electrostatic and pH environments
(371,372,373). Resulting immediate changes in sperm motility and function, if demonstrated
clinically, might give such a method an advantage over vasectomy by shortening the
postprocedure time to contraceptive efficacy. A phase III trial of this method is apparently under
way and hopefully will include data on reversibility. Until such data are published, RISUG
should only be considered an experimental alternative to vasectomy.
D. Immunological approaches to contraception
Employing the immune system as a contraceptive by targeting sperm- or egg-specific proteins, or
even gonadotropins, has some natural parallel because antisperm antibodies can play a role in
infertility. Indeed, sperm antigens have been suggested as ideal targets for contraceptive vaccine
development (recently reviewed in Ref. 374). In light of immunological memory, it is difficult
conceptually to think of a vaccine approach as a reversible contraceptive method, but a recent
study in nonhuman primates suggested that this might be possible. O’Rand et al. (375) reported
that immunization of nine male monkeys with recombinant human eppin resulted in reversible
contraception in five of nine animals. Eppin is a testes-epididymal-specific protease inhibitor
found on spermatozoa thought to play a role in sperm-semenogelin interaction in the coagulum
of human ejaculate (376). Although this represents a novel success in the field of
immunocontraception in the male, a number of concerns for further clinical development of this
approach were raised in this pilot study. First, booster immunizations were required every 3 wk
throughout the treatment to maintain high titer anti-Eppin antibodies, a requirement for
contraception. Second, for unknown reasons, two of nine animals failed to mount a significant
enough immune response to warrant fertility testing. Finally, two of nine animals failed to sire an
offspring after cessation of injections, even after 450 d of observation. It is likely that any
vaccine approach to contraception might have similarly inconsistent responses among
individuals and that reversibility may also be unpredictable, given the variability in
immunogenicity of such a vaccine among individuals.
Although controversial, vaccine approaches to contraception aimed at gonadotropins or GnRH
have reached phase I clinical trials in women (377), and a similar approach could in theory also
be used in men. Again, variability in the immune response leading to irreversibility and
triggering autoimmune disease and perhaps anaphylactic shock has concerned critics in this area
(378). In men, GnRH and FSH have been suggested as possible targets for immunocontraception
(379), although blockade of the latter would require exogenous testosterone administration for
maintenance of androgenicity. Included among most recent work are vaccines aimed at GnRH-1
DNA (380), but there has been very little progress in male contraceptive vaccine development in
the last 10 yr, with most work in this area focusing on medical alternatives to castration
(permanent sterility) for veterinary use.
Go to:
VII. Conclusions
From a global standpoint, there is clearly a desire and need for more contraceptive options.
Couples desire more choices for fertility control, and unplanned pregnancies continue to occur at
alarming rates. The hormonal approach to male contraception has made significant progress in
the last decade in terms of clinical development. The efficacy of this approach appears to surpass
condoms, and these methods seem to appeal to men and their partners. The long experience with
female contraceptives sets the bar very high in terms of minimizing side effects for male
hormonal contraceptives, thus continued refinements of male hormonal contraceptive regimens
to this end are under way. Because the direct health benefits of pregnancy prevention for men are
less tangible, male contraceptive development faces additional challenges because agents used
for this purpose might be used by healthy individuals over many years. Therefore, acceptance of
side effects, or even potential side effects, is very low. New forms of androgen delivery have
been introduced over the last 5–10 yr, including transdermal, oral, and long-acting injectable
androgens. These could allow for a very acceptable delivery system for male hormonal
contraceptive users. Moreover, the hormonal approach to male fertility control has the potential
to further benefit men by contributing to chemoprevention of other diseases, as the female oral
contraceptive has.
Unfortunately, over the last 2 yr, the major pharmaceutical sponsors of male hormonal
contraceptive research have withdrawn their support in this area of product development, making
it difficult to complete the final phases of clinical development. Government and not-for-profit
sponsors will be needed in this environment to devote the necessary resources for long-term
efficacy studies. The potential rewards of preventing unwanted pregnancies and providing more
contraceptive choices for couples will hopefully attract visionary leaders to support this mission.
Array technology at both the RNA and protein levels is likely to provide an explosion in spermand fertilization-specific contraceptive targets in the coming years. Genetic engineering using
murine models has already revealed some intriguing nonhormonal targets. Caution must be taken
in translating preclinical results, and these methods will require extensive nonhuman primate and
human testing. However, although such approaches are a number of years away from clinical
introduction, they offer the potential for sperm-specific interventions and thus great promise as
reversible contraceptives with minimal side effects suitable for long-term use.
Population control remains one of humankind’s greatest challenges in the 21st century. The
population burden continues to tax our environment and contribute to morbidity and mortality
globally. It is the hope of researchers in the field of male contraceptive development that
approaches to blocking sperm production and function will bring the dream of the “male pill” to
fruition and significantly impact the health and future of the planet.
Go to:
Acknowledgments
We thank Dr. Andrea Coviello for permission to include unpublished data (Fig. 22).
Go to:
Footnotes
This work was supported by the National Institute of Child Health and Human Development, a
division of the National Institute of Health (NIH), through cooperative agreements U54-HD-
12629 and U54 HD42454 as part of the specialized Cooperative Centers Program in
Reproductive Research and the Cooperative Contraceptive Research Centers Program (to W.J.B.,
S.T.P., and J.K.A). In addition, S.T.P. is supported in part by the National Institute of Aging, a
Division of the NIH, by Grant K23 AG027238. J.K.A. is supported, in part, by the National
Institute of Child Health and Human Development, a Division of the NIH, through Grant K23
HD45386.
Disclosures: S.T.P. and J.K.A. have received a lecture fee from Solvay Pharmaceuticals. J.K.A.
has been a consultant for the Takeda Pharmaceutical Company. W.J.B. has nothing to disclose.
First Published Online April 24, 2008
Abbreviations: DHT, Dihydrotestosterone; DMPA, depomedroxyprogesterone; GAPD,
glyceraldehydes 3-phosphate dehydrogenase; GPR, G protein receptor; hCG, human chorionic
gonadotropin; HDL, high-density lipoprotein; INSL3, insulin-like factor 3; MENT, 7α-methyl19-nortestosterone; PSA, prostate-specific antigen; sAC, soluble adenylate cyclase; SARM,
selective androgen receptor modulator; SFEC, sperm flagellar energy carrier; sNHE, soluble
sodium-hydrogen exchanger; TD, testosterone decanoate; TE, testosterone enanthate; TU,
testosterone undecanoate.
