Treatment of symptomatic uterine leiomyomas with selective progesterone receptor modulators

Keywords::

• medical therapy
• progestins
• selective progesterone receptor modulators
• uterine leiomyomas

Uterine leiomyomas, also known as fibroids, are benign tumors of both smooth muscle and connective tissue origin. They are the most common solid tumor of the female pelvis and occur in approximately 50–70% of all reproductive-aged women [1]. Risk factors for fibroids include race, with black women being at increased risk for fibroids, obesity and reduced parity [2]. Family clustering has also been demonstrated with a woman’s risk for fibroids being increased two- to six-times if she has an affected first-degree relative [3]. Although sometimes asymptomatic, fibroids may cause severe signs and symptoms such as menorrhagia, menometorrhagia, anemia, fatigue, abdomino–pelvic pain and pressure, and bowel and urinary symptoms [4]. Furthermore, fibroids can have an impact on fertility and cause complications in pregnancy. As a result of the signs and symptoms induced by fibroids, they can have a significant economic impact on an individual. The estimated combined direct medical care and indirect costs due to loss of work caused by symptomatic fibroids is US$4624 per individual per year [5].

Current approaches to the treatment of symptomatic fibroids

Signs and symptoms associated with fibroids are commonly treated with both medical and surgical interventions. In regards to surgical intervention, approximately 200,000 hysterectomies are performed each year in the USA for fibroid-related problems [6]. While both hysterectomy and myomectomy are effective treatments for fibroids, surgery is associated with significant costs and morbidity including blood loss, risk of transfusion, infection, induction of adhesions, chronic pain and injury to nearby organs. In addition, there is the potential need for cesarean delivery and further fibroid-directed treatment after myomectomy. Less invasive procedures such as uterine artery embolization and magnetic resonance-guided focused ultrasound are now more widely available and accepted by obstetrician–gynecologists, but are expensive and certainly not without risks and specific contraindications [7].

Pharmaceutical therapy offers the potential for a widely available, noninvasive, cost-effective treatment of symptomatic fibroids. Medical therapy has been used as a temporizing measure for women with symptomatic fibroids who are awaiting definitive surgical treatment, for women who are not good surgical candidates and for women who are perimenopausal. However, most patients who have menorrhagia or menometorrhagia as their primary fibroid-associated complaint are advised to try medical therapy as a ‘first-line’ approach. Many pharmaceutical agents have been used to reduce bleeding associated with fibroids including oral contraceptives, oral and parenteral progestins and progestin-containing intrauterine devices. Gonadotropin-releasing hormone (GnRH) agonists and GnRH antagonists not only reduce bleeding associated with fibroids, but can also reduce their size [8]. Furthermore, preliminary studies regarding the use of both aromatase inhibitors and selective estrogen receptor modulators have demonstrated that these agents may also both reduce the size of fibroids and alleviate their associated symptoms [9,10]. However, GnRH agonists, GnRH antagonists, aromatase inhibitors, and selective estrogen receptor modulators all cause vasomotor symptoms, and therefore are not good choices for single-agent therapy. Furthermore, GnRH agonists and antagonists, and aromatase inhibitors all reduce bone density, and are therefore not good long-term single-agent therapies for the treatment of fibroids.

Scientific plausibility for fibroid-associated selective progesterone receptor modulator therapy

Neither the etiology nor the pathophysiology of fibroids is completely understood. The basic pathological appearance of a bisected fibroid is one of concentrated areas of myometrial cells surrounded by a pattern of spiral or whorled collagenous bands. Most fibroids are thought to be clonal [11]. In other words, it appears that a genetic alteration in a single myometrial cell leads to rapid proliferation of that new cell type, and is the genesis of a fibroid. However, not all fibroids arise from the same genetic alteration. The cellular and extracellular proliferation and therefore growth of a fibroid is thought to be mediated by numerous factors [12]. Based on observations that fibroids are rarely present before puberty and tend to regress after menopause, it was deduced that gonadal steroids must play a role in the development or proliferation of fibroids. More recent research has shown that both estrogen and progesterone receptors are found in fibroids, and commonly at greater concentrations than in the surrounding myometrial cells [13,14]. Furthermore, it has been shown that the rate of growth of a fibroid is positively correlated with the concentration of both estrogen and progesterone receptors [15]. Therefore, it is certainly plausible that the administration of pharmaceutical agents that are either pure progesterone antagonists or selective progesterone receptor modulators to women with symptomatic fibroids may prove to be efficacious.

