GnRH Agonists, Add-Back Therapies, and GnRH Antagonists Treatments for Fibroids

GnRH Agonists

Gonadotropin-releasing hormone (GnRH) agonists have been the mainstay of medical treatment for uterine fibroids.

As discussed in this article on the endocrinology of the uterus, the hourly pulses of the brain hormone GnRH are critical to normal reproductive function; without GnRH, the ovaries and uterus return to the state they were in before puberty. Interfering with the GnRH system shuts down the entire reproductive system, and this mechanism can be used to treat uterine fibroids.

GnRH agonists are the major class of drugs used in the treatment of fibroids and other gynecologic diseases, including endometriosis and polycystic ovaries. An agonist is a substance that acts like the hormone in question. Therefore, GnRH agonists (a key) bind to GnRH receptors (the lock) and act just like GnRH. The difference between GnRH and GnRH agonists is that the latter molecules have been engineered so that the body does not break them down quite as rapidly. Therefore, they are like long-acting GnRH, and their effect on the body is like having natural GnRH around for long periods of time without the critical pulses.

Thus, when a woman takes a GnRH agonist, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are initially stimulated, which leads to stimulation of estrogen and, in some cases, progesterone, which can lead to a “flare” in symptoms, especially bleeding. Fairly soon after, however, the system shuts down and the levels of LH, FSH, estrogen, and progesterone decrease to the levels that exist before puberty (the down-regulated phase). This is how GnRH agonists function to treat uterine fibroids.

This low-estrogen, low-progesterone state is often incorrectly termed a medical menopause. In menopause the levels of FSH and LH are high, whereas following GnRH-agonist treatment these hormone levels are low. We know that in most women menopause leads to shrinkage of the uterus and no menstrual periods. Therefore, the terminology is useful for indicating what happens, even though it may not accurately describe the hormonal patterns. The first report of using GnRH agonist to treat fibroids was in 1983, and there have been numerous studies since that time. Most women have a reduction in uterine volume between 30 and 60 percent with 3 to 6 months of therapy. Both the fibroid and the normal myometrium undergo shrinkage. Most women will also stop having periods, although some women will have a heavy bleed as the estrogen levels climb during the first, or flare, phase.

Considering this good response, why aren’t GnRH agonists more widely used for the treatment of fibroids? There are several reasons. First, these medications have significant side effects; for this reason, women do not want to take them for long periods. The side effects are exaggerated symptoms of menopause, including hot flashes, difficulty sleeping, muscle aches or pain, and changes in concentration and mood. Just as young women whose ovaries are surgically removed can often have more severe menopause symptoms than a woman who has been gradually transitioning over a number of years, side effects of GnRH-agonist treatment can be severe for some women.

Second, even if a woman tolerates these low-estrogen side effects, bone tissue cannot stay strong without estrogen. Like menopausal women, women undergoing long-term GnRH-agonist treatment tend to have accelerated bone loss that can lead to osteoporosis. Therefore, treatment is usually restricted to 6 months or less, or the bone density is actively monitored.

Third, there is no carry-over effect. After GnRH-agonist treatment is stopped, there is a rapid return of symptoms and a rebound of the uterus to its original size, or sometimes bigger. Therefore, unlike some medications, a short-term treatment will not give long-term results. Finally, the expense and inconvenience of long-term medical therapy limit its use.

For all these reasons, although GnRH agonists are very effective medications, they are used now only in preparation for surgery, as a temporizing agent for women with acute medical issues, or for women who are close to menopause.

Many formulations of GnRH agonist are available worldwide. The earliest forms of GnRH agonist were given as daily injections. Daily shots are almost never used for the treatment of fibroids, although they are still widely used as a part of infertility treatments. The daily treatment that is still used for fibroids is the nasal spray Synarel. Most women, however, use a long-acting form of the drug. In the United States, Lupron is available as both a 1-month and a 3-month Depo injection, and Zoladex is a 1-month and a 3-month injectable implant. The only medical therapy for fibroids approved by the Food and Drug Administration (FDA) involves the use of the GnRH agonist Lupron for the presurgical treatment of uterine fibroids to correct anemia in conjunction with iron administration (see this article on abdominal myomectomy).

