Hormonal Contraception

Mechanism of Action

The primary mechanism of action of hormonal contraceptives is that they suppress the secretion of gonadotropins (follicle stimulating hormone, FSH and luteinizing hormone, LH) by mimicking feedback inhibition (shown in the figure at right). Through various means of delivery (oral, depot injection, implant, transdermal), a woman receives a combination of estrogen and progesterone, or just progesterone by itself. Progesterone with estrogen naturally inhibits gonadotropin secretion as, for instance, during the luteal phase of the cycle. The goal is to suppress ovulation. The inhibition provided by hormonal contraceptives prevents the rise in FSH that is necessary to initiate the growth phase of follicle development and selection of a dominant follicle. This inhibition also prevents the LH surge that is necessary to trigger ovulation.

There are other ways that hormonal contraceptives interfere with conception. One important strategy is to interfere with the movement of sperm in the female reproductive tract. Sperm are deposited in the vagina and must traverse the cervix. In the follicular phase, estrogen promotes the production of thin, watery mucus by the cervical glands. By contrast, progesterone promotes secretion of thick cervical mucus, which acts as a barrier, and inhibits sperm movement past the cervix. This effect on the cervical mucus is particularly important for the efficacy of low-dose progesterone-only oral contraceptives, because the low dose of progesterone may not consistently suppress ovulation.

Types

Combination contraceptives

Combination contraceptives contain both an estrogen and a progestin (a drug that binds to progesterone receptors). In typical formulations, a pill is taken every day for three weeks, with one week of placebo pills.  During the week when she is taking the placebo pills, the woman experiences a withdrawal bleed. The withdrawal bleed serves as a convenient signal that the woman has not become pregnant, but it is not essential. There are also continuous-use oral contraceptives that eliminate the placebo pills.  Continuous-use contraceptive pills are designed for women who would like to have fewer menstrual periods because they suffer from menorrhagia (excessive menstrual bleeding) or dysmenorrhea (painful menstruation).

Because steroid hormones are nonpolar, they can be delivered topically. Combination contraceptives using this method of administration are a patch that is changed weekly, and a vaginal ring that is inserted and left in place for three weeks.

Progesterone-only contraceptives

There are several different types of contraceptives that use only progestins. The long-acting methods are useful in those women who don’t want to or can’t remember to take a pill every day. Another advantage to these methods is that the woman may have medical reasons to avoid exposure to increased levels of estrogen.

These are not as effective as combination contraceptives at preventing ovulation. Their effectiveness depends upon the ability of progesterone to alter the cervical mucus. It is very important for these pills to be taken at the same time each day, so that the plasma level of the progestin is sufficient to affect the cervical mucus.

Why would a woman opt for this method if it is less effective? This type of contraceptive is useful in women who need to avoid estrogen.  Also, low-dose progesterone only contraceptives are recommended for use in women who are lactating and don’t wish to become pregnant because high levels of estrogen and progesterone inhibit milk synthesis.

Long-acting progesterone-only contraceptives are the most effective methods of hormonal contraception. These methods include an implantable rod that releases a progestin (Nexplanon^®), an intrauterine device (IUD) that releases a progestin, and an injection (Depo-Provera^®) that is given once every 3 months.  The progestin diffuses out at a steady rate to prevent ovulation through negative feedback inhibition, and to prevent fertilization through changes to the cervical mucus.  Of these methods, the implantable rods and the IUD have greater contraceptive efficacy because once they are inserted they work effectively for several years without any other action required.  By contrast, the Depo-Provera shot requires that the woman get a shot every 3 months, and delays in getting the shot decrease contraceptive efficacy. 

A concern with the injection method, Depo-Provera, has been that it causes enough inhibition of estrogen production by the ovary to cause a decrease in bone density.  (Estrogen maintains bone density by preventing bone resorption through inhibition of osteoclasts.) However, the decrease in bone density is small, and appears to reverse after contraceptive use is discontinued. 

Emergency contraception

Emergency contraception is hormonal contraception that is used by a woman after she has had unprotected intercourse. Note the timing of events surrounding fertilization as depicted in the figure below. Because sperm are viable for several days, and because women can’t be sure of the exact timing of ovulation, it may be possible to prevent fertilization by a contraceptive method that blocks or delays ovulation.

The emergency contraceptive pill Plan B^® uses a higher dose of progestin (levonorgestrel) than found in typical oral contraceptives. It works by delaying or inhibiting ovulation via the same mechanism (feedback inhibition of gonadotropin secretion) as conventional hormonal contraception. In a study in which LH levels were measured (as a marker for ovulation), it was found that levonorgestrel emergency contraception only worked when taken before the LH surge. The figure at right shows the pattern of hormone secretion and indicates the start of the LH surge (red arrow).  Plan B is most effective when used within 12 hours of unprotected intercourse, but can be effective for up to 5 days (120 hours) following unprotected intercourse.

