Description of the condition
Uterine fibroids are common, benign, smooth muscle tumours arising from the uterus. They are also known as leiomyomata or myomas. The prevalence of these tumours depends on the population’s ethnicity and method of detection. More than 80% of black women and nearly 70% of white women will develop fibroids before the age of 50 years (Baird 2003). These tumours, although benign, can cause significant distortion of the uterus and result in symptoms in up to 50% of women (Baird 2003). Fibroids are commonly associated with abnormal uterine bleeding, bulk symptoms (pelvic pressure, urinary dysfunction, constipation, pain) and reproductive dysfunction (subfertility, miscarriage, pregnancy complications) (Stovall 2001).
In the United States alone, the direct cost for treatment of fibroids is estimated to be over four billion dollars annually (Cardozo 2012). Treatment of fibroid-related symptoms can include surgery (hysterectomy, myomectomy, endometrial ablation, myolysis), minimally-invasive procedures (uterine artery embolization, magnetic resonance-guided focused ultrasound) or medical therapies (Wallach 2004). Despite these treatment options, hysterectomy is the second most frequently performed surgical procedure in the United States, with fibroids being the most common indication (Wallach 2004). This has contributed to significant surgical morbidity and escalating healthcare costs. As such, a focus on more conservative options is required.
Description of the intervention
Currently, there are no pharmacological agents approved specifically for the long-term treatment of uterine fibroids. The mainstay of medical management has been the use of gonadotropin-releasing hormone analogues (GnRHa) for pre-operative optimization by decreasing blood loss, correcting anaemia and reducing fibroid volume (Sabry 2012). However, the challenges with GnRHa therapy include decreased bone mineral density, vasomotor symptoms and an initial estrogen flare that may exacerbate symptoms. Although medical therapies such as combined hormonal contraceptives, oral progestins, progestin-releasing intrauterine systems and danazol may be used to decrease menstrual blood flow, their specific effects on fibroids and bulk symptoms are limited. They often cause side effects sufficient to discontinue use (Ke 2009; Sangkomkamhang 2013; Van Voorhis 2009).
Traditionally estrogen has been known to be the most important hormone in stimulating fibroid growth. More recently, progesterone has also been shown to be essential in the maintenance and growth of fibroids (Ishikawa 2010). For this reason, selective progesterone receptor modulators (SPRMs) have shown promise in the treatment of uterine fibroids (Chwalisz 2005). These molecules bind to the progesterone receptor and have varying levels of antagonistic activity. SPRMs were first discovered in 1980 and mifepristone, a powerful progesterone antagonist, was the pioneer drug. Its main use has been for pregnancy termination but it has also been evaluated as a therapeutic agent for fibroids. Meta-analysis of three randomized trials showed that mifepristone is effective in reducing bleeding symptoms and improving fibroid-related quality of life, without any effect on fibroid volume (Tristan 2012).
Other SPRMs have been subsequently developed, each with different affinity for the progesterone receptor and with varying amounts of antagonistic activity. The clinical activity of each SPRM class member reflects the subtlety of the SPRM’s spectrum of agonist and antagonist activity, along with the tissue specific expression of progesterone receptor (PR) subtypes. Asoprisnil, telapristone acetate and ulipristal acetate are SPRMs that have shown clinical effectiveness for fibroids (Donnez 2012; Sabry 2012; Wilkens 2008).
How the intervention might work
The ‘progesterone hypothesis’ suggests that progesterone is a key hormone in the development of fibroids, by increasing the mitotic rates and reducing apoptosis of fibroid smooth muscle cells (Rein 1995). Data also suggest signalling between estrogen and progesterone receptors, where estrogen induces increased expression of the progesterone receptor in fibroid cells (Ishikawa 2010). The importance of progesterone in fibroid pathogenesis supports SPRMs as effective treatment. Fibroid cells cultured with SPRMs demonstrate inhibited proliferation and increased apoptosis, without affecting normal myometrium (Bouchard 2011). SPRMs can also down-regulate the number of growth factors and reduce collagen synthesis in cultured fibroid cells (Bouchard 2011). SPRMs act upon the uterine endometrium to provide relief of bleeding symptoms in women with fibroids.
SPRMs may be used to treat fibroids in a number of clinical scenarios. Currently, the only SPRM approved for fibroids is ulipristal acetate (Esmya®, Gedeon-Richter, Europe February 2012; Fibristal®, Watson Laboratories Inc, Canada July 2013). It was approved to treat bleeding symptoms and decrease fibroid size for up to three months prior to surgical management. Future applications may include the use of SPRMs as a long-term medical treatment of fibroid-related symptoms. This would decrease surgical intervention and the associated morbidity and costs. Long-term medical therapy would be particularly beneficial in peri-menopausal women to bridge them until menopause, when fibroids would then spontaneously decrease. Although pregnancy is contraindicated with SPRMs, there is evidence that the decrease in fibroid size is sustained after the medication has been discontinued (Donnez 2012). This may have a potential impact on fibroid-related subfertility, where medical management may reduce fibroid volume and facilitate pregnancy after SPRM discontinuation.
Why it is important to do this review
Despite the prevalence of uterine fibroids, only few high quality studies examine the effectiveness of medical therapies. With an increasing demand for less invasive fibroid therapies, the benefits and risks of medical treatments must be critically evaluated. Furthermore, women are delaying child-bearing and hence there is a need for fertility sparing therapeutic options. There is both biochemical and clinical evidence that SPRMs may decrease fibroid growth and ameliorate symptoms (Chwalisz 2005). Although a Cochrane review on mifepristone has recently been completed (Tristan 2012), the newer SPRMs still require systematic evaluation of their benefits and harms.