“Hormones for MEN”
→ Male Menopause
→ Andropause
→ PADAM Partial Androgen Deficiency Aging Men
Condition may affect millions, but symptoms are rarely recognized
Public awareness campaign launched to help them-SARCASM
2 page ad in Time. In last several years, lots of ads in Money, Forbes, and
various magazines.
“testosterone running on empty”
Video game at Endocrine Meeting since 2003- several drug Co many
marketing Test
Primary Care Journals
Doctors told screen symptoms ↓ T
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andropause
Symptoms, Causes & Treatments. Free Info on Erectile Dysfunction.
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“Hormones for MEN”
“testosterone running on empty”
Video game at Endocrine Meeting since 2003- several drug Co many
marketing Test
Primary Care Journals
Doctors told screen symptoms ↓ T
Ads paid by Unimed, a part of Belgian conglomerate
(Solvay)
Make Androgel – FDA approved In 2000
Fastest growing T replacement therapy for men
Pills (introduced in the 60’s) – often causes liver damage
IntraMus injection – sharp T spike then mall, mood swings,
libido, energy
Transdermal Patch (late 80’s) – still widely used. Safe
steady dose, skin irritation, falls off in exercise
Androgel – colorless drying gel rubbed on
shoulders 1x a day
Convenient to use in almost any man
If HRT for andropause common as menopause –
Which is the ambition of drug companies
DRAMATIC medical and financial consequences
Given popular desire to reverse human aging and
growing intimacy of commercial and clinical
concerns-trend may be irresistible (look up
Andropause on net----anti aging web sites)
Pharm. Company is “in the business of inventing
treatments”
how about diseases?
Dr. Abraham Morgentaler – urologist specializes in male
sexual dysfunction and infertility
Views T deficiency in older men as silent epidemic
5 million USA men affected and >95% not diagnosed
Replace T??
Restore youthful muscle tone, bone strength, potency,
vigor
AD in Boston Globe-have T tested-paid for by Unimed
Patient in office was getting T levels tested.
Doctor said several patients (professors)
“made their brains much sharper”
Need to make sure no prostate cancer –
highly aggravated by T
Six biopsies samples to check -PSA
(prostate specific antigen) blood test
Give you prescription now and you can start
once we complete tests
T-derived from cholesterol, primarily made in testes via pituitary signals
Men older than 40, decreased T by 1.2% per year
Patient 1 – little low, excited about T therapy
Patient 2 – said Primary care doc normal T 800 ng/dl
Morgantaler – T normal range
“free T” was another matter
Normally 2% free – not bound to other proteins & thus active
Patient’s free T little under lower limit (for normal men in mid 20’s)
Check PSA & start Androgel
FDA never approved Androgel for andropause.
Intended for use Klinfelter’s & pituitary dysfunction and
viral effected testes
Klinfelter’s - Congenital disorder in men,
have extra X and underdeveloped testes
Not many people with these or similar conditions
(pit or hypothamic), yet 35 million US men over
50 so if “andropause takes of”… billions $$$
ERT in menopausal women
> 2 billion year for Wyeth, for Premarin
Marketing & Medicine part ways
Big Pharmaceutical gets approval for drug of rare disease
to hopefully expand/profit later on
Drug approved – doctor can legally prescribe for any
clinical condition
FDA prohibits ads of “off label uses”-alternative strategies
Run an ad to “raise awareness” of condition
Align themselves with experts and “opinion leaders”
Finance Certain Research from MD’s
Offer them consulting opportunities
Endorsed by a major medical society
Endocrine Society 2000 – 1st Ann. Andropause Conference
Support by Medical Society Helps
Panel to define andropause and how it should be treated
Men over 50 should be screened & get T therapy if lower than 300
And no condition that would rule out therapy (Prostate
cancer)
}
NO STUDY TO SHOW BENEFIT OF T IN OLDER MEN
Panel predicted that
Low T found in more than 10% of males over 50
30% of males over 70
7 million MEN in USA
Unimed grant sole source of conference funding and recommended
panel members. 9 out 13 panelist had ties to drug company
BAD!!!!!!!!!!!!!!!!!!!!
“Bid to Medicalize Middle age may be supported by pharmaceutical
industry, but it remains poorly supported by scientific research”
Decline In T levels really responsible for most symptoms in aging
men???
What T levels normal???
Andropause exist???
