Novel and Emerging Strategies
Selective Progesterone Receptor Modulators
The hormone progesterone is an important contributor to uterine fibroid development. Fibroids have higher levels of the progesterone receptor than the surrounding normal tissue, and inhibition of the progesterone receptor decreases fibroid growth in animal models. Drugs that are selective progesterone receptor modulators (SPRMs) include ulipristal acetate (Ella) and mifepristone (Mifeprex). They interfere with the progesterone receptor and are entering clinical practice for the treatment of uterine fibroids (Chwalisz 2005; Whitaker 2014; Donnez, Donnez 2014; Islam 2013).
Ulipristal acetate was approved by the FDA in 2010 as an emergency contraceptive (Kim 2011; Watson Pharma Inc. 2010). It has been approved in Europe (Esmya) and Canada (Fibristal) for pre-surgical medical treatment of uterine fibroids, to be used for no more than three months (Delev 2013; Health Canada 2014; Actavis 2013). In a trial comparing ulipristal acetate to placebo, the drug effectively controlled bleeding, shrank fibroids, and had a similar side effect profile to placebo (Donnez, Tatarchuk 2012). Another trial compared ulipristal acetate to the GnRH agonist leuprolide and found them similarly effective, though ulipristal acetate had a lower incidence of moderate-to-severe hot flashes (Donnez, Tomaszewski 2012). While it has not been approved for the treatment of fibroids in the United States, ulipristal acetate 5 mg is considered a new standard of medical treatment for uterine fibroids in regions where it is approved (Donnez, Donnez 2014; Whitaker 2014; Biglia 2014).
Mifepristone was approved by the FDA in 2000 for early termination of pregnancy up to day 49 after conception (Danco Laboratories 2009; Allen 2009). An open-label trial in 33 women with fibroids assessed the effects of a 3-month treatment with mifepristone, delivered as a vaginal suppository. Treatment was well tolerated, with no serious side effects, and resulted in a significant decrease in fibroid volume and bleeding as well as a significant increase in quality of life score (Yerushalmi 2014). However, an earlier review of three randomized controlled trials concluded that oral mifepristone did not decrease fibroid or uterine volume, but did decrease heavy menstrual bleeding and improve quality of life (Tristan 2012). Side effects of mifepristone may include hot flashes and changes in liver enzyme activity. Additional long-term, randomized trials are required to determine if oral or vaginally delivered mifepristone effectively treats uterine fibroids (Doherty 2014).
SPRM-Induced Endometrial Changes
The endometrium – the inner lining of the uterus – plays an important role in preparation for pregnancy. During a menstrual cycle, increased levels of estrogen cause the endometrium to thicken to allow a fertilized egg to become implanted. After ovulation, progesterone levels increase to further prepare the endometrium to receive the fertilized egg. If the egg does not become fertilized, estrogen and progesterone levels decrease, causing the endometrial lining to shed, which causes menstruation (ACOG 2012).
If estrogen levels increase or progesterone levels decrease, the endometrial lining may thicken without being shed. This is known as endometrial hyperplasia. Endometrial hyperplasia often occurs after menopause when progesterone levels decrease, or in situations that lead to increased estrogen levels, such as the use of medication that mimics estrogen or the administration of high-dose estrogen without progesterone after menopause (Figueroa-Casas 2001; Carlson 2012; ACOG 2012). If endometrial hyperplasia is not treated, endometrial cancer may develop in 8-29% of cases (ACS 2014b).
Early studies of SPRMs, particularly mifepristone, found they cause endometrial hyperplasia. However, additional studies determined this response is dose-dependent. Higher doses of mifepristone can induce hyperplasia, whereas lower doses cause endometrial changes that are reversible. Pathologists should be aware of endometrial changes that can occur with SPRM treatment and not misdiagnose these alterations as hyperplasia (Doherty 2014).
Fibroid tissue contains high levels of aromatase, the enzyme that converts testosterone into estrogen. Thus, blocking aromatase to reduce estrogen levels may be an effective treatment for uterine fibroids (Ishikawa 2009). The aromatase inhibitors letrozole (Femara) and anastrozole (Arimidex) are approved for the treatment of hormone receptor-positive breast cancer (Sanford 2008; Knoche 1999; Cohen 2002) and are currently being studied for the treatment of uterine fibroids (Khan 2014).
In a small study of 16 premenopausal women, letrozole decreased fibroid volume and improved heavy menstrual bleeding (Gurates 2008). Another study in 20 women showed similar effects (Hilario 2009). In a randomized study in 70 women, letrozole reduced fibroid volume by 45.6%, while the GnRH agonist triptorelin (Trelstar) decreased fibroid volume by 33.2% (Parsanezhad 2010). Anastrozole treatment in 20 women reduced fibroid volume by an average of 9.3% and reduced the amount of menstrual bleeding (Hilario 2009).