Go to:
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Vasectomy in the United States, 1991 and 1995.[Am J Public Health. 1999]
Use of contraception and use of family planning services in the United States: 19822002.[Adv Data. 2004]
Trends in contraceptive use in the United States: 1982-1995.[Fam Plann Perspect. 1998]
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The risk of pregnancy after vasectomy.[Obstet Gynecol. 2004]
Complications of vasectomy: review of 16,000 patients.[Br J Urol. 1984]
Vasectomy by section, luminal fulguration and fascial interposition: results from 6248
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Vasectomy related infertility: a major and costly medical problem.[Hum Reprod. 1998]
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Patient characteristics associated with vasectomy reversal.[J Urol. 1999]
Review Safety and effectiveness of vasectomy.[Fertil Steril. 2000]
Results of 1,469 microsurgical vasectomy reversals by the Vasovasostomy Study
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Risk factors for antisperm antibodies in infertile men.[Am J Reprod Immunol. 1994]
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A long-term study of mortality in men who have undergone vasectomy.[N Engl J Med.
1992]
Review Clinical practice. Long-acting methods of contraception.[N Engl J Med. 2005]
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Review The molecular action and regulation of the testis-determining factors, SRY (sexdetermining region on the Y chromosome) and SOX9 [SRY-related high-mobility group
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Hypophysial responses to continuous and intermittent delivery of hypopthalamic
gonadotropin-releasing hormone.[Science. 1978]
Episodic luteinizing hormone secretion in man. Pulse analysis, clinical interpretation,
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Operating characteristics of the male hypothalamo-pituitary-gonadal axis: pulsatile
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Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide
receptor GPR54.[Proc Natl Acad Sci U S A. 2003]
The GPR54 gene as a regulator of puberty.[N Engl J Med. 2003]
The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the
orphan G protein-coupled receptor GPR54.[J Biol Chem. 2001]
AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1.[J
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Somatic alterations of the DPC4 and Madr2 genes in colorectal cancers and relationship
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Review Minireview: kisspeptin neurons as central processors in the regulation of
gonadotropin-releasing hormone secretion.[Endocrinology. 2006]
Developmental and hormonally regulated messenger ribonucleic acid expression of
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Regulation of Kiss1 gene expression in the brain of the female mouse.[Endocrinology.
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Continuous human metastin 45-54 infusion desensitizes G protein-coupled receptor 54induced gonadotropin-releasing hormone release monitored indirectly in the juvenile
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Chronic subcutaneous administration of kisspeptin-54 causes testicular degeneration in
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Developmental and hormonally regulated messenger ribonucleic acid expression of
KiSS-1 and its putative receptor, GPR54, in rat hypothalamus and potent luteinizing
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Modulation of pulsatile gonadotropin secretion by testosterone in man.[J Clin Endocrinol
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Is aromatization of testosterone to estradiol required for inhibition of luteinizing hormone
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Acute androgen receptor blockade increases luteinizing hormone secretory activity in
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Studies on the role of sex steroids in the feedback control of gonadotropin concentrations
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Androgen-receptor blockade enhances pulsatile luteinizing hormone production in late
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Effect of flutamide or cyproterone acetate on pituitary and testicular hormones in normal
men.[J Clin Endocrinol Metab. 1984]
Evidence that androgen negative feedback regulates hypothalamic gonadotropinreleasing hormone impulse strength and the burst-like secretion of biologically active
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Long-term transdermal dihydrotestosterone therapy: effects on pituitary gonadal axis and
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Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80year-old men.[J Clin Endocrinol Metab. 1994]
Tissue expression of the nuclear progesterone receptor in male non-human primates and
men.[J Endocrinol. 2006]
Estrogen and progesterone receptor mRNA are expressed in distinct pattern in male
primate reproductive organs.[J Assist Reprod Genet. 1995]
Immunocytochemical localization of progestin receptors in monkey hypothalamus: effect
of estrogen and progestin.[Endocrinology. 1992]
Enhanced sexual behaviors and androgen receptor immunoreactivity in the male
progesterone receptor knockout mouse.[Endocrinology. 2005]
Review A review of androgen-progestin regimens for male contraception.[J Androl.
2003]
Demonstration of progesterone receptor-mediated gonadotrophin suppression in the
human male.[Clin Endocrinol (Oxf). 2003]
Relationship between serum gonadotropins and spermatogenic suppression in men
undergoing steroidal contraceptive treatment.[J Clin Endocrinol Metab. 2004]
Coexistence of intracellular and membrane-bound progesterone receptors in human
testis.[J Clin Endocrinol Metab. 2005]
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Direct effect of progestogen on gene expression in the testis during gonadotropin
withdrawal and early suppression of spermatogenesis.[J Clin Endocrinol Metab. 2006]
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Review Inhibins in normal male physiology.[Semin Reprod Med. 2004]
Evidence that in a physiological setting Sertoli cell number is the major determinant of
circulating concentrations of inhibin B in the adult male rhesus monkey (Macaca
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Activating mutations in the luteinizing hormone receptor gene: a human model of nonfollicle-stimulating hormone-dependent inhibin production and germ cell maturation.[J
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Serum inhibin B levels reflect Sertoli cell function in normal men and men with testicular
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Response of serum inhibin B and pro-alphaC levels to gonadotrophic stimulation in
normal men before and after steroidal contraceptive treatment.[Hum Reprod. 2003]
Male hypogonadism due to a mutation in the gene for the beta-subunit of folliclestimulating hormone.[N Engl J Med. 1998]
Men homozygous for an inactivating mutation of the follicle-stimulating hormone (FSH)
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Effects of follicle-stimulating hormone (FSH) and human chorionic gonadotropin in
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Physiological relationships between inhibin B, follicle stimulating hormone secretion and
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Importance of inhibin B in the regulation of FSH secretion in the human male.[J Clin
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The low gonadotropin-independent constitutive production of testicular testosterone is
sufficient to maintain spermatogenesis.[Proc Natl Acad Sci U S A. 2003]
Molecular characterization of postnatal development of testicular steroidogenesis in
luteinizing hormone receptor knockout mice.[Endocrinology. 2004]
Androgens in various fluid compartments of the rat testis and epididymis after
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Androgens in male rat reproductive tract fluids: hypophysectomy and steroid
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Comparison between testosterone enanthate-induced azoospermia and oligozoospermia
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Sex steroid production and secretion in the male.[Andrologia. 1978]
Determination of testosterone production rates in men and women using stable
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Circadian variations of plasma testosterone and estrogens in normal men. A study by
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Circadian rhythm of plasma testosterone, cortisol and gonadotropins in normal male
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Testosterone metabolic clearance and production rates determined by stable isotope
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Loss of circadian rhythmicity in blood testosterone levels with aging in normal men.[J
Clin Endocrinol Metab. 1983]
Age-specific changes in the regulation of LH-dependent testosterone secretion: assessing
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Intratesticular testosterone concentrations comparable with serum levels are not sufficient
to maintain normal sperm production in men receiving a hormonal contraceptive
regimen.[J Androl. 2004]
Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal
men with testosterone-induced gonadotropin suppression.[J Clin Endocrinol Metab.