Add-Back Therapies

Many strategies have been tried to extend the use of GnRH agonists to provide women with longer-term relief. These strategies are termed the add-back therapies. Additional drugs are added back to the GnRH agonist to give some relief of the hypoestrogenic (low-estrogen) symptoms without raising the level of hormones to the point where the fibroids regrow. The traditional add-backs have been low doses of estrogen or progestin (or both). It is important when evaluating the steroidal add-back regimens to pay attention to both the kind of hormone given and how it is given relative to the GnRH agonist.

The two most widely tested regimens involve adding back either medroxyprogesterone acetate (a synthetic progestin used widely in hormone therapy) or estrogen plus progestin combinations used in menopausal hormone therapy.

Originally it was thought that since estrogen was the important hormone for fibroids, simply using a progestin would be the perfect add-back. However, two early studies found that although women’s periods stopped with this regimen, the uterus did not shrink. This was the first time physicians began to wonder whether progestins played an important role in fibroids.

How the GnRH agonist is given in relationship to the add-back can also be important with steroid hormones. Add-back can be started at the same time as the GnRH agonist (this is called simultaneous administration), or the GnRH agonist can be started first; in that case, only after the low-estrogen or down-regulated state is reached are the steroid hormones added back (sequential administration), since these two steps happen in sequence.  For many disease processes, such as endometriosis and abnormal hair growth (hirsutism), simultaneous add-backs have been successful. To produce uterine shrinkage with fibroids, however, a sequential regimen, with progestin or estrogen-progestin regimens, is preferable.

The other important point regarding steroid hormone add-backs for fibroids is that they need to be low dose, such as those used for postmenopausal hormone replacement, rather than high dose, as in birth control pills. Although birth control add-back can work for diseases such as hirsutism, a lower level of steroid hormones is necessary for the treatment of fibroids. There are also preliminary results suggesting that using low-dose estradiol alone in a simultaneous add-back regimen can be potentially useful. 

Some studies are exploring the use of innovative steroidal compounds for add-back therapies. The selective estrogen receptor mod-ulators (SERMs) tamoxifen and raloxifene both appear to be very effective treatments for fibroids in animals.  However, in several small studies of humans, standard doses of SERMs have not been effective with GnRH agonists for the treatment of fibroids, although one study of a very high dose SERM showed some benefit.

Tibolone is used outside the United States as a single-agent medical therapy for hormone replacement, since it has both estrogen- and progesterone-like actions. It appears to result in less vaginal bleeding than ordinary estrogen-progestin hormone therapy both in the general postmenopausal population and specifically in women with uterine fibroids. Ipriflavone, which is a weak estrogen, and isoflavone (a phytoestrogen, one derived from plants, and an antioxidant) have also been used in women participating in a small study, with good results. In addition, researchers have experimented with adding compounds such as calcium to make strong bones.

GnRH Antagonists

GnRH antagonists are also effective treatments for uterine fibroids. These drugs bind to the GnRH receptor and lead the system to shut down without the flare effect seen with GnRH agonists. The first GnRH antagonists tended to have significant side effects, which made GnRH agonists better treatment options. However, several different formulations have been shown to provide effective treatment for uterine fibroids.  In addition to having no flare, the antagonists work more quickly (over days to weeks rather than months) to bring levels of estrogen and progesterone down to menopausal levels. GnRH antagonists are available in the United States, since they are FDA-approved for use in ovarian stimulation for women in in vitro fertilization (IVF) fertility procedures. However, the doses available for IVF are different from those tested with fibroids, and because the medications are packaged for use for only a few days at a time, they are difficult to use in treating fibroids.