Another oral emergency contraceptive pill, ulipristal (marketed as ella^®) was approved in 2010. Ulipristal is classified as a selective progesterone receptor modulator. In the ovary, it acts as a progesterone antagonist that blocks progesterone action in the follicle. Note that there is a small increase in progesterone secretion induced by the LH surge, and it appears that this is necessary for ovulation to occur (blue arrow in figure). An advantage of ulipristal is that it is still effective at delaying ovulation even if it taken after the beginning of the LH surge.  Ulipristal is not effective if taken after the peak of the LH surge.

Progesterone is necessary to maintain the endometrium for implantation. Thus, it is theoretically possible that ulipristal may work to prevent pregnancy through post-fertilization mechanisms.  However, ulipristal used for emergency contraception is at a low dose that is not likely to affect the endometrium.  A study from 2019 concluded that ulipristal is unlikely to have any effect on implantation.

Risks

Many women use hormonal contraceptives without experiencing any adverse effects, while some experience minor adverse effects such as abnormal menstrual bleeding, or weight gain. Below, only the most serious adverse effects of hormonal contraceptives are considered, followed by a discussion of the various benefits of hormonal contraceptives.

Cardiovascular risks

Cardiovascular disorders comprise the most serious adverse effects associated with hormonal contraceptives. Although oral contraceptives increase the risk for certain cardiovascular disorders, these disorders are extremely rare among young women. A key thing to keep in mind is that pregnancy increases the risk for these cardiovascular disorders to a greater degree than hormonal contraceptives.

Hormonal contraceptives promote thrombosis (the formation of a blood clot).  The synthetic hormones in hormonal contraceptives have a variety of effects on the coagulation system that make the formation of a clot more likely. Clot formation in the venous system is known as venous thromboembolism (VTE), the most serious consequence being a pulmonary embolism. If a clot forms in the arterial system, it can lead to a myocardial infarction or stroke.  The increase in clotting is thought to be primarily an effect of estrogen.

Hormonal contraceptives increase the risk for venous thromboembolism. This increased risk was higher with the earliest formulations of contraceptives that used higher doses of estrogen. Current formulations of oral combination contraceptives increase the risk of VTE from 3-6 fold. This seems high, but it is important to note that the absolute risk of VTE among young, reproductive age women is only 1 in 10,000. Oral contraceptive use also increases the risk of myocardial infarction and stroke, particularly among older users who smoke.

Breast cancer

Because many breast tumors may have their growth stimulated by estrogen, it is reasonable to think that estrogen-containing contraceptives might increase the risk of breast cancer. Several large case-control studies have shown there is no increase in the risk of breast cancer among current and former users of combined contraceptives, however these studies focused on older women. There is evidence of an increased risk of breast cancer among young hormonal contraceptive users compared to young non-users. It is important to keep in mind that the number of young women who get breast cancer is very, very low—most breast cancers are diagnosed in post-menopausal women.

Benefits

The major benefit of hormonal contraceptives is reliable, reversible contraception. Hormonal contraceptives are the most effective methods of reversible contraception available to woman, being 97-99% effective if used properly. Furthermore, there are a number of non-contraceptive benefits associated with hormonal contraceptives.

Menstrual symptoms

Because hormonal contraceptives decrease endometrial proliferation, they are beneficial for women who suffer from menorrhagia or dysmenorrhea. They are particularly helpful for treating women with polycystic ovary syndrome who do not wish to conceive, because they reduce endometrial proliferation and normalize menstrual periods.

Endometrial cancer

Decreased endometrial proliferation probably also underlies the positive effect on rates of endometrial cancer. Hormonal contraceptive use decreases the risk of endometrial cancer, with longer duration of use causing a greater protective effect.

Ovarian cancer

Many studies have shown a decreased risk for the development of ovarian cancer among women who have ever used hormonal contraceptives. Like endometrial cancer, the reduction in risk is greatest for those women who have used hormonal contraception the longest. The hypothesis is that reduced risk is related to reducing the lifetime number of ovulations, since there is also a reduction in ovarian cancer risk associated with having been pregnant.

Androgen secretion

Hormonal contraceptives are used to treat hyperandrogenism because they decrease gonadotropin stimulation of androgen production by the ovary. Androgens may cause masculinization, and they also stimulate the production of sebum, which promotes acne. Randomized, placebo-controlled trials have shown that oral contraceptives are better than placebo at reducing the severity of acne.

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