Lectures
Lecture 1: Hormonal contraception
HORMONAL CONTRACEPTIVE
METHODS
Hormonal contraceptives are the most commonly used reversible means of
preventing pregnancy in the United States and consist of combined (estrogen
and progesterone) and progesterone-only methods. Currently, combined
hormonal methods are available in oral, transdermal, and vaginal forms,
whereas progesterone-only methods are available in oral, injectable,
implantable, and intrauterine forms. At this time, there are several hormonal
contraceptives in various stages of the FDA approval process in the United
States including new formulations for oral use, new subdermal implants and
vaginal delivery systems, self-injectables, and male hormonal methods.
COMBINED ESTROGEN AND PROGESTIN METHODS
Oral Contraceptive Pills (OCPs)
Method of Action
Oral contraceptive pills (OCPs) are composed of progesterone alone or a
combination of progesterone and estrogen. (The progesterone-alone pill is
described later in the progesterone-only section.) Over 150 million women
worldwide—including one-third of sexually active women in the United
States—use oral contraceptives.
Figure 24-9 • Serum levels of FSH and LH during a normal menstrual cycle.
Figure 24-10 • Serum levels of FSH and LH while taking monophasic oral
contraceptive pills.
Oral contraceptives place the body in a pseudo-pregnancy state by
interfering with the pulsatile release of follicle-stimulating hormone (FSH)
and luteinizing hormone (LH) from the anterior pituitary. This pseudopregnancy state suppresses ovulation and prevents pregnancy from
occurring. Figure 24-9 illustrates the serum levels of FSH and LH during the
normal menstrual cycle, and Figure 24-10 shows FSH and LH levels during
a cycle on the combination pill. Because the FSH and LH surges do not
occur, follicle growth, recruitment, and ovulation do not occur. The bleeding
that takes place during the hormone-free interval is actually a bleed due to
the withdrawal of hormone rather than a menstrual period induced by
endogenous hormone fluctuation.
Secondary mechanisms of action for OCPs include thickening the cervical
mucus to render it less penetrable by sperm and changing the endometrium
to make it unsuitable for implantation.
Monophasic (Fixed-Dose) Combination Pills
Monophasic combination pills contain a fixed dose of estrogen and a fixed
dose of progestin in each tablet. Nearly 30 combinations of estrogen and
progestins are available in the United States. In general, the selection of a
particular pill for each patient depends on the individual side effects and risk
factors for each patient. The combination pill containing both estrogen and
progestin is taken for the first 21 days out of a 28-day monthly cycle. During
the last 7 days of the cycle, a placebo pill or no pill is taken. Bleeding should
begin within 3 to 5 days of completion of the 21 days of hormones. Newer
formulations are now available that give 24 days of hormone (rather than the
traditional 21 days) and a 4-day hormone-free interval. So-called 24/4
regimens (i.e., Yaz and Loestrin 24 Fe) result in a shorter 3- to 4-day
menstrual cycle for most users.
Multiphasic (Dose Varying) Combination Pills
Multiphasic oral contraceptives differ from monophasic pills only in that
they vary the dosage of estrogen and/or progestin in the active hormone
pills in an effort to mimic the menstrual cycle. The advantage of the
multiphasic dosing is that it may provide a lower level of estrogen and
progestin overall but is still highly effective at preventing pregnancy.
TABLE 24-3 Interactions of Oral Contraceptives with Other
Medications That Reduce the Efficacy of Oral Contraceptives
Medications Whose Efficacies are Changed by Oral Contraceptives
Barbiturates Chlordiazepoxide (Librium)
Carbamazepine (Tegretol) Diazepam (Valium)
Griseofulvin Hypoglycemics
Phenytoin (Dilantin) Methyldopa
Rifampin Phenothiazides
St. John's wort Theophylline
Topiramate (Topamax) Tricyclic antidepressants
TABLE 24-4 Complications Associated with Oral Contraceptives
Cardiovascular*
Deep vein thrombosis (DVT)
Pulmonary embolism (PE)
Cerebrovascular accident (CVA)**
Myocardial infarction (MI)**
Hypertension
Other
Cholelithiasis
Cholecystitis
Benign liver adenomas (rare)
Cervical adenocarcinoma (rare)
Retinal thrombosis (rare)
* These complications occur mainly in smokers.