2005]
Clomiphene citrate: a correlation of its effect on sperm concentration and morphology,
total gonadotropins, ICSH, estrogen and testosterone excretion, and testicular cytology in
normal men.[J Clin Endocrinol Metab. 1969]
Pituitary-testicular function of prostatic cancer patients during treatment with a
gonadotropin-releasing hormone agonist analog. I. Circulating hormone levels.[J Androl.
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Effects of testosterone plus medroxyprogesterone acetate on semen quality, reproductive
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Testosterone concentrations in testes of normal men: effects of testosterone propionate
administration.[J Clin Endocrinol Metab. 1973]
Effects of testosterone and levonorgestrel combined with a 5alpha-reductase inhibitor or
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levels in normal men.[J Clin Endocrinol Metab. 2005]
Contraceptive efficacy of testosterone-induced azoospermia in normal men. World
Health Organization Task Force on methods for the regulation of male fertility.[Lancet.
1990]
Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in
normal men.[Fertil Steril. 1996]
The low gonadotropin-independent constitutive production of testicular testosterone is
sufficient to maintain spermatogenesis.[Proc Natl Acad Sci U S A. 2003]
Molecular characterization of postnatal development of testicular steroidogenesis in
luteinizing hormone receptor knockout mice.[Endocrinology. 2004]
Higher testosterone dose impairs sperm suppression induced by a combined androgenprogestin regimen.[J Androl. 2002]
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Review Androgen receptor in prostate cancer.[Endocr Rev. 2004]
Review The androgen receptor in spermatogenesis.[Cytogenet Genome Res. 2003]
Generation and characterization of androgen receptor knockout (ARKO) mice: an in vivo
model for the study of androgen functions in selective tissues.[Proc Natl Acad Sci U S A.
2002]
Differential effects of spermatogenesis and fertility in mice lacking androgen receptor in
individual testis cells.[Proc Natl Acad Sci U S A. 2006]
Oligozoospermia with normal fertility in male mice lacking the androgen receptor in
testis peritubular myoid cells.[Proc Natl Acad Sci U S A. 2006]
Infertility with defective spermatogenesis and hypotestosteronemia in male mice lacking
the androgen receptor in Sertoli cells.[Proc Natl Acad Sci U S A. 2004]
A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in
meiosis.[Proc Natl Acad Sci U S A. 2004]
Androgen receptor function is required in Sertoli cells for the terminal differentiation of
haploid spermatids.[Development. 2004]
The effect of a sertoli cell-selective knockout of the androgen receptor on testicular gene
expression in prepubertal mice.[Mol Endocrinol. 2006]
Transcriptional profiling of androgen receptor (AR) mutants suggests instructive and
permissive roles of AR signaling in germ cell development.[Mol Endocrinol. 2007]
Androgen receptor in sertoli cell is essential for germ cell nursery and junctional complex
formation in mouse testes.[Endocrinology. 2006]
Testosterone-dependent restoration of spermatogenesis in adult rats is impaired by a
5alpha-reductase inhibitor.[J Androl. 1999]
Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors:
dissociation from transcriptional activity.[Cell. 2001]
Reversal of bone loss in mice by nongenotropic signaling of sex steroids.[Science. 2002]
Kinase-mediated regulation of common transcription factors accounts for the boneprotective effects of sex steroids.[J Clin Invest. 2003]
Review Sex steroids, ANGELS and osteoporosis.[Bioessays. 2003]
Bone protection by estrens occurs through non-tissue-selective activation of the androgen
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Review Trinucleotide repeats in the human androgen receptor: a molecular basis for
disease.[J Mol Endocrinol. 1998]
The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal
domain affect transactivation function.[Nucleic Acids Res. 1994]
Transcriptional activation modulated by homopolymeric glutamine and proline
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A comprehensive endocrine description of Kennedy's disease revealing androgen
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The CAG repeat within the androgen receptor gene and benign prostatic
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X-chromosome inactivation patterns and androgen receptor functionality influence
phenotype and social characteristics as well as pharmacogenetics of testosterone therapy
in Klinefelter patients.[J Clin Endocrinol Metab. 2004]
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Review Drug insight: testosterone preparations.[Nat Clin Pract Urol. 2006]
Review Testosterone replacement therapy: current trends and future directions.[Hum
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Pharmacokinetics of testosterone undecanoate injected alone or in combination with
norethisterone enanthate in healthy men.[J Androl. 2006]
Clinical trial of transdermal testosterone and oral levonorgestrel for male contraception.[J
Clin Endocrinol Metab. 1999]
Levonorgestrel implants (Norplant II) for male contraception clinical trials: combination
with transdermal and injectable testosterone.[J Clin Endocrinol Metab. 2002]
A novel male contraceptive pill-patch combination: oral desogestrel and transdermal
testosterone in the suppression of spermatogenesis in normal men.[J Clin Endocrinol
Metab. 2001]
Testosterone gel combined with depomedroxyprogesterone acetate is an effective male
hormonal contraceptive regimen and is not enhanced by the addition of a GnRH
antagonist.[J Clin Endocrinol Metab. 2006]
Testosterone dose-response relationships in healthy young men.[Am J Physiol Endocrinol
Metab. 2001]
Testosterone enanthate at a dose of 200 mg/week decreases HDL-cholesterol levels in
healthy men.[Int J Androl. 1995]
The effects of supraphysiologic doses of testosterone on muscle size and strength in
normal men.[N Engl J Med. 1996]
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Review Male germline stem cells: from mice to men.[Science. 2007]
Review Technology insight: In vitro culture of spermatogonial stem cells and their
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Follicle-stimulating hormone and human spermatogenesis.[J Clin Invest. 1981]
Stimulation of sperm production by human chorionic gonadotropin after prolonged
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Chronic human chorionic gonadotropin administration in normal men: evidence that
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spermatogenesis in man.[J Clin Endocrinol Metab. 1986]
Reinitiation of sperm production in gonadotropin-suppressed normal men by
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The relative roles of follicle-stimulating hormone and luteinizing hormone in maintaining
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Review Identification of specific sites of hormonal regulation in spermatogenesis in rats,
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FSH immunoneutralization acutely impairs spermatogonial development in normal adult
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Immunization of male bonnet monkeys (M. radiata) with a recombinant FSH receptor
preparation affects testicular function and fertility.[Endocrinology. 1997]
