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Uterine fibroids are almost always benign, but the debilitating symptoms experienced by an estimated 30% of women with fibroids can feel far from it. The nature and severity of fibroid symptoms depends on the size, and/or classification (submucosal, subserosal, intramural, or pedunculated) of the fibroids: common symptoms include abnormally heavy uterine bleeding, pelvic pain and bloating, abdominal pressure, urinary frequency, and constipation. A variety of surgical options are available to eliminate the tumors; for many women, however, the first step in addressing their condition is to seek relief of the symptoms through pharmacological treatments.

How Hormone Therapies Work

The majority of pharmacological products used to treat uterine fibroids do so by acting on the body’s hormonal balance. Research has shown that fibroid growth is fueled by hormones, specifically the hormones estrogen and progesterone. By directly or indirectly altering the levels of these hormones in the body, hormonal therapies can reduce the severity of fibroid symptoms like heavy bleeding and potentially shrink or inhibit the growth of fibroids. Approved hormonal therapies include GnRH agonists, oral contraceptives, progestins, aromatase inhibitors (AI), and other hormone-suppressing drugs like mifepristone.

Gonadotripin-releasing hormone agonists (GnRH-a) suppresses the body’s production of estrogen, creating a post-menopausal degree of estrogen deficiency. GnRH-a therapy has proven effective in both shrinking fibroids and managing symptoms like heavy bleeding. However, these effects are not sustained after discontinuing treatment. Use of GnRH agonists carries certain serious long-term health risks, including bone loss. Furthermore, because GnRH-a therapy essentially pushes the body into a menopausal state, women undergoing the treatment experience menopausal symptoms like hot flushes, vaginal dryness, weakness and fatigue, mood swings, and lowered libido. The negative effects of GnRH-a therapy can be countered by supplemental hormone treatments, but its associated health risks make GnRH agonists appropriate only for short term use, typically no longer than 6 months. Perhaps its most useful clinical application is rapidly shrinking large fibroids in preparation for surgical removal.

Oral contraceptives and progestins can be used for symptom relief, but their ability to reduce fibroid size is still uncertain. Studies have shown improvement in abnormal uterine bleeding with oral contraceptives. Drugs in this category, including lynestrenol, dienogest, and norethisterone, are considered relatively safe, and their low cost combined with potential benefit make them a promising choice for some women. However, women with pressure symptoms may not experience relief with oral contraceptives and progestins since they do little to shrink the fibroids or provide relief of bulk symptoms.

Aromatase inhibitors (AIs), part of a class of drugs known as anti-oestrogens, suppress the activity of the enzyme aromatase, which is responsible for the conversion of androgens into estrogens. Studies have suggested that use of AIs could inhibit fibroid growth and eliminate the need for surgery; however, further research has failed to provide sufficient evidence of this effect. Research surrounding the usefulness of AI’s in treating uterine fibroids continues, but in the meantime, the treatment is still considered experimental.

Mifepristone, a drug formerly known as RU486, belongs to a class of drugs known as progesterone receptor antagonists. As the category name implies, the drug acts on progesterone receptors. Mifepristone has proven effective in reducing uterine volume, thereby reducing blood loss and relieving related “bulk symptoms” like pelvic and lower back pain, abdominal pressure, and urinary frequency. The side effects of mifepristone are similar to GnRH-a therapy’s menopausal symptoms: hot flushes, mood swings, fatigue, and decreased libido are common, as well as headache, nausea, and diarrhea. In clinical trials, endometrial hyperplasia, a thickening of the uterine lining that creates a potential cancer risk, frequently resulted from mifepristone use. Due to a lack of data related to the safety outcomes of mifepristone use, the drug is not indicated for long-term use.

Comparing Pharmacological Treatment Options

How do these various hormonal therapies compare in terms of effectiveness? Comparative study data is still somewhat limited. One study compared the oral progestin lynestrenol with leuprolide, a GnRH agonist, and found no significant difference in their effectiveness for relieving pelvic pain and heavy bleeding. A separate, randomized clinical trial compared the GnRH agonist triptorelin with an aromatase inhibitor called letrozole, and revealed similarly significant decreases in fibroid volume (33% and 45%, respectively) with both therapies. In the latter study, however, none of the women treated with the aromatase inhibitor reported experiencing hot flushes, whereas 96% of the women taking a GnRH-a did. All of the approved hormonal therapies have shown some degree of effectiveness in treating fibroid-related symptoms; what determines their relative usefulness is predominantly the patient’s unique health history, as well as the nature and severity of each drug’s known side effects.

Limitations

While the available treatments vary in their mechanism for altering hormone levels, the hormonal therapies have a common limitation: they are not meant for long-term use. Clinical studies have consistently associated safety concerns with continued use of hormonal therapies in the treatment of fibroids. For many women, however, pharmacological treatments are an appropriate first step in addressing symptomatic fibroids. When symptoms persist and fibroids continue to impact a woman’s quality of life after trying a pharmacological treatment, a surgical approach would be an appropriate next step. For women concerned about the invasiveness of surgery, or the potential harm to the uterus that a procedure like hysterectomy entails, less invasive surgical options are worth consideration. Minimally invasive, uterine-sparing fibroid treatments like the Acessa Procedure offer a quicker recovery then major surgeries like hysterectomy, while providing the longstanding results that pharmacological therapies cannot.

