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Reprint requests: Obianuju Sandra Madueke-Laveaux M.D., M.PH., Department of Obstetrics and Gynecology, Section of Minimally Invasive Gynecologic Surgery, University of Chicago Medicine and Biological Sciences, 5841 S. Maryland Ave, MC 2050, Chicago, Illinois 60637.
Treatment of heavy menstrual bleeding associated with uterine fibroids (UF) is evolving. Historically, treatment options were limited to predominantly invasive surgery; today, conservative and novel oral medical treatments are widely available for use with significant efficacy. This evolution was directly driven by our improved understanding of UF pathophysiology. Specifically, our recognition of the hormone-mediated pathway in UF development and growth laid the framework for using GnRH agonist analogs in treating UF. In this report, we explore the use of GnRH analogs in the treatment of heavy menstrual bleeding associated with UF in phases. We review historical perspectives, discuss the development and use of aternatives to GnRH analogs, a period we refer to as the “Dark Ages” of GnRH analogs, we then provide an overview of the later years and present-day use of GnRH analogs and discuss opportunities for future directions.
Historical perspective
Archeologic evidence consisting of calcified masses found among human skeletal remains dating up to 5,000 years old supports the existence of uterine fibroids (UF) in the Neolithic period (
). However, written documentation about individual experiences with UF dates back to Hippocrates, approximately 400 BC, when they were known as uterine stones. Over the years, this tumor earned many names—“scleroma,” “mole,” “mola,” and “fleshy tubercle.” In 1854, Dr. Virchow, a German pathologist, coined the name myoma, and in 1860, Rokitansky, a Bohemian physician, started using the name uterine fibroid (
). Despite this long-dated history of UF, the treatment of this pathology, which was predominantly operative in nature, did not make an appearance until the nineteenth century when American surgeons documented their experience in the treatment of these large masses. During this time, the treatment options for UFs were quite limited. Surgical treatments included hysterectomy, myomectomy, oophorectomy, and the removal of the appendages (
). In the mid- to the late nineteenth century, many theories and speculations were developed as regards the etiology of UF. The role of hormones in uterine fibroid etiology was not understood. However, 2 theories that recognized the role of the ovaries and perhaps hormones in fibroid etiology were the “Circulation Theory of Robert Meyer” and “The Hormonal Theory” (
). The Circulation Theory of Robert Meyer was based on the regression of UFs and cessation of heavy menses in women who had undergone natural menopause or oophorectomy. Meyer theorized that the ovary had a trophic effect on the uterus itself and that loss of the ovary led to the diminution of blood supply and, thus, atrophy of the uterus and the tumor. Although this was incorrect, it was perhaps the beginning of an understanding that the ovary had a role in uterine fibroid etiology. The Hormonal Theory of the 19th century was based on ovulatory dysfunction. This ovulatory dysfunction led to a hyperestrogenic state, leading to uterine congestion and fibroid formation. Although this theory would prove incorrect, it recognized estrogen as a key player in fibroid etiology and would serve as a stepping stone in the right direction (
As we entered the twentieth century, the alarming public health impact of UFs was globally palpable, and the need to understand the etiology of these tumors and develop innovative treatment options became urgent (
). Many scientists joined the quest to understand the pathogenesis of UF and, in time, the role of estrogen and progesterone in fibroid etiology; in essence, the modern-day Hormonal Theory was validated. Although there was universal agreement that UFs were hormone-dependent, there were competing ideas about the interplay between estrogen and progesterone in fibroid development. Some investigators suggested that estrogen was the predominant hormone in fibroid growth, whereas others disagreed, stating that progesterone played a critical role in fibroid growth (
Regardless of this lack of consensus, understanding this hormone-mediated pathway lay the framework for using GnRH (previously named LHRH) agonist analogs in treating UF (
). If estrogen increases tissue sensitivity to progesterone by increasing the availability of the progesterone receptors (PR) and progesterone allows for the complete development and proliferation of fibroid tumor cells, then the suppression of these hormones should inhibit tumor growth and lead to a decrease in the symptoms of these tumors. This hypothesis was indeed correct.
The use of GnRH agonist analogs resulted in an initial increase in estrogen and progesterone production. However, the continuous dosing of GnRH agonists, as opposed to the pulsatile release of GnRH from the pituitary gland, eventually resulted in ovarian suppression and decreased estrogen and progesterone production (
). The clinical effectiveness of the GnRH agonist analogs was a direct consequence of this ovarian suppression, leading to a decrease in heavy menses and a reduction in the size or volume of the tumors. However, the complete cessation of steroid hormone production was associated with life-altering side effects, including climacteric symptoms of hot flushes and bone mineral density loss leading to osteopenia and osteoporosis. Because of these adverse effects, GnRH agonists were unsuitable for long-term use in the treatment of UF in premenopausal patients. It was therefore considered to be of the utmost value for women approaching the age of natural menopause and for preoperative administration to both control symptoms and reduce surgical morbidity and operative blood loss (
). It was also used when surgery was contraindicated. Therapy duration was limited to four- to six-month duration, and add-back therapy with progesterone or combined hormonal pill was required for longer use, with the maximum use limited to 12 months (
). An additional limitation of GnRH agonist analogs was the immediate rebound in fibroid growth noted on the cessation of therapy. This and the previously mentioned adverse effects necessitated the exploration of alternative options in UF treatment.