Specific immunoneutralization of FSH leads to apoptotic cell death of the pachytene
spermatocytes and spermatogonial cells in the rat.[Endocrinology. 1996]
Spermiation failure is a major contributor to early spermatogenic suppression caused by
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Review Identification of specific sites of hormonal regulation in spermatogenesis in rats,
monkeys, and man.[Recent Prog Horm Res. 2002]
Structure and control of a cell-cell adhesion complex associated with spermiation in rat
seminiferous epithelium.[J Androl. 2001]
Review Junction restructuring and spermatogenesis: the biology, regulation, and
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Review Sperm maturation in the epididymis: a new look at an old problem.[Asian J
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Androgen-regulated genes in the murine epididymis.[Biol Reprod. 2004]
The rat epididymal transcriptome: comparison of segmental gene expression in the rat
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Review Identification of epididymis-specific transcripts in the mouse and rat by
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Proteomic profiling of regionalized proteins in rat epididymis indicates consistency
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Epididymis-specific promoter-driven gene targeting: a transcription factor which
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Volume regulation of mature and immature spermatozoa in a primate model, and possible
ion channels involved.[Hum Reprod. 2004]
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Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in
normal men.[Fertil Steril. 1996]
Review Editorial: hormonal male contraception--lessons from the East when the Western
market fails.[J Clin Endocrinol Metab. 2003]
Factors in nonuniform induction of azoospermia by testosterone enanthate in normal
men. World Health Organization Task Force on Methods for the Regulation of Male
Fertility.[Fertil Steril. 1995]
Levonorgestrel implants enhanced the suppression of spermatogenesis by testosterone
implants: comparison between Chinese and non-Chinese men.[J Clin Endocrinol Metab.
2006]
Testosterone metabolic clearance and production rates determined by stable isotope
dilution/tandem mass spectrometry in normal men: influence of ethnicity and age.[J Clin
Endocrinol Metab. 2004]
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Contraceptive efficacy of testosterone-induced azoospermia in normal men. World
Health Organization Task Force on methods for the regulation of male fertility.[Lancet.
1990]
Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in
normal men.[Fertil Steril. 1996]
A multicenter contraceptive efficacy study of injectable testosterone undecanoate in
healthy Chinese men.[J Clin Endocrinol Metab. 2003]
Contraceptive efficacy of a depot progestin and androgen combination in men.[J Clin
Endocrinol Metab. 2003]
Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in
normal men.[Fertil Steril. 1996]
10th Summit Meeting consensus: recommendations for regulatory approval for hormonal
male contraception.[J Androl. 2007]

Contraceptive efficacy of testosterone-induced azoospermia in normal men. World
Health Organization Task Force on methods for the regulation of male fertility.[Lancet.
1990]

Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in
normal men.[Fertil Steril. 1996]

Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in
normal men.[Fertil Steril. 1996]
Testosterone enanthate at a dose of 200 mg/week decreases HDL-cholesterol levels in
healthy men.[Int J Androl. 1995]
Metabolic and behavioral effects of high-dose, exogenous testosterone in healthy men.[J
Clin Endocrinol Metab. 1994]
Testosterone dose-response relationships in healthy young men.[Am J Physiol Endocrinol
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Contraceptive steroids influence the hemostatic activation state in healthy men.[J Androl.
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Endogenous progesterone and the exogenous progestin norethisterone enanthate are
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Testosterone for male contraception during one year: attitudes, well-being and quality of
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Review Evidence for the acceptability of an injectable hormonal method for men.[Fam
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Plasma androgen levels in men after oral administration of testosterone or testosterone
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Intramuscular injection of testosterone undecanoate for the treatment of male
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An oral regimen of cyproterone acetate and testosterone undecanoate for spermatogenic
suppression in men.[Fertil Steril. 1997]
A clinical trial of injectable testosterone undecanoate as a potential male contraceptive in
normal Chinese men.[J Clin Endocrinol Metab. 1999]
Intramuscular testosterone undecanoate with or without oral levonorgestrel: a randomized
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Intramuscular testosterone undecanoate and norethisterone enanthate in a clinical trial for
male contraception.[J Clin Endocrinol Metab. 2001]
A multicenter contraceptive efficacy study of injectable testosterone undecanoate in
healthy Chinese men.[J Clin Endocrinol Metab. 2003]
The acceptability of an injectable, once-a-month male contraceptive in
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Transdermal testosterone therapy in the treatment of male hypogonadism.[J Clin
Endocrinol Metab. 1988]
Clinical trial of transdermal testosterone and oral levonorgestrel for male contraception.[J
Clin Endocrinol Metab. 1999]
Levonorgestrel implants (Norplant II) for male contraception clinical trials: combination
with transdermal and injectable testosterone.[J Clin Endocrinol Metab. 2002]
A novel male contraceptive pill-patch combination: oral desogestrel and transdermal
testosterone in the suppression of spermatogenesis in normal men.[J Clin Endocrinol
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AA2500 testosterone gel normalizes androgen levels in aging males with improvements
in body composition and sexual function.[J Clin Endocrinol Metab. 2003]
Pharmacokinetics of transdermal testosterone gel in hypogonadal men: application of gel
at one site versus four sites: a General Clinical Research Center Study.[J Clin Endocrinol
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Testosterone gel combined with depomedroxyprogesterone acetate is an effective male
hormonal contraceptive regimen and is not enhanced by the addition of a GnRH
antagonist.[J Clin Endocrinol Metab. 2006]
Norethisterone enanthate has neither a direct effect on the testis nor on the epididymis: a
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Current efforts to develop male hormonal contraception.[Stud Fam Plann. 1978]
Pregnancies associated with sperm concentrations below 10 million/ml in clinical studies
of a potential male contraceptive method, monthly depot medroxyprogesterone acetate
and testosterone esters.[Contraception. 1979]
Endogenous progesterone and the exogenous progestin norethisterone enanthate are
associated with a proinflammatory profile in healthy men.[J Clin Endocrinol Metab.