Limits of our medical knowledge was evident from a visit to
Dr. William Crowley & Dr. Hayes
MGH measure hormone levels
Found Huge variability in T levels
Studied hypogonadalim and needed good
indication of normal T levels
Healthy Men in Early 20’s –drew blood every
10 min for 24hrs
15% below normal levels during day
> 50% below cutoff
T LEVELS REALLY VARY in healthy MEN
Efficiency of T receptors
(highly efficient, don’t need much T?)
- Stress decreases sex steroids
- Unsure of Variation in T levels, maybe
effected by drug interactions
T deficiency may be easily over diagnosed
because of variability
Don’t understand where # of 5 million
andropause men comes from
Commercial Tests physicians use
notoriously unreliable (300-900) with one
test and (160-700) on another
Test for free T even less accurate
Dr. Morgentaler says doesn’t matter – even
gives it as preventative treatment
No waiting for scientific validation
NIH “closest thing to independent scientific consensus” – says
Andropause UNPROVEN
Studies on increased lean muscle mass strength and bone mineral
density are small (40 men) and effects not dramatic
Largest & longest term study showed no improvements in Energy level,
sex performance, or strength
Uncertainty about effects on decreased T with age
UPDATE ON NOVEMBER 2006
NIH (NIA) is conducting a clinical trial to examine declining T levels in
men >65
• Expected Total Enrollment: 75
• Expected completion: February 2007
Approximately 20% of men over the age of 70 have low testosterone
levels. In some studies, testosterone replacement has resulted in
improvement in bone mass, muscle strength, quality of life and
memory function. In the body, testosterone is converted into estrogen.
Hence, it is unclear whether these beneficial effects are due to
testosterone or estrogen.
Side effects of T
gynecomastia (abnormal breast enlargement)
testicular shrinkage (gonads compensate by making less
hormone)
Also Increases circulating RBC and if excessive blood gets viscous and
can lead to congestive heart failure or stroke
Men 100 mg/day Androgel over a year
20% prostate disorder like prostatic hyperplasia
T really accelerates growth of Prostate Cancer
Most Men over 65 have clusters of cancer cells in prostate “occult” and
“indolent”
Hard to find, may not cause trouble
Here the perils are 2 fold
1-unnecessary biopsies lead to unnecessary surgery aimed at
eradicating cancer may have stayed inactive
2-biopsies can miss cancer that under T therapy will be more
aggressive and become dangerous
Safety issue – huge concern
NIH thinking of 6 yr study placebo controlled
Andropause driven by Pharmaceutical Co rather than physiology
Elevate T in 72 yr old man to levels he had at 20 – is this normal
Might be better to have lower levels with aging-protect against P
cancer
Cause epidemic of prostate cancer??
Conventional HRT in women increases risk of Breast Cancer,
heart attack, blood clots, and stroke
Nationwide trials were SHUT DOWN
26% increase in invasive Breast cancer
Nonetheless, T replacement increasingly popular
In 2001 sales transdermal T doubled
Well over ¼ million US Men use T
Rates Continue – 1 million within 2 years
Total sales of testosterone in the United States
were about $18 million until 1988; the figure rose
to $400 million in 2002
In 2004, the testosterone replacement market in
Europe and in the US was estimated to be
approximately $600 million. The US market is by
far the most attractive with a growth rate of 40%
(cash) and sales of $537million, of which $422
million were sales of testosterone gels
VAST UNCONTROLLED EXPERIMENT
APRIL 2010
global sales of testosterone therapies have
grown to more than $1 billion per year, with
sales of testosterone gels in the US comprising
$700 million.
Action of T on target cells
Hormone binds SHBG in circulation.
Sex hormone binding globulin
When free can diffuse across PM
Acted upon by 5a-reductase to make DHT
AR is in cytosol and bound to HSP
Displaced by DHT (DihydroT)
AR gets phosphorylated and forms a dimer
and translocated to the nucleus
Binds to promoters at AREs
(Androgen Response Elements)
Does Menopause exist?
Ovary is unique in that woman’s age at
which it ceases to function appear to have
remained constant despite our increased
longevity over last century
Loss of ovary function-profound impact on
hormonal milieu
Risks of disease due to decreased Estrogen
In males, germ cells become quiescent and
maintain stem cell identity
In females, all germ cells differentiate prior
to birth
90% of women experience menopause at 51.2
years. Remainder prior to age 46
Only 1% before the age of 40
Both genetic and environmental factors effect
decline in fertility and onset of M
M=ovarian aging supported by
Coincident occurrence of follicular depletion
Elevation of gonadotropins
Menstrual irregularity with ultimate cessation
Estrogens
Main estrogen during premenopause is 17b
estradiol. Controlled by developing follicle
and corpus luteam
95% derived from ovaries
Other sources
Peripheral conversion from T to estradiol
In post menopausal women-estrone
Biological potency 1/3 that of estradiol
Derived from peripheral conversion from
androstenedione.
