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Clinical Pharmacology at the Intersection of Women's Health and Regulation: Drug Development Considerations for Uterine Fibroids

Uterine fibroids (UFs) are a common gynecological disorder and one of the leading reasons for surgery or hospitalization in women of reproductive age, imposing a high health burden.1 Uterine fibroids are benign tumors but can lead to serious clinical manifestations such as severe pain, heavy menstrual and abnormal bleeding, pressure-associated urinary retention, constipation, infertility, and obstetric complications such as recurrent early pregnancy loss and preterm labor and delivery.2 Surgery is an elective option for the treatment of UFassociated symptoms.3 However, surgical procedures such as myomectomy and hysterectomy carry risks of complications, and hysterectomy is not an option for women who desire future pregnancies.4 Alternatives to surgical intervention such as uterine artery embolization and interventions performed under radiologic guidance are also available to treat uterine fibroids.5 However, the surgical and alternative interventions are not always suitable for the management of uterine fibroids and may present a high economic burden.5 Although specific pathogenetic mechanisms of uterine fibroids still remain unclear, it is well-known that ovarian steroid hormones, estrogen and progesterone, stimulate the growth of fibroids, and the most bothersome symptoms, pain and abnormal bleeding, are associated with menstrual periods.6,7 Therefore, medical management with pharmacotherapies that can modulate ovarian hormones during menstrual cycles offers an alternative for treating UF-associated symptoms.3 Long-term medical treatment may help to avoid surgical treatments and their complications and could be more cost-effective.5,8 Although combined oral contraceptives (COCs) and progestin-only products are commonly used as initial therapy for UF-associated pain as a short-term symptom control option, they are not approved by the U.S. Food and Drug Administration (FDA) for this purpose.9 Furthermore, hormonal therapy has limited efficacy in the management of pain and bleeding and provides minimal symptomatic relief for women who are affected by bulk symptoms, leaving fibroid volume and uterine size unchanged.3 Leuprolide acetate, a gonadotropin-releasing hormone (GnRH) agonist, is the first FDA-approved drug for preoperative hematologic improvement of patients with anemia caused by and a symptom associated with uterine fibroids.10 However, because of hypoestrogenic side effects such as significant bone mineral density (BMD) loss, hot flashes, and vaginal dryness, the use of leuprolide acetate is limited to 3 months or less.10,11 Because there were no pharmacological agents that were effective and approved for long-term therapy of uterine fibroids,4 considerable effort in recent years has been put on developing new drugs for the management of uterine fibroids and UF-associated symptoms. Diverse classes of investigational new drugs have been evaluated for the long-term treatment of UF-associated symptoms. Clinical trials and/or development programs of some investigational