Abstract
Uterine fibroids (UFs) are the most common non-malignant neoplasms affecting women of reproductive age. Some estimates suspect nearly 70–80% of all women will develop at least one fibroid during their lifetime [1]. Women suffering from UFs can present with heavy or prolonged vaginal bleeding, pain or pressure in pelvic region, dysmenorrhoea, dyspareunia, bladder problems, constipation, subfertility, and even loss of pregnancy [2]. Many women with fibroids experience heavy menstrual bleeding (HMB), thereby making them more prone to developing iron deficiency anaemia [3]. Many women suffering from severe symptomatic fibroids choose to have a hysterectomy, making it the second most commonly performed procedure in the United States [4]. Unfortunately the risks involved with surgery, in conjunction with the possibility of eradicating any hope of future pregnancies, make it a less favourable option for women. Thus understanding the pathogenesis behind fibroid formation is paramount for the development of novel therapeutic strategies.
3.1 Introduction
3.1.1 Uterine Fibroids
Uterine fibroids (UFs) are the most common non-malignant neoplasms affecting women of reproductive age. Some estimates suspect nearly 70–80% of all women will develop at least one fibroid during their lifetime [1]. Women suffering from UFs can present with heavy or prolonged vaginal bleeding, pain or pressure in pelvic region, dysmenorrhoea, dyspareunia, bladder problems, constipation, subfertility, and even loss of pregnancy [2]. Many women with fibroids experience heavy menstrual bleeding (HMB), thereby making them more prone to developing iron deficiency anaemia [3]. Many women suffering from severe symptomatic fibroids choose to have a hysterectomy, making it the second most commonly performed procedure in the United States [4]. Unfortunately the risks involved with surgery, in conjunction with the possibility of eradicating any hope of future pregnancies, make it a less favourable option for women. Thus understanding the pathogenesis behind fibroid formation is paramount for the development of novel therapeutic strategies.
3.1.2 Role of Female Sex Hormones
The current perspective on the development and maintenance of fibroids portrays a critical role of ovarian steroid hormones [5]. Fibroids have been shown to have an increased expression of oestrogen receptors (ERs) and progesterone receptors (PRs) when compared to adjacent tissue [6]. Interestingly, the female sex hormones oestrogen (E2) and progesterone (P4) have been implicated as having a critical role in the regulation of various pathways involved in fibroid growth and progression. Clinically, fibroids have been shown to increase in size during the first part of pregnancy, which is thought to be due to an increase in circulating E2 and P4 [7]. Conversely, fibroids are expected to shrink once patients become post-menopausal due to a decline in ovarian hormone production. Subsequently, common therapeutic approaches targeting hormonal regulation have become a prime focus of research efforts.
3.2 Pharmacologic Treatment
3.2.1 Role of Pharmacologic Treatment
Uterine fibroids are difficult to treat, as there is currently no long-term cure, barring surgical intervention. Primary treatment goals of non-surgical intervention include improvement of patients’ quality of life, a marked reduction in symptoms, and preservation of fertility. Many of these medical interventions exploit fibroid dependence on hormonal regulation. These therapies seek to alleviate symptoms until surgical intervention is necessary or there is a natural regression of fibroids.
3.2.2 Selective Progesterone Receptor Modulators (SPRMs)
Once the role of progesterone in promoting growth and maintenance of fibroids was established, therapeutic avenues emerged targeting progesterone and its respective receptors. Consequently, selective progesterone receptor modulators (SPRMs) were developed. SPRMs are a class of agents with mixed agonistic and antagonistic activities targeting tissue-specific progesterone receptors (PRs) [8]. Currently, the principal indication for SPRMs is emergency contraception and pregnancy termination [9]. Research avenues are, however, exploring the use of SPRMs in a multitude of other conditions such as UFs, endometriosis and breast cancer [10]. The number of drugs in this family has expanded considerably since the advent of mifepristone (RU-486) to include ulipristal acetate (UPA), asoprisnil, onapristone, lonaprisan, vilaprisan and telapristone. Five agents in particular – UPA, mifepristone, asoprisnil, vilaprisan and telapristone acetate – have shown the ability to reduce fibroid size and/or control uterine bleeding [11, 12].