** Most MIs and CVAs occur in users of high-dose estrogen products.
Effectiveness
OCPs are remarkably effective in preventing pregnancy. In fact, the
theoretical failure rate for the first year of use is less than 1%. However, the
failure rate with actual real-life usage is closer to 8%. Nausea, breakthrough
bleeding, and the necessity of taking the pill every day are often cited as
reasons for discontinuing the pill. Several medications are thought to interact
with oral contraceptives and reduce the effectiveness of the pill. Conversely,
oral contraceptives can also reduce the efficacy of many medications (Table
24-3).
Side Effects
stroke, DVT, and PE if they use OCPs.
The progestins in oral contraceptives have been found to raise low-density
lipoproteins while lowering high-density lipoproteins in pill users smoking
more than 1 pack per day. For these reasons, oral contraceptives are
contraindicated in women over age 35 who smoke 15 or more cigarettes
a day. The advent of new progestins and lower estrogen doses has led to pill
formulations that are essentially neutral in terms of cardiovascular effect.
However, combination oral contraceptive use is still contraindicated in
women over age 35 who smoke. These women often benefit from
progesterone-only IUDs or permanent female or male sterilization.
Neoplastic complications of oral contraceptive use are rare. The effect of
long-term oral contraceptive use on breast cancer has been studied
extensively over the past decade Table 24-4 lists some of the cardiovascular,
neoplastic, and biliary complications associated with oral contraceptive
use.Oral contraceptives with estrogen doses greater than 50 mg can increase
coagulability, leading to higher rates of myocardial infarction, stroke,
thromboembolism, and pulmonary embolism, particularly in women who
smoke. Even at lower doses of estrogen (35 mcg or less), women over 35
who smoke more than one pack of cigarettes per day are still at increased
risk of heart attackwith no conclusive findings. There is, however, an
increased incidence of gallbladder disease and benign hepatic tumors
associated with oral contraceptive use.
Table 24-5 outlines both the absolute and relative contraindications to oral
contraceptive use.
TABLE 24-5 Contraindications to Combination Estrogen-Progesterone
Contraceptives
Absolute Contraindications
Thromboembolism
Pulmonary embolism
Coronary artery disease
Cerebrovascular accident
Smokers over the age of 35
Breast/endometrial cancer
Unexplained vaginal bleeding
Abnormal liver function
disease
Known or suspected pregnancy
Severe hypercholesterolemia
Severe hypertriglyceridemia
Relative Contraindications
Uterine fibroids
Lactation
Diabetes mellitus
Sickle-cell disease or sickle C disease
Hepatic disease
Hypertension
Lupus (SLE)
Age 40+ and high risk for vascular
Migraine headaches
Seizure disorders
Elective surgery
TABLE 24-6 Noncontraceptive Health Benefits of Oral Contraceptives
Decrease risk of serious diseases
Ovarian cancer
Endometrial cancer
Ectopic pregnancy (combination pills only)
Severe anemia
Pelvic inflammatory disease
Salpingitis
Improve quality-of-life problems
Iron-deficiency anemia
Dysmenorrhea
Functional ovarian cysts
Benign breast disease
Osteoporosis (increased bone density)
Rheumatoid arthritis
Treat/manage many disorders
Dysfunctional uterine bleeding
Control of bleeding in bleeding disorders and anovulation
Dysmenorrhea
Endometriosis
Acne/hirsutism
Premenstrual syndrome
Advantages/Disadvantages
The major advantages of OCPs include their extremely high efficacy rates
and the noncontraceptive health benefits primarily attributable to
decreased pregnancy, decreased menstrual flow, and decreased ovulation.
These benefits include a reduced incidence of ovarian cancer, endometrial
cancer, ectopic pregnancy, pelvic inflammatory disease (PID), and benign
breast disease (Table 24-6). By taking OCPs, nearly 50,000 women avoid
hospitalizations; of these, 10,000 avoid hospitalization for life-threatening
illnesses. Disadvantages include cardiovascular complications, increased
gallbladder disease, increased incidence of benign hepatic tumors, and the
need to take a medication every day Because they contain estrogen,
combination OCPs are not suitable for many women. Many women also
complain of nausea, headaches, breakthrough bleeding, and weight gain
associated with OCP use. Most of these symptoms are generally mild and
transient.