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Combined administration of levonorgestrel and testosterone induces more rapid and
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Intramuscular testosterone enanthate plus very low dosage oral levonorgestrel suppresses
spermatogenesis without causing weight gain in normal young men: a randomized
clinical trial.[J Androl. 2005]
A lower dosage levonorgestrel and testosterone combination effectively suppresses
spermatogenesis and circulating gonadotropin levels with fewer metabolic effects than
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Male hormonal contraception: suppression of spermatogenesis by injectable testosterone
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Desogestrel plus testosterone effectively suppresses spermatogenesis but also causes
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Investigation of hormonal male contraception in African men: suppression of
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A multicentre study investigating subcutaneous etonogestrel implants with injectable
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A combined regimen of cyproterone acetate and testosterone enanthate as a potentially
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Low dose of cyproterone acetate and testosterone enanthate for contraception in
men.[Hum Reprod. 1998]
An oral regimen of cyproterone acetate and testosterone undecanoate for spermatogenic
suppression in men.[Fertil Steril. 1997]
Twenty-one day administration of dienogest reversibly suppresses gonadotropins and
testosterone in normal men.[J Clin Endocrinol Metab. 2002]
Potential of norethisterone enanthate for male contraception: pharmacokinetics and
suppression of pituitary and gonadal function.[Clin Endocrinol (Oxf). 2000]
Intramuscular testosterone undecanoate and norethisterone enanthate in a clinical trial for
male contraception.[J Clin Endocrinol Metab. 2001]
Norethisterone enanthate plus testosterone undecanoate for male contraception: effects of
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Pharmacokinetics of testosterone undecanoate injected alone or in combination with
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An effective hormonal male contraceptive using testosterone undecanoate with oral or
injectable norethisterone preparations.[J Clin Endocrinol Metab. 2002]
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Contraceptive efficacy of a depot progestin and androgen combination in men.[J Clin
Endocrinol Metab. 2003]
Male hormonal contraception: effects of injections of testosterone undecanoate and depot
medroxyprogesterone acetate at eight-week intervals in chinese men.[J Clin Endocrinol
Metab. 2004]
Testosterone gel combined with depomedroxyprogesterone acetate is an effective male
hormonal contraceptive regimen and is not enhanced by the addition of a GnRH
antagonist.[J Clin Endocrinol Metab. 2006]
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10th Summit Meeting consensus: recommendations for regulatory approval for hormonal
male contraception.[J Androl. 2007]
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Depot gonadotropin-releasing hormone agonist blunts the androgen-induced suppression
of spermatogenesis in a clinical trial of male contraception.[J Clin Endocrinol Metab.
1992]
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Combined administration of a gonadotropin-releasing hormone antagonist and
testosterone in men induces reversible azoospermia without loss of libido.[J Clin
Endocrinol Metab. 1991]
Induction of azoospermia in normal men with combined Nal-Glu gonadotropin-releasing
hormone antagonist and testosterone enanthate.[J Clin Endocrinol Metab. 1992]
Comparison of a gonadotropin releasing-hormone antagonist plus testosterone (T) versus
T alone as potential male contraceptive regimens.[J Clin Endocrinol Metab. 1993]
Suppression of spermatogenesis in man induced by Nal-Glu gonadotropin releasing
hormone antagonist and testosterone enanthate (TE) is maintained by TE alone.[J Clin
Endocrinol Metab. 1998]
Suppression of spermatogenesis to azoospermia by combined administration of GnRH
antagonist and 19-nortestosterone cannot be maintained by this non-aromatizable
androgen alone.[Hum Reprod. 2001]
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The gonadotropin-releasing hormone antagonist abarelix depot versus luteinizing
hormone releasing hormone agonists leuprolide or goserelin: initial results of
endocrinological and biochemical efficacies in patients with prostate cancer.[J Urol.
2001]
A single dose of the potent gonadotropin-releasing hormone antagonist acyline
suppresses gonadotropins and testosterone for 2 weeks in healthy young men.[J Clin
Endocrinol Metab. 2004]
Testosterone gel combined with depomedroxyprogesterone acetate is an effective male
hormonal contraceptive regimen and is not enhanced by the addition of a GnRH
antagonist.[J Clin Endocrinol Metab. 2006]
Influence of surgical manipulation on prostate gene expression: implications for
molecular correlates of treatment effects and disease prognosis.[J Clin Oncol. 2006]
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Suppression of serum luteinizing hormone in postmenopausal women by an orally
administered nonpeptide antagonist of the gonadotropin-releasing hormone receptor
(NBI-42902).[J Clin Endocrinol Metab. 2006]
Efficacy and safety of histrelin subdermal implant in patients with advanced prostate
cancer.[J Urol. 2006]
Attitudes toward male fertility control: results of a multinational survey on four
continents.[Hum Reprod. 2005]
Liver damage from long-term methyltestosterone.[Lancet. 1977]
Important effect of food on the bioavailability of oral testosterone
undecanoate.[Pharmacotherapy. 2003]
Plasma androgen levels in men after oral administration of testosterone or testosterone
undecanoate.[Acta Endocrinol (Copenh). 1975]
Oral testosterone, a reappraisal.[Horm Res. 1978]
Therapeutic effectiveness of oral testosterone.[Lancet. 1974]
Oral testosterone in oil plus dutasteride in men: a pharmacokinetic study.[J Clin
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See more ...