Derived from peripheral conversion from
androstenedione.
AROMATASE
Extra glandular aromatase-fat, liver, some
nuclei in hypothalamus
Activity increases with age and amount of
FAT
Estrone and Estradiol
40ug/dl and 6 ug/dl post MEN
80-500 ug/dl in PreMEN
Nearly all Estrogen derived from ESTRONE
POST men
Menopausal consequences
1. Vasomoter symptoms (hot flash)
80% women have for at least a year
25% still have 5 yrs after last period
Correlate with pulses of LH
Likely some central mediator as LH does not
induce hot flash
Disturb REM sleep
Usually treated with estrogen
Menopausal consequences
2. Genital Atrophy
Vagina, vulva, urethra and bladder all have
estrogen receptors
No estrogen-atrophy
Itching and vaginal thinning
Dryness, painful intercourse
pH changes, different flora increase risk of
UT infections
Treatment-vaginal estrogen.
Menopausal consequences
3. Osteoporosis-condition in which bone loss
has been sufficient to allow mechanical
fracture with limited stress.
Menopausal bone loss begins before final
menstrual period
Post men osteoporosis accounts of 1.3
million fractures per year in USA
Most hip fractures (250,000) due to
osteoporosis
15% patients die within one year of hip
fracture and 75% lose independence
Menopausal consequences
3. OSTEOPOROSIS cont…..
Bone loss premen 1-2% year
Compared to 4% post men
Treatment –estrogen
Alternative therapies
Calcitonin-hormone made by thyroid gland
Effect in bone density in 12-18 months
SERMS-selective estrogen receptor
modulators
Calcium and Vitamin D
Discussion POINTS
Does Menopause exist? YOU BET
Women different then men (GERM CELLS)
Does andropause EXIST? Maybe not
How evil are drug companies?
How greedy are some doctors? (politicians)
vacation areas for conference
Consulting fees
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HOMOSEXUALITY
Proc Natl Acad Sci U S A. 2005 May 17;102(20):7356-61.
Brain response to putative pheromones in homosexual men.
Savic I, Berglund H, Lindstrom P.
Department of Clinical Neuroscience, Karolinska University Hospital, Stockholm,
Sweden.
The testosterone derivative 4,16-androstadien-3-one (AND) and the
estrogen-like steroid estra-1,3,5(10),16-tetraen-3-ol (EST) are candidate
compounds for human pheromones. AND is detected primarily in male
sweat, whereas EST has been found in female urine. In a previous study,
we found that smelling AND and EST activated regions covering sexually
dimorphic nuclei of the anterior hypothalamus, and that this activation was
differentiated with respect to sex and compound. In the present study, the
pattern of activation induced by AND and EST was compared among
homosexual men, heterosexual men, and heterosexual women. In contrast
to heterosexual men, and in congruence with heterosexual women,
homosexual men displayed hypothalamic activation in response to AND.
Maximal activation was observed in the medial preoptic area/anterior
hypothalamus, which, according to animal studies, is highly involved in
sexual behavior. As opposed to putative pheromones, common odors
were processed similarly in all three groups of subjects and engaged only
the olfactory brain. These findings show that our brain reacts differently to
the two putative pheromones compared with common odors, and suggest
a link between sexual orientation and hypothalamic neuronal processes.
• HOMOSEXUALITY
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J Genet. 2004 Dec;83(3):251.
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Excess of counterclockwise scalp hair-whorl rotation in homosexual men.
Klar AJ.
While most men prefer women as their sexual partners, some are
bisexual and others are homosexuals. It has been debated for a long
time whether a person's sexual preference is innate, learned, or due to
a combination of both causes. It was recently discovered that the
human right-versus-left-hand use preference and the direction of scalp
hair-whorl rotation develop from a common genetic mechanism. Such
a mechanism controls functional specialization of brain hemispheres.
Whether the same mechanism specifying mental makeup influences
sexual preference was determined here by comparing hair-whorl
rotation in groups enriched with homosexual men with that in males at
large. Only a minority of 8.2% (n = 207) unselected 'control' group of
males had counterclockwise rotation. In contrast, all three samples
enriched with homosexual men exhibited highly significant (P <
0.0001), 3.6-fold excess (29.8%, n = 272) counterclockwise rotation.