Transdermal Estrogen and Progestin Hormonal Contraception—Ortho
Evr
\
Mechanism of Action
The contraceptive patch (Fig. 24-11) with the brand name Ortho Evra
releases progestin and ethinyl estradiol. The patch releases 150 mg per
day of the progestin, norelgestromin, and 20 μg per day of ethinyl
estradiol. Although it is difficult to compare the estrogen levels in Ortho
Evra users to those in women taking standard OCPs, limited data suggests
that the overall average estrogen concentration is higher in Ortho Evra users.
Therefore, these patients should be made aware of the possible increased
risk of thromboembolism, specifically DVT and PE in Ortho Evra users.
There does not appear to be an increased risk of heart attack and stroke in
these patients.
Women apply one patch each week for 3 weeks followed by 1 week patchfree during which they will have a withdrawal bleed.
Effectiveness
The patch has been shown to have a 1% pregnancy rate in actual use—
similar to other combination hormonal methods. Ortho Evra has been found
to have a decreased effectiveness in markedly overweight women
(greater than 198 pounds or 90 kg).
Advantages/Disadvantages
The same primary side effects and noncontraceptive health benefits of OCPs
apply to the patch as well. The patch can cause skin irritation in some users.
The patch has the added benefit of being self-administered only once a
week.
Vaginal Estrogen and Progestin Hormonal Contraception-NuvaRing
Method of Action
The hormone-releasing vaginal ring (Fig. 24-11) with the brand name of
NuvaRing releases a daily dose of 15 mcg of ethinyl estradiol and 120 mcg
of etonogestrel (the active form of desogestrel). The ring is placed in the
vagina for 3 weeks (it is likely effective for 4 weeks), and is removed for 1
week to allow for a withdrawal bleed. Again, this hormone-free period can
be skipped to allow for continuous dosing, typically for 3 months.
Effectiveness
Clinical studies are ongoing, but the vaginal ring is highly effective (0.8%
failure rate in actual use), similar to other forms of combined hormonal
contraception.
Advantages/Disadvantages
Because one size of vaginal ring fits all women, the vaginal ring need does
not need to be fitted by a clinician. Women place the ring in the vagina
themselves for 3 continuous weeks and then remove it for 1 week. Because
the ring is left in place continuously it provides a low, steady release of
hormone with lower total hormone exposure compared to other combination
hormone methods. And, while douching with the NuvaRing in place is
discouraged, the use of antifungal agents and spermicides is permitted.
PROGESTERONE-ONLY CONTRACEPTION
Progesterone-only contraception consists of oral, injectable, implantable,
and intrauterine options. These all function primarily using the same
mechanisms: thickening the cervical mucus, inhibiting sperm motility, and
thinning the endometrial lining so that it is not suitable for implantation.
Progestin-Only Oral Contraception Pills (The Minipill)
Method of Action
Progestin-only pills (POPs; Micronor, Nor-QD) deliver a small daily dose
of progestin (0.35 mg norethindrone) without any estrogen. POPs have
lower progestin doses than combination pills, thus the nickname minipills.
POPs also differ from traditional pills in that they are taken every day of
the cycle with no hormone-free days. POPs are believed to thicken the
cervical mucus making it less permeable to sperm. This effect, however,
decreases after 22 hours so the minipill must be
taken at the same time each day. Other mechanisms of action include
endometrial atrophy and ovulation suppression (50% of cycles).
Effectiveness
Progestin-only pills are generally not as effective (failure rate of 8%) as
combination hormone regimens. This failure rate
increases if punctual dosing is not achieved.
Side Effects
Side effects of the progesterone-only OCP include irregular ovulatory
cycles, breakthrough bleeding, increased formation of follicular cysts, and
acne. POPs can also cause breast tenderness and irritability.
Advantages/Disadvantages
Because they contain no estrogen, progestin-only pills are ideal for nursing
mothers and women for whom estrogens are contraindicated including
women over 35 who smoke and women with hypertension, CAD, CVD,
lupus, migraines, and those with a personal history of thromboembolism.
The disadvantages include irregular menses ranging from amenorrhea to
irregular spotting. Also, POPs must be taken at the same time each day. A
delay of more than 3 hours is akin to a missed pill.