 

SOURCES:
Levy, B. S. “Modern Management of Uterine Fibroids”, ACTA Obstetricia et Gynecologica, 2008, pp. 812-823

Song, H. et al. “Aromatase inhibitors for uterine fibroids”, Cochrane Database for Systematic Reviews/Cochrane Library, Oct 23, 2013. Web: http://onlinelibrary.wiley.com/enhanced/doi/10.1002/14651858.CD009505.pub2. Retr: Aug 1,2015

 

 

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If you’ve done a little homework on fibroid treatments or discussed treatment options with your gynecologist, you may have encountered the term “GnRH agonist”. Here’s what it is: GnRH stands for Gonadotrophin Releasing Hormone; it is a hormone that the body naturally produces and in women, it serves the function of stimulating egg production in the ovaries. The term “agonist” refers to a synthetic drug that simulates the body’s own, naturally produced material (or in this case, hormone).  Supplementing the body’s natural supply of GnRH with a GnRH agonist effectively inhibits the ovaries’ production of estrogen and testosterone, pushing the body into a menopausal state.

GnRH agonists have multiple uses in reproductive medicine, including treating pain associated with endometriosis and temporarily relieving symptoms of uterine fibroids. GnRH agonists can be used to treat heavy bleeding, one of the most common symptoms experienced by fibroid sufferers and women with endometriosis. In fact, for women taking GnRH agonists, bleeding tends to cease altogether, a condition known as amenorrhea. In this way, the treatment (also referred to as “GnRH analogue therapy”) helps to resolve anemia and a low blood cell count. When taken in advance of surgery, GnRH agonists can reduce the likelihood of a blood transfusion being required.

Furthermore, the drug’s significant effect on the growth of fibroids has been observed in many clinical studies. It’s not surprising: fibroids, benign uterine tumors, are estrogen-dependent. When estrogen levels in the body drop, fibroids shrink. By decreasing the body’s estrogen production, GnRH agonists—commercially available in such drugs as Lupron, Zoladex, Synarel, Buserelin, and Prostap—cause fibroids to shrink. Research indicates that continuous use of a GnRH agonist reduces fibroid size by approximately 50% after 3 months. Due to its fibroid-shrinking properties, GnRH agonists are commonly prescribed to women who are scheduled to undergo myomectomy; shrinking the fibroids in advance of the procedure minimizes the invasiveness of their extraction through laparoscopic surgery.

The most common symptoms experienced by patients undergoing the hormone-suppressing treatment are the symptoms typically associated with menopause: these can include hot flashes, vaginal dryness, moodiness or depression, headaches, and loss of bone density. “Add-back” hormone therapies (i.e. taking estrogen drugs) can usually provide some relief from these symptoms, without undermining the effectiveness of the primary therapy. No permanent side effects have been noted in human studies, though GnRH agonists are not indicated for long-term use. Studies have demonstrated the continuous use of a GnRH agonist, in conjunction with hormone add-back therapy to counteract bone density loss and other symptoms of estrogen deficiency, to be safe and effective for up to 2 years.

While the effects of taking a GnRH agonist may be profound, they are not permanent. Once the GnRH agonist is discontinued, estrogen levels start to return to the pretreatment state, reversing menopausal symptoms triggered by the treatment. In a study conducted by the research team of Rein et al., fibroid patients who were treated with a GnRH agonist became amenorrheic shortly after starting treatment. Four to ten weeks after discontinuing the treatment, the patients’ menses returned. The researchers also observed a rapid regrowth of fibroids once patients discontinued the GnRH agonist therapy. However, since fibroid patients GnRH agonists are most commonly prescribed in preparation for myomectomy, regrowth of fibroids following cessation of the drug is not a matter of concern.

 

SOURCES:

  1. Rein M. S. et al. “Fibroid and myometrial steroid receptors in women treated with gonadotropin-releasing hormone agonist leuprolide acetate” Fertility & Sterility. 1990; Vol. 53: pp.1018-1023
  2. American Society for Reproductive Medicine, “GnRH Agonist Therapy”, ReproductiveFacts.org: 2011. Retrieved July 10, 2015, from https://www.asrm.org/detail.aspx?id=1884
  3. Burbank, F. Fibroids, Menstruation, Childbirth, and Evolution, pp. 93-98. Wheatmark, 2009. Tucson, AZ.
  4. Friedman, A.J. et al. “Long-term medical therapy for leiomyomata uteri: a prospective, randomized study of leuprolide acetate depot plus either oestrogen-progestin or progestin add-back for 2 years”, Human Reproduction. 1994; Vol. 9: pp.1618-1625

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