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Dimethandrolone undecanoate: a new potent orally active androgen with progestational
activity.[Endocrinology. 2006]
Review Pharmacokinetics and pharmacodynamics of nonsteroidal androgen receptor
ligands.[Pharm Res. 2006]
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Rate, extent, and modifiers of spermatogenic recovery after hormonal male
contraception: an integrated analysis.[Lancet. 2006]
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Review Safety concerns and health benefits associated with oral contraception.[Am J
Obstet Gynecol. 2004]
Review Proof of the effect of testosterone on skeletal muscle.[J Endocrinol. 2001]
Long-term effect of testosterone therapy on bone mineral density in hypogonadal men.[J
Clin Endocrinol Metab. 1997]
Effects of testosterone replacement in hypogonadal men.[J Clin Endocrinol Metab. 2000]
The male contraceptive regimen of testosterone and levonorgestrel significantly increases
lean mass in healthy young men in 4 weeks, but attenuates a decrease in fat mass induced
by testosterone alone.[J Clin Endocrinol Metab. 2003]

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Contraceptive efficacy of testosterone-induced azoospermia and oligozoospermia in
normal men.[Fertil Steril. 1996]
Levonorgestrel implants (Norplant II) for male contraception clinical trials: combination
with transdermal and injectable testosterone.[J Clin Endocrinol Metab. 2002]
Combined administration of levonorgestrel and testosterone induces more rapid and
effective suppression of spermatogenesis than testosterone alone: a promising male
contraceptive approach.[J Clin Endocrinol Metab. 1996]

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

The male contraceptive regimen of testosterone and levonorgestrel significantly increases
lean mass in healthy young men in 4 weeks, but attenuates a decrease in fat mass induced
by testosterone alone.[J Clin Endocrinol Metab. 2003]
Intramuscular testosterone enanthate plus very low dosage oral levonorgestrel suppresses
spermatogenesis without causing weight gain in normal young men: a randomized
clinical trial.[J Androl. 2005]
A lower dosage levonorgestrel and testosterone combination effectively suppresses
spermatogenesis and circulating gonadotropin levels with fewer metabolic effects than
higher dosage combinations.[J Androl. 1999]
Desogestrel plus testosterone effectively suppresses spermatogenesis but also causes
modest weight gain and high-density lipoprotein suppression.[Fertil Steril. 2000]
The male contraceptive regimen of testosterone and levonorgestrel significantly increases
lean mass in healthy young men in 4 weeks, but attenuates a decrease in fat mass induced
by testosterone alone.[J Clin Endocrinol Metab. 2003]
Review Progestins and progesterone in hormone replacement therapy and the risk of
breast cancer.[J Steroid Biochem Mol Biol. 2005]
An effective hormonal male contraceptive using testosterone undecanoate with oral or
injectable norethisterone preparations.[J Clin Endocrinol Metab. 2002]
Desogestrel plus testosterone effectively suppresses spermatogenesis but also causes
modest weight gain and high-density lipoprotein suppression.[Fertil Steril. 2000]
Oral desogestrel with testosterone pellets induces consistent suppression of
spermatogenesis to azoospermia in both Caucasian and Chinese men.[Hum Reprod.
2002]
See more ...
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Review Progestins and progesterone in hormone replacement therapy and the risk of
breast cancer.[J Steroid Biochem Mol Biol. 2005]
Endogenous progesterone and the exogenous progestin norethisterone enanthate are
associated with a proinflammatory profile in healthy men.[J Clin Endocrinol Metab.
2005]
Serum testosterone and the risk of prostate cancer: potential implications for testosterone
therapy.[Cancer Epidemiol Biomarkers Prev. 2005]
Review Managing the risks of prostate disease during testosterone replacement therapy in
older men: recommendations for a standardized monitoring plan.[J Androl. 2003]
Occult prostate cancer in men with low serum testosterone levels.[JAMA. 1996]
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A multicenter contraceptive efficacy study of injectable testosterone undecanoate in
healthy Chinese men.[J Clin Endocrinol Metab. 2003]
Contraceptive efficacy of a depot progestin and androgen combination in men.[J Clin
Endocrinol Metab. 2003]
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Male hormonal contraception: effects of injections of testosterone undecanoate and depot
medroxyprogesterone acetate at eight-week intervals in chinese men.[J Clin Endocrinol
Metab. 2004]
A multicentre study investigating subcutaneous etonogestrel implants with injectable
testosterone decanoate as a potential long-acting male contraceptive.[Hum Reprod. 2006]
The effect of exogenous testosterone on total and free prostate specific antigen levels in
healthy young men.[J Urol. 1996]
Review Pharmacokinetics and pharmacodynamics of nonsteroidal androgen receptor
ligands.[Pharm Res. 2006]
Exogenous testosterone or testosterone with finasteride increases bone mineral density in
older men with low serum testosterone.[J Clin Endocrinol Metab. 2004]
Exogenous testosterone (T) alone or with finasteride increases physical performance, grip
strength, and lean body mass in older men with low serum T.[J Clin Endocrinol Metab.
2005]
The influence of finasteride on the development of prostate cancer.[N Engl J Med. 2003]
Direct effect of progestogen on gene expression in the testis during gonadotropin
withdrawal and early suppression of spermatogenesis.[J Clin Endocrinol Metab. 2006]
Comparison between testosterone enanthate-induced azoospermia and oligozoospermia
in a male contraceptive study. III. Higher 5 alpha-reductase activity in oligozoospermic
men administered supraphysiological doses of testosterone.[J Clin Endocrinol Metab.
1996]
Effects of testosterone plus medroxyprogesterone acetate on semen quality, reproductive
hormones, and germ cell populations in normal young men.[J Clin Endocrinol Metab.