3.2.2.1 Ulipristal Acetate (UPA)
Within the family of SPRMs, ulipristal has become the most promising agent for non-surgical management of UFs. UPA has already been approved for the management of UFs in Europe, Canada and several other countries. Recently, the pharmaceutical company Allergan announced that the US Food and Drug Administration (FDA) had accepted Allergan’s New Drug Application (NDA) for the use of UPA in the treatment of abnormal uterine bleeding in women with UFs. Excitingly, if approved, UPA will become the first oral agent to be FDA-approved for the treatment of UFs in the United States.
The European Medicines Agency (EMA) and Canada have approved the use of UPA in the management of fibroids. Meanwhile, in the United States, UPA is currently the only FDA-approved drug for emergency contraception, due to its ability to inhibit ovulation and its immediate effects on the endometrium preventing implantation.
To date, the only pharmacologic agent approved by the FDA for use in fibroids is leuprolide, a gonadotrophin-releasing hormone (GnRH) agonist. However, GnRH agonists come with adverse effects that are not present with UPA, such as vasomotor symptoms and loss of bone mineral density [13]. A randomized double-blind study published data citing that a daily dose of 5 or 10 mg of UPA was non-inferior to once-a-month leuprolide in symptomatic control of UFs and had better compliance [14].
UPA is a synthetic steroid with tissue-specific mixed agonistic and antagonistic activity targeting particularly the uterus, cervix, ovaries and hypothalamus [15]. At the molecular level, UPA has been shown to increase apoptosis, decrease proliferation, decrease angiogenesis and reduce collagen synthesis [13]. It does so by regulating several factors involved in molecular pathways including caspase 3, B-cell lymphoma 2 (BCL2), tumour necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), as well as many others [13, 16]. Additionally, UPA alters the ratio between two isoforms of the progesterone receptor, PR-A and PR-B, both of which have increased expression within fibroid tissue [13, 16]. Alteration of this ratio giving preference towards one isoform versus the other can lead to anti-proliferative and pro-apoptotic effects [16].
Fibroids contain large deposits of ECM which increase over time [11]. UPA shrinks extracellular matrix (ECM) volume by reducing collagen deposition within the fibroids [17]. One study found that UPA-treated fibroids had a decreased fraction of ECM volume when compared to untreated fibroids [18].
A pivotal series of well-designed trials called the PEARL studies (PEARL I/II/III/IV) demonstrated that UPA use resulted in significant control of symptomatic fibroids with rapid control of bleeding, thereby improving anaemia, and showed a reduction in fibroid volumes [14, 19]. It was shown that over 90% of patients experienced relief from uterine bleeding after 5–7 days of UPA use [14, 20]. Additionally, the PEARL III trial assessed the safety profile of UPA. The results showed that emergent adverse events occurred in 120 women (57.4%); however, only 8 women (3.8%) described severe adverse events such as headache (16.3%) and abdominal pain (5.3%) [14, 20].
Another important trial assessed long-term use of UPA by administering four 12-week treatment cycles of UPA 5 and 10 mg. The study found that long-term use was well tolerated by patients, with high compliance [21]. At the end of the treatment, patients reported better quality of life (QoL), decreased bleeding and pain, and no increase in fibroid size [21].
The safety profile after extended use of UPA was assessed by a study published in 2017 which showed that after extended repeats of 3 months of treatment with UPA 10 mg/day, there were no major adverse events to contraindicate its use [22]. Interestingly, in all trials involving UPA, patients did not experience fibroid regrowth after discontinuation of UPA, in contrast with GnRH agonists which have shown regrowth after cessation [14, 20, 21].