Patient selection for medical therapy

There are multiple issues to consider when deciding which patient with fibroids should be offered fibroid-directed medical therapy. First, not all uterine leiomyomas cause symptoms. Therefore, one could argue that medical therapy should only be considered for women who have symptomatic fibroids. Second, as women without fibroids can have many, if not all of the fibroid-associated symptoms including menorrhagia, menometorrhagia, pelvic pain, and urinary symptoms, how can one be sure that the patient’s fibroids are the cause of her problems? Furthermore, leiomyomas can undergo conversion to cancer, known as a leiomyosarcoma. Should this be a concern for medical therapy as a primary long-term treatment without assessment for cancer? Fortunately, conversion from leiomyoma to leiomyosarcoma in the uterus is very rare (0.1–1.7%), and therefore does not warrant myometrial biopsy prior to medical therapy, nor does this risk itself indicate the need for treatment of a fibroid.

In addition to the bothersome signs and symptoms, other variables for consideration in the selection of an appropriate candidate for fibroid-directed medical therapy are; the number, size and location of an individual’s fibroids. Although the majority of women with fibroids may be good candidates for medical therapy, based on these characteristics, the less commonly identified patient with a single solitary submucosal fibroid might be better treated with hysteroscopic myomectomy. Furthermore, one could argue that a patient with a single fibroid that can be removed with minimal morbidity via an outpatient laparoscopy, might be better served by that procedure as opposed to medical therapy. However, as fibroids are not commonly solitary, and very small myomas can be missed on ultrasound or other imaging modalities, most patients with symptomatic fibroids are likely to be good candidates for medical therapy. Nevertheless, the decision to offer or recommend medical therapy for the treatment of fibroid(s) is certainly one that is very much individualized as almost no two fibroid uteri are the same.

Progesterone antagonists and selective progesterone receptor modulators

Mifepristone

The progesterone receptor antagonist, mifepristone (RU-486) is well known for its use in the medical termination of pregnancy. Mifepristone binds to progesterone receptors with a high affinity, and it also binds to both the androgen and glucocorticoid receptors. Pure progesterone antagonists both inhibit progesterone receptor activation and reduce progesterone-associated target organ effects. Mifepristone has been shown to reduce the number of progesterone receptors in fibroids. In a few small randomized trials, mifepristone used at doses much lower (5–50 mg) than those used for pregnancy termination (200–800 mg) was administered to women with fibroids. These data demonstrated that treatment with mifepristone reduced fibroid size by up to 50%, and improved pressure, pain and bleeding symptoms, and induced a high rate of amenorrhea [16]. However, mifepristone increased the rate of simple endometrial hyperplasia which was identified in 28% of study participants. Other adverse events included vasomotor symptoms, but there were no changes in bone density in the study group.

Asoprisnil

The adverse event profile of mifepristone led to the synthesis of selective progesterone receptor modulators (SPRMs). One of the first was asoprisnil. Asoprisnil is a new SPRM with progesterone receptor agonist/antagonist properties, a lower level of glucocorticoid and estrogen receptor affinity as compared with mifepristone, and a marginal androgen receptor affinity [17,18]. Phase I studies with asoprisnil showed reversible suppression of menstruation and variable effects on ovulation. Phase II multicenter double-blinded randomized trials with asoprisnil demonstrated reduced fibroid size in a dose-dependent manner (5, 10 and 25 mg), and a similar effect on improvement with menorrhagia with a 28–83% amenorrhea rate [19]. A subsequent study with asoprisnil demonstrated a decrease uterine artery blood flow and a decrease in the largest leiomyoma volume up to 25.8% with the 25 mg dose [20].