Injectable Progesterone-Only Contraception—Depo-Provera
Method of Action
Although it was only approved for contraceptive use in the United States in
1992, Depo-Provera (medroxyprogesterone acetate; DMPA) has been
used in other countries since the mid-1960s. Depo-Provera is injected
intramuscularly every 3 months in a vehicle that allows the slow release of
progestin over a 3-month period. Depo-Provera acts by suppressing
ovulation, thickening the cervical mucus, and making the endometrium
unsuitable for implantation. After an injection, ovulation does not occur for
14 weeks; therefore, patients have a 2-week grace period in their every 12week dosing.
Effectiveness
With a first-year failure rate of only 0.3% when used correctly, DepoProvera is one of the most effective contraceptive methods available. A
newer low-dose DMPA is also available although not widely used yet. This
formulation carries the benefit of lower progestin levels but the same
efficacy rates.
Side Effects
The primary side effects experienced by Depo-Provera users include
irregular menstrual bleeding, depression, weight gain, hair loss, and
headache. Over 70% of patients experience spotting and irregular menses
during the first year of use. Irregular bleeding is the primary reason for
discontinuing Depo-Provera. It is anticipated that 50% of DMPA users will
have amenorrhea after 1 year of use and 80% after 5 years of DMPA use.
However, the possibility of amenorrhea makes Depo-Provera a good option
for women with bleeding disorders, women on anticoagulation, women in
the military, and women who are mentally or physically disabled. Women
using DMPA for more than 2 years may experience a reversible decrease in
bone mineralization similar to that seen in lactating women.
Advantages/Disadvantages
The primary advantages of Depo-Provera are that it is highly effective, acts
independent of intercourse, and only requires injections every 3 months.
Like other progestins, Depo-Provera reduces the risk of endometrial
cancer and PID and also the amount of menstrual bleeding. It is also useful
in the treatment of menorrhagia, dysmenorrhea, endometriosis,
menstrualrelated anemia, and endometrial hyperplasia. DMPA is especially
useful in women who desire effective contraception but may have
concomitant medical conditions that prevent the use of estrogen-containing
contraceptives such as women with migraines, seizure disorders, lupus,
hypertension, coronary artery disease, and who smoke.
TABLE 24-7 The Effects of Depo-Provera Use on Bone Mineralization
Bone density is decreased in women using Depo-Provera
The decrease in bone density is most rapid in the first year of use
The decrease in bone density increases with length of use
The decrease in bone density is reversible and occurs over 6 mo to 2
years
There is no role for the use of bone density screening (DEXA) in DMPA
users
There is no role for the use of bisphosphonates, estrogens, SERMS in
DMPA users
Women on Depo-Provera should be encouraged to take calcium and
vitamin D, to stop smoking, and to do regular weight-bearing exercise
Irregular bleeding, weight gain, and mood changes are the major
disadvantages. Although not con-traindicated, Depo-Provera should be used
with caution in patients with a history of depression, mood disorders, PMS,
and PMDD. Similarly, Depo- Provera use is not contraindicated in obese
women but weight monitoring should be employed when using the medicine
in women who may be at increased risk for weight gain.
Implantable Progesterone-Only Contraception—Implanon
Method of Action
Implanon is a single-rod, progestin implant that provides 3 years of
uninterrupted contraceptive coverage. The progestin used in Implanon is
etonogestrel, the same progestin as used in the NuvaRing. The device
provides slow release of 68 mg of etonogestrel over 3 years. It is the size of
a matchstick and is placed in the subdermal skin of a woman's upper arm.
When appropriate timing of placement is utilized, Implanon is affective 24
hours after placement and has quick return to fertility once
the device is removed by a clinician.
Effectiveness
Implanon is highly effective with only a 0.4% failure rate.
Side Effects
Irregular and unpredictable light bleeding is the major side effect of
Implanon. In the majority of cases (75%), the bleeding is lighter than a
normal menstrual bleed and requires only a panty liner or less for protection.
However, irregular bleeding was the reason for 20% of discontinuations.
Advantages/Disadvantages
The major advantage of Implanon is that it is implantable and provides 3
uninterrupted years of contraceptive coverage. There is no maintenance
associated with the device and thus no interruption of sexual spontaneity.
The disadvantages include the need for a provider to insert and remove the
device and the unpredictable bleeding profile.