It is worth noting that UPA’s teratogenicity has not been assessed; however, it should be avoided in pregnant women as it is also used as an emergency contraceptive agent. Additionally, hormonal contraceptive options may interfere with UPA’s therapeutic effect; thus, it is suggested that patients use barrier methods for contraception as opposed to oral or injection methods.
Of note, there is concern about endometrial morphological change with SPRM use. This histologic change is known as progesterone receptor modulator-associated endometrial changes (PAECs). Fortunately, these changes have been proven to be benign and are reversible within a few weeks to 6 months after cessation of the agent [13, 15].
3.2.2.2 Mifepristone (RU-486)
Mifepristone (RU-486), considered the pioneer agent in the SPRM family, acts predominantly through almost pure antagonistic activity on PRs. It is currently used as an abortifacient. A large meta-analysis of mifepristone used to treat symptomatic fibroids found that a dose of 2.5 mg/day for 3–6 months improved fibroid-related quality of life and bleeding, and showed a reduction in fibroid volume [23]. Contrastingly, another systematic review found there was no reduction of fibroid volume after mifepristone use [19]. Several initial studies were discontinued after there was fear of endometrial hyperplasia; however, there has been a recent resurgence of studies focusing on mifepristone.
3.2.2.3 Telapristone Acetate
Telapristone acetate, also branded as Proellex, is a newer SPRM being evaluated for use in UFs and endometriosis. Unfortunately, phase III trials were terminated early due to safety concerns over significantly elevating liver enzyme levels [24]. At present, there is an ongoing phase II clinical trial started in 2014 aiming to evaluate both safety and efficacy of lower oral as well as vaginal doses of telapristone acetate.
3.2.2.4 Asoprisnil (J867)
Asoprisnil has been studied in the treatment of UFs, endometriosis, and dysfunctional uterine bleeding. A large study found that a 12-week regimen of asoprisnil resulted in a reduction in fibroid size and control of uterine bleeding [25]. However, further studies have been discontinued due to the agent failing a phase III trial showing unsafe changes in the endometrial lining [25].
3.2.2.5 Vilaprisan
Vilaprisan is a novel SPRM which recently passed a 12-week phase I clinical trial successfully, in which most of the women who took the medication, at a daily dose of 1–5 mg, reported absence of menstrual bleeding. These results supported the initiation of advanced clinical trials to evaluate vilaprisan in women with symptomatic UFs [26]
3.2.3 Gonadotrophin-Releasing Hormone Agonists
To date, leuprolide acetate, a GnRH agonist, is the only FDA-approved non-surgical treatment modality for uterine fibroids. Leuprolide targets the pituitary gland, down-regulating GnRH receptors by continuous stimulation. Leuprolide is an analogue and thus it has an initial ‘flare’ effect in which hormone levels rise before they are suppressed after continuous stimulation. The result is a decrease in follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and consequently suppression of ovarian steroid hormone production [27]. This creates an iatrogenic reversible menopause-like state. The downstream effect is a reduction in both bleeding and bulk-related symptoms, and a reduction in fibroid volume [27].
Unfortunately, GnRH analogues have a side-effect profile that includes hypo-oestrogenic symptoms such as hot flashes, vaginal dryness, headaches, and loss of bone mineral density [28]. Due to these adverse effects, therapy is limited to 6 months or less without the addition of add-back therapy [29]. Add-back therapy is an approach to alleviate hypo-oestrogenic side effects by concomitant use of a second agent. Hormonal regimens have explored the use of progestins, oestrogens, a combination of progestin/oestrogen, tibolone and raloxifene as add-back therapies [29]. Accordingly, alleviating hypo-oestrogenic symptoms through add-back therapy improves compliance to therapy.
However, in addition to the adverse effects from GnRH analogue therapy, fibroids regrow rapidly after discontinuing therapy [29]. Accordingly, leuprolide is only approved for preoperative shrinkage of fibroids rather than a long-term management option.
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