2002]
Effects of testosterone and levonorgestrel combined with a 5alpha-reductase inhibitor or
gonadotropin-releasing hormone antagonist on spermatogenesis and intratesticular steroid
levels in normal men.[J Clin Endocrinol Metab. 2005]
Suppression of spermatogenesis with desogestrel and testosterone pellets is not enhanced
by addition of finasteride.[J Androl. 2001]
7alpha-methyl-19-nortestosterone (MENT): the optimal androgen for male contraception
and replacement therapy.[Int J Androl. 2000]
Prostate-sparing effects in primates of the potent androgen 7alpha-methyl-19nortestosterone: a potential alternative to testosterone for androgen replacement and male
contraception.[J Clin Endocrinol Metab. 1998]
Pharmacokinetics and pharmacodynamics of 7alpha-methyl-19-nortestosterone after
intramuscular administration in healthy men.[Hum Reprod. 1997]
Gonadotrophin and testosterone suppression by 7alpha-methyl-19-nortestosterone acetate
administered by subdermal implant to healthy men.[Hum Reprod. 1999]
A clinical trial of 7 alpha-methyl-19-nortestosterone implants for possible use as a longacting contraceptive for men.[J Clin Endocrinol Metab. 2003]
7alpha-methyl-19-nortestosterone (MENT) vs testosterone in combination with
etonogestrel implants for spermatogenic suppression in healthy men.[J Androl. 2007]
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Characterisation of the pharmacological profile of desoxymethyltestosterone (Madol), a
steroid misused for doping.[Toxicol Lett. 2007]
Tetrahydrogestrinone induces a genomic signature typical of a potent anabolic steroid.[J
Endocrinol. 2005]
Tetrahydrogestrinone is a potent androgen and progestin.[J Clin Endocrinol Metab. 2004]
Dimethandrolone undecanoate: a new potent orally active androgen with progestational
activity.[Endocrinology. 2006]
Review Pharmacokinetics and pharmacodynamics of nonsteroidal androgen receptor
ligands.[Pharm Res. 2006]
Pharmacological and x-ray structural characterization of a novel selective androgen
receptor modulator: potent hyperanabolic stimulation of skeletal muscle with
hypostimulation of prostate in rats.[Endocrinology. 2007]
An orally active selective androgen receptor modulator is efficacious on bone, muscle,
and sex function with reduced impact on prostate.[Endocrinology. 2007]
Novel series of potent, nonsteroidal, selective androgen receptor modulators based on
7H-[1,4]oxazino[3,2-g]quinolin-7-ones.[J Med Chem. 2007]
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Relationship between serum gonadotropins and spermatogenic suppression in men
undergoing steroidal contraceptive treatment.[J Clin Endocrinol Metab. 2004]
Daily testosterone and gonadotropin levels are similar in azoospermic and
nonazoospermic normal men administered weekly testosterone: implications for male
contraceptive development.[J Androl. 2001]
Comparison between testosterone enanthate-induced azoospermia and oligozoospermia
in a male contraceptive study. I: Plasma luteinizing hormone, follicle stimulating
hormone, testosterone, estradiol, and inhibin concentrations.[J Clin Endocrinol Metab.
1993]
Direct effect of progestogen on gene expression in the testis during gonadotropin
withdrawal and early suppression of spermatogenesis.[J Clin Endocrinol Metab. 2006]
Comparison between testosterone enanthate-induced azoospermia and oligozoospermia
in a male contraceptive study. III. Higher 5 alpha-reductase activity in oligozoospermic
men administered supraphysiological doses of testosterone.[J Clin Endocrinol Metab.
1996]
Effects of testosterone plus medroxyprogesterone acetate on semen quality, reproductive
hormones, and germ cell populations in normal young men.[J Clin Endocrinol Metab.
2002]
Effects of testosterone and levonorgestrel combined with a 5alpha-reductase inhibitor or
gonadotropin-releasing hormone antagonist on spermatogenesis and intratesticular steroid
levels in normal men.[J Clin Endocrinol Metab. 2005]
Suppression of spermatogenesis with desogestrel and testosterone pellets is not enhanced
by addition of finasteride.[J Androl. 2001]
See more ...
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A novel circulating hormone of testis origin in humans.[J Clin Endocrinol Metab. 2004]
The effects of gonadotropin suppression and selective replacement on insulin-like factor
3 secretion in normal adult men.[J Clin Endocrinol Metab. 2006]
Paracrine regulation of mammalian oocyte maturation and male germ cell survival.[Proc
Natl Acad Sci U S A. 2004]
Elevated end-of-treatment serum INSL3 is associated with failure to completely suppress
spermatogenesis in men receiving male hormonal contraception.[J Androl. 2007]
CAG repeat length in the androgen receptor gene and gonadotrophin suppression
influence the effectiveness of hormonal male contraception.[Clin Endocrinol (Oxf).
2002]
Pharmacogenetic polymorphisms of the AR and metabolism and susceptibility to
hormone-induced azoospermia.[J Clin Endocrinol Metab. 2001]
Clinical trial of gossypol as a male contraceptive drug. Part II. Hypokalemia study.[Fertil
Steril. 1987]
Clinical trial of gossypol as a male contraceptive drug. Part I. Efficacy study.[Fertil
Steril. 1987]
Recovery of sperm production following the cessation of gossypol treatment: a twocentre study in China.[Int J Androl. 1988]
Review Gossypol: reasons for its failure to be accepted as a safe, reversible male
antifertility drug.[Int J Androl. 1998]
Low dose gossypol for male contraception.[Asian J Androl. 2000]
Review Tripterygium wilfordii, a Chinese herb effective in male fertility
regulation.[Contraception. 1987]
Male antifertility compounds from Tripterygium wilfordii Hook f.[Contraception. 1993]
Long-term effects of triptolide on spermatogenesis, epididymal sperm function, and
fertility in male rats.[J Androl. 2000]
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Transient testicular warming enhances the suppressive effect of testosterone on
spermatogenesis in adult cynomolgus monkeys (Macaca fascicularis).[J Clin Endocrinol
Metab. 2006]
Mild testicular hyperthermia induces profound transitional spermatogenic suppression
through increased germ cell apoptosis in adult cynomolgus monkeys (Macaca
fascicularis).[J Androl. 2002]
Review Role of temperature in regulation of spermatogenesis and the use of heating as a
method for contraception.[Fertil Steril. 1988]
Single exposure to heat induces stage-specific germ cell apoptosis in rats: role of
intratesticular testosterone on stage specificity.[Endocrinology. 1999]
See more ...
