Uterine Fibroids and Progestogen Treatment: Lack of Evidence of Its Efficacy: A Review.

Traditionally, estrogen has been considered the major promoter of myoma growth, but the role of progesterone has become increasingly obvious over the years. Back in 1949, elevated mitotic activity was observed in uterine fibroids removed from women treated with 20 mg of progesterone daily for 1 to 6 months [ 19 ]. In the 1980s, higher mitotic activity was confirmed in myomas treated with medroxyprogesterone acetate (MPA) [ 20 ] and in those in the secretory phase compared to the proliferative phase [ 21 ]. During the early 1990s, Lamminen et al. showed that the proliferation index in fibroids from postmenopausal women receiving estrogen and progestin was higher than that in myomas removed from postmenopausal women given estrogen alone [ 22 ]. By the late 1990s, the crucial role of progesterone was abundantly clear. A number of studies reported greater expression of both progesterone receptor A (PR-A) and progesterone receptor B (PR-B) in leiomyoma tissue [ 23 , 24 ] than in adjacent normal myometrium. Moreover, higher proliferative activity, evidenced by proliferating cell nuclear antigen (PCNA) and the mitotic index, was encountered in leiomyomas during the luteal (secretory) phase [ 24 ] compared to the proliferative phase. During the last decade, Kim et al. proved that progesterone promotes growth of uterine fibroids by increasing proliferation, cellular hypertrophy and deposition of the extracellular matrix (ECM) [ 25 ]. In an extensive review, Moravek et al. concluded that progesterone and progestin play key roles in uterine fibroid growth [ 26 ]. Ishikawa et al. determined that estrogen alone is not an in vivo mitogen, but plays a permissive role, acting via the induction of PR expression and thereby allowing leiomyoma responsiveness to progesterone [ 27 , 28 ]. Concentrations of PR-A and PR-B proteins were also found to be higher in leiomyomas than in matched myometrium [ 29 ]. Kim and Sefton and Reis et al. described activation of signaling pathways in uterine fibroids by both estrogen and progesterone [ 30 , 31 ]. Progesterone is able to cause rapid membrane-initiated effects, independent of gene transcription, which alter the production of second messengers involved in cell signaling transduction pathways. The PI3K/AKT pathway is mediated by progesterone, which can quicky activate this pathway through its receptors. PTEN, on the other hand, should be considered a negative regulator of AKT [ 30 ]. Progesterone and growth factor signaling pathways are interconnected and govern numerous physiological processes, such as proliferation, apoptosis and differentiation ( Figure 2 ). As illustrated in Figure 2 , numerous autocrine and paracrine mechanisms are activated by ERα and PRs in leiomyoma cells, demonstrating the crucial role of progesterone and progestogens in the pathogenesis of uterine fibroids.

Back in the early 1960s, it was reported that 15 out of 16 patients with uterine myomas treated with a synthetic progestin (norethynodrel, 20 to 40 mg daily) showed significantly enlarged uterine myomas, which returned to pretreatment size after discontinuation of progestin therapy in 70% of cases [ 32 ]. Only one randomized clinical trial (RCT), comparing lynestrenol and GnRHagonist, was published by Verspyck et al. (2000). This study showed that there was a statistically significant reduction in mean uterine fibroid volume at 16 weeks in the leuprolin group (26.5 +/− 4.5%) compared to lynestrenol (7.3% +/− 5%). However, as pointed out by Sangkomkamhang et al., the quality of the study was very low. Indeed, the risk of bias was judged to be high due to many patients being lost to follow-up (up to 22.7% in the lynestrenol group vs. 9.3% in the leuprolin group) [ 33 ]. Other studies were performed in France with promegestrone (Surgestone ® ) [ 34 ] and nomegestrol acetate [ 35 ]. Neither was able to demonstrate any significant reduction in bleeding or myoma size in most cases. Indeed, no individual study has established that progestogens have a beneficial effect on the different pathogenetic mechanisms involved in fibroid related HMB. Moreover, Boyd and McCluggage described morphological changes induced by progestogens in myomas. They included small and/or large areas of infarct-type necrosis, with increased surrounding cellularity, mitotic activity, nuclear pyknosis, cytoplasmic eosinophilia, epithelioid morphology, stromal edema, hemorrhage myxoid changes and inflammatory infiltrates, including granulated lymphocytes. As stressed by the authors, pathologists should be aware of these progestogen-associated changes, since erroneous diagnoses of leiomyosarcoma or smooth muscle tumor of uncertain malignant potential cell (STUMP) may otherwise be reached [ 36 ]. Several clinical trials evaluating the association of GnRH agonist plus add-back therapy strongly suggested an important role for progesterone and progestogens in myoma growth. Friedman et al. demonstrated that there were no significant changes in myoma volume during cotreatment with GnRH agonist plus MPA, although a significant reduction was observed in patients treated with GnRH agonist alone (leuprolide) [ 37 ]. These authors concluded that MPA appears to inhibit the ability of GnRH agonist to shrink uterine myomas. In an RCT, Friedman et al. showed that high doses of norethindrone can reverse the effectiveness of GnRH agonist induced myoma shrinkage in a dose-dependent manner [ 38 ]. In another RCT, Carr et al. compared the effectiveness of administering MPA (20 mg/day) along with GnRH agonist (leuprolide acetate 1 mg/day subcutaneously) [ 39 ]. Total uterine volume, as determined by magnetic resonance imaging, decreased to 73% of the baseline at 12 weeks ( p < 0.04) in the group treated with GnRH agonist alone, but did not change in the group treated with GnRH agonist plus MPA. Once again, the effectiveness of GnRH agonist was reversed by a high dose of progestin administration (MPA 20 mg/day). In 1999, the add-back consensus working group recommended use of appropriate add-back therapy with GnRH agonist treatment to improve the hypoestrogenic symptoms and potentially extend the duration of therapy while preserving therapeutic efficacy [ 40 ]. Based on results from RCTs in women with endometriosis, the progestin norethindrone acetate (NETA), known as norethisterone acetate in Europe, was approved by the Food and Drug Administration at a daily dose of 5 mg, combined with synthetic GnRH agonist (leuprolide acetate), as add-back therapy in women with endometriosis [ 41 ]. The ESHRE guidelines stated that progestogen only as an add-back therapy does not preserve bone mineral density (BMD) [ 42 ]. Chwalisz et al. believed that the inconsistent results obtained in some studies are due to confusion and the multitude of add-back regimens evaluated to date [ 41 ]. It should nevertheless be stressed that in vivo, NETA exhibits strong tissue-specific progestogenic, estrogenic or antiestrogenic and androgenic effects and the mean conversion ratio by aromatization of NETA to ethynyl estradiol is 0.7% to 1% at doses of 5 mg NETA [ 43 ]. According to Chwalisz et al., the estrogenic activity of NETA may explain its favorable impact on BMD [ 41 ]. However, endometriosis and uterine fibroids are different diseases. Hence, the optimal dose for each indication should be determined. It is recommended to use the minimal dose of progestogens (combined with 1 mg E2) to reach the primary endpoint (decrease in fibroids, HMB or both), while preventing BMD loss. Having clearly demonstrated the clinical evidence in women of reproductive age, it is also logical to pursue additional investigations into the action of progestogens in postmenopausal women treated with estrogens and progestogens. Indeed, in postmenopausal women with uterine leiomyomas given 2 mg/day of micronized E2, significant changes in mean uterine leiomyoma size were detected in the group treated with 5 MPA mg daily vs. 2.5 mg, revealing the dose-dependent impact of progestogens on fibroid growth. Based on their studies, Palomba et al. and Sener et al. strongly advocated evaluation of different doses of MPA in order to administer the smallest effective dose of progestin during hormone replacement therapy to minimize the risk of fibroid growth [ 44 , 45 ]. Moro et al. reviewed 17 papers (1122 participants) to assess and ascertain the effects of hormone replacement therapy on leiomyoma development and growth in post-menopausal women [ 46 ]. They reported that some combinations of estrogen and progestins resulted in a significant increase in fibroid size in relation to the dose of progestin compounds [ 45 , 47 , 48 ]. These studies also confirm the pivotal role of progesterone and progestogens in leiomyoma growth. Mifepristone is an antiprogesterone that acts through the inhibition of PRs. Daily administration of 5 and 10 mg of mifepristone yielded uterine volume reduction of 48% after 6 months and 52% after one year [ 49 ]. By modulating the progesterone pathway, SPRMs may exert either an agonistic or antagonistic effect on PRs [ 30 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. Their binding allows these receptors to interact with coactivators and/or corepressors. This is further impacted by the presence of coregulators in a particular cell type, which will dictate whether an SPRM acts more as an agonist or antagonist [ 26 , 50 , 51 ]. Ulipristal acetate (UPA) was shown to effectively and significantly reduce menstrual bleeding (as assessed by PBAC scores), induce amenorrhea, and decrease the size of leiomyomas by up to 50% after 6 months via its antagonist action on myomas level [ 56 , 57 , 58 ]. Courtoy et al. described the specific impact of SPRMs (UPA) on myomas. Increased apoptosis, reduced survival and lower proliferation rates were also evidenced by gene expression changes, as was an increase in ECM resorption due to the high activity of matrix metalloproteinases [ 59 , 60 , 61 ]. UPA was actually a very effective drug [ 56 , 57 , 58 ] but, unfortunately, due to very rare (1/150,000) but non-predictable cases of drug-induced liver injury (DILI), the CHMP very recently decided to significantly limit its use to premenopausal women who cannot undergo surgery or in the case of uterine fibroid embolization, or if the surgical procedure fails (still pending EMA confirmation).