These results suggest that sexual preference may be influenced in a
significant proportion of homosexual men by a biological/genetic
factor that also controls direction of hair-whorl rotation.
• HOMOSEXUALITY-yes, it exists in NATURE
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J Exp Biol. 2005 Mar;208(Pt 5):891-8.
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Social experience and pheromonal perception can change male-male interactions in Drosophila
melanogaster.
Svetec N, Ferveur JF.
Social interaction with conspecifics can influence the
developing brain and behaviour of the exposed animal. This
experience can involve the exchange and retention of visual,
chemical, acoustic and tactile signals. When several Drosophila
melanogaster male flies are associated with mated females in
the presence of food, they show frequent aggressive
interactions. To measure the role of social experience on malemale interaction, two tester males - naive or exposed to
sibling(s) during a variable period of their adult development were confronted in the absence of female and food. The two
males displayed homosexual courtship and aggressive
behaviours, the frequency, intensity and directionality of which
varied according to their experience. The effect of social
experience was greatly enhanced between transgenic males
partially defective for pheromonal perception, indicating that
male inhibitory pheromones are normally used to repress malemale interaction.
• HOMOSEXUALITY-yes, it exists in NATURE
• Evolutionary Theories for HomosexualityBiological Structures and
Male Homosexuality
• Some of these examples of "homosexuality" in phylogenetically
distant animals may be analogous rather than homologous to
human homosexuality, but as we move closer to humans the
likelihood of homologous behaviors increases. In mammals many
different behaviors have been observed that might be associated
with male homosexuality. Among primates homosexual behaviors
are particularly diverse.
• These include such practices as the mounting of one male by
another (e.g. Langurs, pig-tailed macaques, baboons, orangutans,
chimpanzees, bonobos) (Sommer 1990; Oi 1991; Lorenz 1963;
Yamagiwa 1992; Hayaki et al. 1989), including mounting with anal
penetration (e.g. stumptailed macaques, squirrel monkeys)
(Sommer 1990; Maple 1977), and mounting with anal penetration
and ejaculation (Japanese macaques, rhesus macaques, gorillas)
(Sommer 1990; Gadpaille 1980; Edwards and Todd 1991).
• HOMOSEXUALITY-yes, it exists in NATURE
• Homosexuality is a common occurrence in humans and
other species, yet its genetic and evolutionary basis is
poorly understood. Here, we formulate and study a series
of simple mathematical models for the purpose of
predicting empirical patterns that can be used to determine
the form of selection that leads to polymorphism of genes
influencing homosexuality. Specifically, we develop theory
to make contrasting predictions about the genetic
characteristics of genes influencing homosexuality
including: (i) chromosomal location, (ii) dominance among
segregating alleles and (iii) effect sizes that distinguish
between the two major models for their polymorphism: the
overdominance and sexual antagonism models. We
conclude that the measurement of the genetic
characteristics of quantitative trait loci (QTLs) found in
genomic screens for genes influencing homosexuality can
be highly informative in resolving the form of natural
selection maintaining their polymorphism. Genetic models of
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homosexuality: generating testable predictions.
Gavrilets S,
Rice WR. PUBLISHED SEP 2006
• Biological versus nonbiological older brothers and
men's sexual orientation.
• Bogaert AF.
• The most consistent biodemographic correlate of sexual
orientation in men is the number of older brothers (fraternal
birth order). The mechanism underlying this effect remains
unknown. In this article, I provide a direct test pitting
prenatal against postnatal (e.g., social/rearing) mechanisms.
Four samples of homosexual and heterosexual men (total n
= 944), including one sample of men raised in nonbiological
and blended families (e.g., raised with half- or step-siblings
or as adoptees) were studied. Only biological older brothers,
and not any other sibling characteristic, including
nonbiological older brothers, predicted men's sexual
orientation, regardless of the amount of time reared with
these siblings. These results strongly suggest a prenatal
origin to the fraternal birth-order effect.
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• Homosexuality presents a paradox to evolutionary
theory.
If we grant that there could be such a thing as a gay
gene (or at least some kind of genetic basis to sexual
orientation), then how are we to explain the persistence
of a gay gene in the human population over time?
That is, if male homosexuality typically does not lead to
offspring, how do those gay genes survive from one
generation to the next?