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Development of l-CDB-4022 as a nonsteroidal male oral contraceptive: induction and
recovery from severe oligospermia in the adult male cynomolgus monkey (Macaca
fascicularis).[Endocrinology. 2007]
Acute adverse effects of the indenopyridine CDB-4022 on the ultrastructure of sertoli
cells, spermatocytes, and spermatids in rat testes: comparison to the known sertoli cell
toxicant Di-n-pentylphthalate (DPP).[J Androl. 2007]
Disruption of spermatogenesis and Sertoli cell structure and function by the
indenopyridine CDB-4022 in rats.[Biol Reprod. 2001]
The ability of a gonadotropin-releasing hormone antagonist, acyline, to prevent
irreversible infertility induced by the indenopyridine, CDB-4022, in adult male rats: the
role of testosterone.[Biol Reprod. 2004]
Reversible inhibition of spermatogenesis in rats using a new male contraceptive, 1-(2,4dichlorobenzyl)-indazole-3-carbohydrazide.[Biol Reprod. 2001]
Sertoli-germ cell adherens junction dynamics in the testis are regulated by RhoB GTPase
via the ROCK/LIMK signaling pathway.[Biol Reprod. 2003]
Adhering junction dynamics in the testis are regulated by an interplay of beta 1-integrin
and focal adhesion complex-associated proteins.[Endocrinology. 2003]
A male contraceptive targeting germ cell adhesion.[Nat Med. 2006]
Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and male
infertility.[Mol Cell Biol. 2004]
Review New approaches for male fertility control: HE6 as an example of a putative
target.[Mol Cell Endocrinol. 2006]
Review Epididymal secreted protein Crisp-1 and sperm function.[Mol Cell Endocrinol.
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Review Structure and function of epididymal protein cysteine-rich secretory protein1.[Asian J Androl. 2007]
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Review Moving to the beat: a review of mammalian sperm motility regulation.[Reprod
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Requirement of seminolipid in spermatogenesis revealed by UDP-galactose: Ceramide
galactosyltransferase-deficient mice.[J Biol Chem. 2000]
Complex gangliosides are essential in spermatogenesis of mice: possible roles in the
transport of testosterone.[Proc Natl Acad Sci U S A. 1998]
Mutation of beta-glucosidase 2 causes glycolipid storage disease and impaired male
fertility.[J Clin Invest. 2006]
Review The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the
management of type I (non-neuronopathic) Gaucher disease: a position statement.[J
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Sustained therapeutic effects of oral miglustat (Zavesca, N-butyldeoxynojirimycin, OGT
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A sperm ion channel required for sperm motility and male fertility.[Nature. 2001]
CatSperbeta, a novel transmembrane protein in the CatSper channel complex.[J Biol
Chem. 2007]
All four CatSper ion channel proteins are required for male fertility and sperm cell
hyperactivated motility.[Proc Natl Acad Sci U S A. 2007]
Physiological volume regulation by spermatozoa.[Mol Cell Endocrinol. 2006]
The role of potassium chloride cotransporters in murine and human sperm volume
regulation.[Biol Reprod. 2006]
Effects of the ion-channel blocker quinine on human sperm volume, kinematics and
mucus penetration, and the involvement of potassium channels.[Mol Hum Reprod. 2001]
Compartmentalization of a unique ADP/ATP carrier protein SFEC (Sperm Flagellar
Energy Carrier, AAC4) with glycolytic enzymes in the fibrous sheath of the human
sperm flagellar principal piece.[Dev Biol. 2007]
Glyceraldehyde 3-phosphate dehydrogenase-S, a sperm-specific glycolytic enzyme, is
required for sperm motility and male fertility.[Proc Natl Acad Sci U S A. 2004]
Human glyceraldehyde 3-phosphate dehydrogenase-2 gene is expressed specifically in
spermatogenic cells.[J Androl. 2000]
Soluble adenylyl cyclase as an evolutionarily conserved bicarbonate sensor.[Science.
2000]
Mice deficient for soluble adenylyl cyclase are infertile because of a severe spermmotility defect.[Proc Natl Acad Sci U S A. 2004]
Soluble adenylyl cyclase (sAC) is indispensable for sperm function and fertilization.[Dev
Biol. 2006]
The "soluble" adenylyl cyclase in sperm mediates multiple signaling events required for
fertilization.[Dev Cell. 2005]
A new sperm-specific Na+/H+ exchanger required for sperm motility and fertility.[Nat
Cell Biol. 2003]
A sperm-specific Na+/H+ exchanger (sNHE) is critical for expression and in vivo
bicarbonate regulation of the soluble adenylyl cyclase (sAC).[Proc Natl Acad Sci U S A.
2007]

The immunoglobulin superfamily protein Izumo is required for sperm to fuse with
eggs.[Nature. 2005]
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Phase I clinical trial of an injectable contraceptive for the male.[Contraception. 1993]
Phase II clinical trial of a vas deferens injectable contraceptive for the
male.[Contraception. 1997]
Studies on the membrane integrity of human sperm treated with a new injectable male
contraceptive.[Hum Reprod. 2004]
Biophysical mechanism-mediated time-dependent effect on sperm of human and monkey
vas implanted polyelectrolyte contraceptive.[Asian J Androl. 2007]
Quantitative analysis of surface micro-roughness alterations in human spermatozoa using
atomic force microscopy.[J Microsc. 2007]
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Review Antisperm immunity for contraception.[J Androl. 2006]
Reversible immunocontraception in male monkeys immunized with eppin.[Science.
2004]
Eppin: an effective target for male contraception.[Mol Cell Endocrinol. 2006]
Review Recent advances in contraceptive vaccine development: a mini-review.[Hum
Reprod. 2005]
Research into anti-fertility vaccine continues despite protests.[Lancet. 1998]
Review Development of male contraceptive vaccine--a perspective.[Hum Reprod Update.
1997]
Immunisation of male mice with a plasmid DNA vaccine encoding gonadotrophin
releasing hormone (GnRH-I) and T-helper epitopes suppresses fertility in vivo.[Vaccine.
2007]
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