In 2013, Sangkomkamhong conducted a systematic review (Cochrane library) on progestogen use in fibroid therapy [ 33 ]. Progestins have been utilized for many years in the treatment of uterine fibroids and are still used in some countries ( Table 1 ). However, as emphasized in this Cochrane review, the lack of high-quality studies has proved to be a common problem when systematic evaluation of their benefits and potential harms is required. The authors concluded that evidence is insufficient to support the use of progestogens in treating premenopausal women with uterine fibroids. The same conclusion was reached by Lethaby et al. in their systematic review published in 2017 in the Cochrane library [ 62 ]. An extensive review by Bitzer et al. on the medical management of HMB found the LNG-IUS (levonorgestrel-releasing intrauterine system) to be the first-line medical therapy for HMB due to dysfunctional uterine bleeding (characterized by the absence of fibroids). In the presence of HMB due to fibroids, however, it shows much more limited efficacy. These authors reported that MPA and NETA are approved in many countries for the treatment of various forms of “abnormal” uterine bleeding, but their long-term use in fibroid-related HMB is not currently supported by solid evidence, because of the absence of benefits reported in the literature [ 63 ]. In a systematic review and network meta-analysis of RCTs investigating medical therapy for uterine fibroids, Gurusamy et al. identified 75 RCTs among 4237 references [ 64 ]. Only one reported the results of a progestogen, namely the study by Verspijck et al. previously discussed in this manuscript. Since 2000, there have been no reports of RCTs on progestogens in medical therapy for uterine fibroids [ 65 ]. After appraising all available options, Sohn et al. concluded from a literature review and consensus of expert opinion that GnRH agonist and SPRMs are currently the best effective medical therapies, with the best evidence to support their ability to reduce fibroid volume and HMB. Nevertheless, there is a lack of data on the true efficacy of progestogens, which may even promote uterine fibroid growth [ 66 ].

The prevalence of fibroids depends upon ethnic background [ 1 , 2 ]. It varies widely based on the diagnostic approach, but is estimated to be more than 60% in women over the age of 45 years [ 3 , 4 , 5 ]. While some fibroids are asymptomatic, others result in symptoms that warrant therapy [ 3 , 6 ]. The most common symptom is heavy menstrual bleeding (HMB), but pelvic pain, bulk symptoms and infertility are other frequent manifestations that may greatly affect the quality of life of these women [ 2 , 4 , 6 , 7 ]. A number of theories have been proposed to explain fibroid-related HMB. These include an increase in uterine surface area, endometrial ulceration or an enlarged vascular network on the surface of a submucosal fibroid, greater vascular flow into the myometrium, changes in contractility of the inner junctional zone, and congestion of the endometrium and myometrium by compression of the myometrial venous plexus [ 3 ]. Dysregulation of normal myometrial vascular function in uterine fibroids and surrounding myometrium is due to anomalies in the expression of angiogenic growth factors and their receptors [ 8 , 9 ]. The presence of uterine fibroids may also impact the composition of the overlying endometrium, particularly the number of uterine natural killer cells and macrophages [ 10 , 11 ], which are potential producers of angiogenic growth factors. As stressed by Ikhena and Bulun, uterine fibroids significantly affect gene expression in the endometrium [ 12 ]. The consecutive roles of transforming growth factor beta-3 (TGF-β3) and HOXA-10, leading to impaired endometrial receptivity, were first suggested by Rackow and Taylor [ 13 ]. TGF-β is known to be elevated in leiomyomas and acts as a diffusible signaling molecule to alter bone morphogenetic protein 2 (BMP-2), reducing HOXA-10 expression throughout the endometrium [ 14 , 15 ]. Moreover, Sinclair et al. and Taylor both identified defective decidualization and hemostasis in the endometrium, which may partially explain the heavier bleeding in women with uterine fibroids [ 15 , 16 ]. Despite significant advances in understanding the molecular changes in leiomyomas and associated myometrium and endometrium, it remains unclear why clinical symptoms are so