This is not a new issue in evolutionary theory. Edward
O. Wilson deals with it in his 1975 text Sociobiology,
and as far back as the 1950s evolutionary theorists
have been offering explanations for the genetic
persistence of homosexuality.
Moreover, there are a number of other genetic attributes
that present the same paradox of persisting despite
their seeming mal-adaptivity (e.g., in developing
countries sickle cell anaemia usually kills its carriers
before they are able to reproduce, yet its frequency in
these populations remains high).
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Born gay? How biology may drive orientation
By Sandi Doughton
Seattle Times science reporter
As the culture wars rage over gay rights, a flock of sheep at
Oregon State University may help answer a key question behind
the controversy: Is homosexuality a matter of choice or biology?
• The Corvallis herd includes a group of rams that scientists
delicately refer to as "male-oriented." These animals consistently
ignore females and bestow all their amorous attentions on
members of their own sex.
• Researcher Charles Roselli says a decade of study suggests
sexual orientation is largely hard-wired into the sheep's brains
before birth. Now, he's trying to figure out how that happens,
zeroing in on genes and hormones. In a bold test of his ideas, he
hopes to engineer the birth of gay rams by altering conditions in
the womb.
• Sheep aren't people, but the Oregon work adds to a growing body
of research that bolsters biological explanations for sexual
orientation across species — including humans.
Impotence
physiological basis for control
of penile erection is not
totally understood. VIP has
been implicated as
mediator of penile erection
Is released when erection is
induced
Stimulate erection when
administered
VIP injected into penis
doesn’t work so not a good
treatment
Nitric oxide (NO) is an
important mediator of
erections. Viagra maintains
NO levels
• Erectile dysfunction, sometimes called "impotence," is the
repeated inability to get or keep an erection firm enough for
sexual intercourse. The word "impotence" may also be used to
describe other problems that interfere with sexual intercourse
and reproduction, such as lack of sexual desire and problems
with ejaculation or orgasm. ED indicates that other problems
are not involved.
• ED can be a total inability to achieve erection, an inconsistent
ability to do so, or a tendency to sustain only brief erections.
These variations make defining ED and estimating its incidence
difficult. Estimates range from 15 -30 million, depending on the
definition used. According to the National Ambulatory Medical Care
Survey (NAMCS), for every 1,000 men in the United States, 7.7 physician
office visits were made for ED in 1985. By 1999, that rate had nearly
tripled to 22.3. The increase happened gradually, presumably as
treatments such as vacuum devices and injectable drugs
became widely available and discussing ED became accepted.
The most publicized advance was the introduction of the
sildenafil citrate (Viagra) in March 1998. NAMCS data on new
drugs show an estimated 2.6 million mentions of Viagra at
physician office visits in 1999, and 1/3 of those mentions
occurred during visits for a diagnosis other than ED.
What causes ED?
an erection requires a precise sequence of events, ED can occur
when any of the events is disrupted. The sequence includes
nerve impulses in the brain, spinal column, and area around the
penis, and response in muscles, fibrous tissues, veins, and
arteries in and near the corpora cavernosa.
Damage to nerves, arteries, smooth muscles, and fibrous tissues,
often as a result of disease, is the most common cause of ED.
Diseases—such as diabetes, kidney disease, chronic
alcoholism, multiple sclerosis, atherosclerosis, vascular
disease, and neurologic disease—account for about 70% of ED
cases. Between 35- 50 % of men with diabetes experience ED.
• Also, surgery (especially radical prostate and bladder surgery
for cancer) can injure nerves and arteries near the penis,
causing ED. Injury to the penis, spinal cord, prostate, bladder,
and pelvis can lead to ED by harming nerves, smooth muscles,
arteries, and fibrous tissues of the corpora cavernosa.
• In addition, many common medicines—blood pressure drugs,
antihistamines, antidepressants, tranquilizers, appetite
suppressants, and cimetidine (an ulcer drug)—can produce ED
as a side effect.
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What causes ED?
• Experts believe that psychological
factors such as stress, anxiety,
guilt, depression, low self-esteem,
and fear of sexual failure cause 1020 %of ED cases. Men with a
physical cause for ED frequently
experience the same sort of
psychological reactions (stress,
anxiety, guilt, depression).
• Other possible causes are
smoking, which affects
blood flow in veins and
arteries, and hormonal
abnormalities, such as not
enough testosterone.
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John Rock’s error
Countdown to a baby
Stem cell article
Eyes wide shut article
Study guide on web, sex hormone lecture,
Hormones for Men, countdown to a baby,
and pineal gland lecture.