Aromatase inhibitors may promote the formation of ovarian cysts. One study in 16 patients reported that 56% of women developed ovarian cysts after letrozole treatment (Gurates 2008), though cyst formation can be prevented by co-treatment with estrogen, progesterone, or a GnRH agonist (Doherty 2014). An alternative method of aromatase inhibitor treatment may be low-dose letrozole; reductions in fibroid volume without hot flashes or ovarian cysts have been reported (Parsanezhad 2010; Doherty 2014). Additional studies are needed to determine if long-term, low-dose letrozole is safe for women with uterine fibroids (Islam 2013; Doherty 2014).
Growth Factor Inhibitors
Certain growth factors, which are a type of molecular cell messenger, promote the development of fibroids. Several inhibitors of growth factor signaling pathways have shown potential efficacy for the treatment of uterine fibroids in laboratory and case studies. However, these agents have not yet been adequately studied in clinical trials (Doherty 2014).
Insulin-like growth factor (IGF) signaling contributes to the initiation and progression of fibroid growth, and uterine fibroids have higher levels, compared to normal uterine tissue, of the receptors for IGF-1 and IGF-2. Lanreotide (Somatuline Depot) is a medication that blocks the release of growth factors such as IGF (Chanson 2008). A small study in seven women with fibroids reported that lanreotide reduced fibroid volume by an average of 42% over a 3-month period (Khan 2014). In December 2014 lanreotide was approved by the FDA for the treatment of certain gastroenteropancreatic neuroendocrine tumors; it had previously been approved for long-term treatment of acromegaly in patients who did not respond to, or were not candidates for, other types of treatment (FDA 2014c).
VizAblate and Acessa
The VizAblate and Acessa systems are new, noninvasive instruments that remove fibroids via ablation. The VizAblate device (Gynesonics, Inc.) combines real-time sonography to visualize the endometrial cavity with radiofrequencies to treat uterine fibroids in a single device. The instrument is inserted through the cervix, into the uterus, and allows the patient to be treated without incision or general anesthesia (Waltman 2011; Garza-Leal 2011). While the VizAblate device is not currently available as a treatment device in the United States, the results of an international multi-center 12-month study were published in late 2014. This study examined the use of VizAblate as a treatment for 50 women with symptomatic uterine fibroids: a total of 92 fibroids were treated. Three months after treatment, perfused fibroid volume decreased significantly, by an average of 68.8%; after six months, subjective symptom scores decreased by roughly 60%, while quality of life scores increased more than 2.5-fold compared to before treatment. Further results from this study showed that after 12 months there was a median 76% reduction in fibroid volume and a 73% median reduction in menstrual blood loss. The authors reported a good safety profile for the procedure (Gynesonics 2014a; Gynesonics 2014b; Reuters 2014a; Bongers 2014).
The Acessa system, which is available in the United States, also combines ultrasound visualization and radiofrequency ablation (Brucker 2014). Two ports are inserted surgically through the abdomen and into the uterus to locate and target fibroids (Guido 2013; Halt Medical Inc. 2014). A study compared Acessa to standard laparoscopic myomectomy in 51 women with fibroids. Acessa treatment resulted in a significant reduction in hospitalization time and blood loss, and a significant increase in the number of fibroids imaged and excised. Complications following the Acessa procedure were minimal. A 2014 paper presented the results of two phase II and one phase III multi-center trial of the Acessa system for the treatment of symptomatic uterine fibroids. Combined symptom severity scores decreased by nearly 84%, quality of life scores nearly doubled, and mean uterine volume decreased by 24%, all significant outcomes. The rate of side effects and complications was low, and four women became pregnant in the year following the procedure (Brucker 2014; Galen 2014).
Uterine Artery Embolization via Transradial Access
The standard uterine artery embolization (UAE) procedure uses arteries in the groin for treatment access, which can result in significant postsurgical pain (Resnick 2014). A 2014 publication reported a novel procedure using access sites in the wrist (“transradial”), similar to treatment procedures for heart conditions (Resnick 2014; Interventional News 2014). The new UAE technique was performed on 29 women, and the procedure was technically successful in all patients with no major or minor complications reported (Resnick 2014). UAE via transradial access reduces the incidence of pain and complications related to blood loss compared to conventional UAE technique. Patients are able to walk immediately after treatment. Additional studies are needed to validate the efficacy and safety of this procedure before it becomes widely available (Interventional News 2014).
Metformin Inhibits Uterine Fibroid Cell Growth
Due to its proven ability to regulate blood glucose levels, metformin is the most frequently used antidiabetic drug in the world (Li, Takeda 2013). Metformin also possesses other properties that may be beneficial for the treatment of uterine fibroids (Beck 2013; Luo 2010; Hawley 2002). In a laboratory study, scientists measured the rate of proliferation of uterine fibroid cells following exposure to metformin. They found that “Metformin potently inhibited [uterine fibroid cell] proliferation in a dose-dependent manner.” The researchers then analyzed the molecular mechanisms by which metformin exerted this powerful effect. Their investigation revealed that metformin’s mediation of cellular pathways involved in cell proliferation may account for the beneficial effect upon uterine fibroid cells (Li, Takeda 2013). Metformin is thought to retard the growth of various cancers by inhibiting a molecular pathway involved in cell survival, as well as through its ability to modulate insulin signaling (Beck 2013; Hawley 2002).