Traditional Hormonal Therapies: Birth Control Pills and Progestin to Treat Fibroids

When most people think about drugs used for gynecologic purposes, they think first about birth control. High-dose combinations of estrogen and progestin are known as birth control pills (BCPs) or oral contraceptives (OCs). In practice, however, these pills are often also prescribed to provide hormonal therapy for diseases such as fibroids.

Birth control pills have very high levels of both special estrogens and progestins that allow them to be absorbed when taken by mouth. The first generation of OCs had very high hormone levels to prevent ovulation. The BCPs available today have lower hormone levels that often permit ovulation but maintain their contraceptive efficacy through multiple actions such as making the endometrium less hospitable for an embryo and making the cervical mucus thicker and less favorable for sperm transport. Even today’s “low-dose” pills have higher doses of steroid hormones than women normally produce in their body.

The chief advantage of oral contraceptives for fibroids is that they control bleeding in some women. It is not clear whether this therapeutic outcome results from controlling the effects of the fibroids or whether the hormones treat a second problem that leads to bleeding, particularly oligoovulation (failure to release an egg). Estrogen and progestin continuously given together like with OCs lead to a very thin but stable uterine lining. Any thickened endometrium is typically shed within 3 months, which is why most women who have abnormal bleeding see the bleeding resolve within the first three cycles of being on OCs. This is how birth control pills can help decrease the bleeding with fibroids, by thinning the lining.

Many textbooks still state that BCPs should not be used in women with fibroids because of concerns that their fibroids may grow. The high levels of steroid hormones do, in some women, cause the fibroids to grow. However, many women take BCPs for prolonged periods of time and do not seem to experience noticeable fibroid growth. In addition, several studies have suggested that BCPs decrease the chance of fibroids forming. However, one of the larger studies suggests that for very young women, age 16 and under, the exposure to OCs may paradoxically increase the risk of fibroids. 

Treating women with progesterone or a progestin is also a frequent practice in gynecology. Many progestins are chemically synthesized and have androgen or androgen-like actions (all steroid hormones are similar, and the modification of small parts of the molecule can give a steroid an action similar to that of another, normal hormone). Thus, many progestins are “keys” that fit both the progesterone and androgen “lock.”

Progesterone is normally secreted in the time between ovulation and the next period, which is referred to as a luteal or secretory phase. Thus, the side effects of progestins can be similar to those seen in premenstrual syndrome (in which symptoms occur in the luteal phase), with bloating, acne, weight gain, and increased appetite. Progestins can help control bleeding by helping organize endometrium that has been allowed to grow too thick because of oligoovulation.

It is controversial whether progesterone treatment alone is useful for the treatment of fibroids. Because there are so many different formulations of progestins, the type of compound and the way it is used are likely to determine, in part, whether it is effective. Some of the earliest studies done with fibroids suggest that high-dose proges-terone would cause the fibroid uterus to shrink. However, those studies were performed in the days before ultrasound, when obtaining objective information was difficult.  

Several different types of studies have suggested that progesterone may be as important in the control of fibroid growth as estrogen.

First, people have always correlated the states in which estrogen levels are high (e.g., pregnancy) with fibroid growth and states in which estrogen levels are low (e.g., menopause and following treatment with a gonadotropin-releasing hormone [GnRH] agonist) with fibroid shrinkage. This correlation has been extended to argue that estrogen is the important influence on fibroid behavior. However, progesterone levels generally follow estrogen levels in these states, so that progesterone is high during pregnancy and low following menopause and GnRH-agonist therapy.

Second, when GnRH agonists were first being used, the thought was that they could be combined with progestin treatment to provide some support for the woman’s bone density and protection against hot flashes and not cause regrowth of fibroids. However, studies then performed suggested that fibroids failed to shrink when progestin was administered with a GnRH agonist.

More recently, drugs whose primary mechanism of action is to block the action of progestins have been shown to be effective in decreasing fibroid symptoms. The most widely studied is the drug mifepristone (discussed in more detail here: Innovative medical strategies for treating uterine fibroids). Nonetheless, there are studies that suggest that women getting continuous progestin exposure for contraception (such as Depo-Provera) may actually have a decreased risk of fibroid formation. This has recently been confirmed in a large study of African American women. Finally, the use of Mirena, a progestin-containing intrauterine device (IUD), has been shown to substantially decrease bleeding in women with normal uteruses and women with fibroids. 

One of the issues that is not clear is whether the composition of the steroid hormones is the most important factor, or whether maintaining an acyclic environment (not having monthly menses) is what is important. In the normal menstrual cycle, the levels of estrogen and progesterone are actively changing at many points during the cycle. Oral contraceptive pills, particularly monophasic pills (meaning that every tablet contains the same composition of drug), keep the steroid hormone environment constant. Some people have hypothesized that this constant environment is one of the benefits of pregnancy. Even though the steroid hormone levels are high during pregnancy, they stay high throughout pregnancy and don’t have the constant monthly changes that occur when women are having regular menstrual cycles. Thus, although pregnancy, with high hormone levels, and GnRH-agonist treatment, with low hormone levels, initially seem to be at opposite ends of the hormonal spectrum, both can treat gynecologic diseases including fibroids because there is no constant hormonal cycling.

As noted earlier, some gynaecologists like to think about the acyclic environment very much like turning on and off a light bulb. If you keep flicking the switch back and forth rapidly, you are more likely to have a blown light bulb than if you keep it on and leave it on for hours, if not days. Thus, part of the problem with fibroids may be the constant switching back and forth. A stable environment may be the reason that all the different hormone environments (very low estrogen plus progesterone, high estrogen plus progesterone, and progesterone-dominant) work to decrease symptoms.