diverse. Considering the strong association between uterine fibroids and HMB, ultrasound should be performed as a wholly appropriate diagnostic approach. Numerous treatments are available, including pharmacological, surgical, and radiological interventions, such as uterine embolization [ 17 ] or MRI-guided focused ultrasound [ 2 ]. However, as reported in a recent editorial, hysterectomy still remains the go-to one-size-fits-all treatment for uterine fibroids. Nonetheless, many women need an effective alternative to hysterectomy for various reasons, including faster recovery and maintenance of fertility [ 18 ]. There is therefore a need for conservative options, and safe and effective medical therapy is one of them. Among existing medical therapies, tranexamic acid, combined oral contraceptives, oral and injectable progestogens, progestogen-releasing intra uterine systems, antiprogesterone, gonadotropin-releasing hormone (GnRH) agonists and antagonists, selective progesterone receptor modulators (SPRMs), selective estrogen receptor modulators (SERMs), aromatase inhibitors, danazol and gestrinone are frequently cited [ 2 , 3 , 6 , 7 ]. The majority of these therapies are used for the management of abnormal uterine bleeding but are not specifically indicated for uterine fibroids. Among them, the most commonly used are progestogens. A recent decision by the EMA’s human medicines committee (CHMP) recommended restricting the use of medicines containing 5 mg ulipristal acetate as they were linked to cases of serious liver injury. If confirmed by the European Commission, this may push gynecologists to go on prescribing progestogens to treat uterine fibroids, so it is high time to evaluate their efficacy. Progestogen is a natural or synthetic hormone. Progesterone is a natural hormone secreted by the corpus luteum, while progestin is a synthetic progestogen that can be administered orally, vaginally or by intramuscular injection. Progestogens have been used all over the world for many years in the management of uterine fibroids, despite the lack of evidence and absence of adequately designed and powered studies. One of them, depot medroxyprogesterone acetate (DMPA), has been approved for use in more than 100 countries, but other progestogens (lynestrenol, pregnane and nor-pregnane) are still used in uterine fibroids therapy. The objective of this review is to determine the evidence or otherwise regarding the effectiveness of progestogens in treating premenopausal women with uterine fibroids. In particular, we will try to address recurring questions as to whether they are effective or not for managing symptoms commonly attributed to fibroids. A literature search was conducted through an electronic database (PubMed, Embase, the Cochrane library) up to September 2020. The following key words were entered: uterine fibroids, progesterone, progestogen, GnRH agonist, GnRH antagonist, heavy menstrual bleeding, add-back therapy ( Figure 1 ).

In this review of the most significant papers on the relationship between uterine fibroids and progesterone/progestogens ( Table 1 ), we have clearly shown biochemical, histological, and clinical evidence that progesterone and progestogens play a critical role in the pathogenesis of myomas. In their manuscript entitled “Practice guidelines on the management of uterine fibroids”, Vilos et al. did not ever include progestogens in their algorithm, as they felt that evidence of their efficacy was still lacking [ 81 ]. Therefore, summarizing studies on progestogens and uterine fibroids overall, we can conclude that the evidence actually points to a lack of evidence of their efficacy. On the other hand, effective medications such as GnRH agonist and antagonist induce hypoestrogenic symptoms (including progressive BMD loss and vasomotor symptoms), but hormone add-back therapy may well enhance compliance and extend the duration of therapy. The choice of hormone add-back treatment for myomas should aim to exploit the minimal effective dose of progestogens to preserve the therapeutic effects of GnRH agonist and antagonist. Low doses of E2 (1 mg) combined with NETA (0.5 mg) have proved capable of preventing bone loss in early post-menopausal women [ 82 ] and those with endometriosis undergoing GnRH agonist therapy [ 83 ]. This combination may therefore be considered an option for women with uterine fibroids subjected to long-term GnRH agonist or antagonist therapy.