Proellex^®

CDB-4124 (Proellex^®) was specifically developed for use as an antiprogestin in the treatment of uterine fibroids and endometriosis. It has been shown to be effective in decreasing uterine size, reducing pain associated with leiomyomas, and improving quality-of-life scores [21]. Furthermore, Luo et al. demonstrated that CDB 4124 selectively inhibits proliferation and induces apoptosis in cultured leiomyoma cells [22]. Subsequently, however, Roeder et al. showed that apoptosis was not the mechanism of action of CDB-4124, as cultured leiomyoma cells exposed to CDB-4124 failed to show elevated c-cap3 levels [23]. The US FDA placed a full clinical hold on CDB-4124 in August 2009 because of elevated liver enzymes associated with the drug use. The hold has since been reduced to partial clinical hold status in June 2010. The manufacturer, Repros Therapeutics, was allowed to conduct one clinical trial with low-dose Proellex designed to test the safety of the drug and efficacy of escalating doses.

Ulipristal

Similar to CDB-4124, CDB-2914 (ulipristal) was developed as a SPRM with pure progesterone receptor antagonistic activity. It has minimal antiglucocorticoid effects [24]. It was originally synthesized for emergency contraception. Since then, it has been under development for use in symptomatic fibroids. One randomized trial demonstrated that ulipristal decreased the volume of leiomyomas by 36 and 21% in those taking 10 and 20 mg of ulipristal, respectively, for up to 102 days of therapy. In this study, the placebo-controlled group had a 6% increase in leiomyoma size. As there was no evidence to suggest a decrease of leiomyoma size with increasing dose, the two treatment groups were combined and compared with those taking placebo. The result showed a significant decrease (p = 0.01) in the size of leiomyomas (29%) in the combined treatment groups as compared with those taking placebo [24]. A second randomized trial used changes in total fibroid volume as calculated by MRI as their primary outcome measure. This study demonstrated similar results to the previous trial with the placebo group showing a 7% increase in the total fibroid volume as compared with a 17 and 24% decrease in total fibroid volume in the group taking 10 and 20 mg of ulipristal for 12 weeks, respectively [25]. Ulipristal has also been shown to induce amenorrhea in 77% (20 out of 26) [25] and 57% (8 out of 14) of women on therapy in two separate trials [24]. Chabbert-Buffet et al. showed that not only did 5 and 10 mg doses of ulipristal induce amenorrhea in 81.8 and 80% of women, respectively, but it did not induce changes in GnRH levels and did not reduce serum estradiol levels below 50 pg/dl, levels necessary to maintain bone mineral density [26].

Conclusion

Uterine leiomyoma are a highly prevalent problem in women of reproductive age. Many women with uterine leiomyoma have severe symptoms and, therefore, uterine leiomyoma cause a significant clinical and economic burden and are a significant public health problem. Obstetrician–gynecologists have used surgical procedures to treat fibroids for many decades. Other less invasive procedures have been developed by interventional radiologists. Many medical therapies have been used to treat the heavy and irregular bleeding associated with fibroids. However, most of these therapies have little or no effect on the size of the fibroid(s) and do not reduce bulk-associated symptoms. Selective progesterone receptor modulators are a relatively new and innovative class of pharmaceutical agents that are being developed as an oral, daily medical therapy to treat fibroids. Data from Phase I and II trials have demonstrated that these agents have significant promise. To date, SPRMs have been shown to significantly reduce fibroid size and induce amenorrhea in more than half of the women treated. However, large Phase III trials of significant length are needed to better assess the long-term safety and efficacy of these agents. In regards to safety, the effects on endometrial stimulation, bone density, and liver toxicity will be of particular interest. Until then, clinicians will not have these agents as part of their armamentarium in the challenging treatment of uterine leiomyomas.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.