Antiestrogens, antiprogesterone, and androgen steroids were some of the medical options that were investigated for use in UF treatment (
). Antiestrogens, such as aromatase inhibitors, were ineffective in premenopausal patients. Antiprogesterones caused endometrial hyperplasia, and estrinone, a medication with antiprogesterone, antiprogesterone, and androgenic properties, produced endometrial atrophy, reduction in uterine volume and alleviated the symptoms of heavy menses. However, the undesirable side effects, which were mediated by excess androgens, such as acne, hirsutism, and seborrhea, led to high rates of discontinuation (
). Furthermore, none of those therapies was compatible with reproduction, so the quest for the ideal medical therapy for UF continued.
The “dark ages” of GnRH analogs
In the mid- to the late twentieth century, selective estrogen receptor modulators (SERMs) and selective progesterone receptor modulators (SPRMs) were investigated as UF treatment options. The estrogen blockade activity of SERMs supported its potential therapeutic activity against fibroids. However, the endometrial hyperplasia effect of Tamoxifen and the lack of appreciable fibroid volume reduction in premenopausal women noted with Raloxifene resulted in limited use and lack of advancement in the use of SERMs in UF treatment (
). Conversely, the results seen with SPRMs were significantly more promising. In the PEARL trials, ulipristal acetate (UPA), an SPRM, triggered a significant decrease in menstrual bleeding at 10 days in >90% of women given a 3-month course compared with 50% in the GnRHa group and 10% in the placebo group. Also, the median time to achieve bleeding control was shorter in the UPA group (5–7 days) than in the GnRHa group (30 days). Fibroid tumor volume decreased by up to 35% within the first 3 months of UPA treatment and showed sustained effect for up to 6 months after treatment cessation. This observation was in sharp contrast to the 23% rate of regrowth of UFs at 3 months and return to baseline levels by 6 months after the cessation of GnRHa administration. Lastly, and of critical importance, UPA was not associated with a decrease in bone mineral density (BMD) (
In 2012, UPA was approved by the European Medicines Agency for intermittent and symptomatic treatment of heavy menses in patients with UF. We may refer to this period as the “dark ages” of GnRH agonist analogs. However, this “reign” did not last very long. Long-term use of SPRMs was associated with 2 significant adverse events. The first one included endometrial change induced by SPRMs, referred to as PAEC (progesterone receptor modulator-associated endometrial changes). The changes, although benign, required that UPA be administered as a 3-month therapy course followed by an 8-week interval, allowing for 2 menstrual bleedings and the reversal of those benign endometrial changes. Liver impairment which led to injuries severe enough to require liver transplants, was the second adverse event (
). Within 6 years of its approval, in 2018, the safety profile of UPA was investigated by the European Medicines Agency. Around this time, the FDA rejected its use for treating symptomatic UF in the United States (
). By 2020, the European Medicines Agency mandated that ulipristal acetate only be used in dire situations when a patient cannot undergo uterine fibroid embolization or surgical treatment for their UF symptoms (
). These events were immediately followed by the return of GnRH agonist analogs as the only approved medical treatment for heavy menses in women with UF. This would remain the case for many years to follow.
Later years and present day
The need for patients to discontinue the use of medications that effectively inhibited severe symptoms led to the nervous search for various alternatives (
). Despite the scale of the problem, not many options were available. Although drugs such as aromatase inhibitors (AI) were an option, minimal research was conducted showing the effective use of AI for UF treatment. Nutraceuticals, including vitamin D and catechins, gained some popularity (
). However, their universal use has been limited by the early stage of investigations, with minimal evidence to confirm the efficacy and a desire for drugs that have been subjected to suitable research and scientific evidence. As a result, many health care providers returned to the use of GnRH agonists, which, as previously discussed, were widely employed to treat symptoms related to UF (
). Although known to be very effective, the decrease in circulating estrogen and the resulting clinical result continued to be the reason for patients' reluctance to use the GnRH agonist analogs. Thus, the need remained to develop effective solutions with minimal side effects that would not significantly interfere with appropriate treatment.
The levonorgestrel (LNG) intrauterine system (IUS), which had been introduced in Finland in 1990, and initially approved for contraception, was observed in clinical trials to cause a decrease in menstrual blood loss. This observation led to its eventual approval to treat “heavy menstrual bleeding without identifiable underlying pathology,” otherwise known as “idiopathic menorrhagia.” However, similar effects of improved bleeding profiles were seen in patients with structural causes of heavy menses, and many health care providers began to use LNG-IUS to treat heavy menstrual bleeding due to identifiable underlying structural causes, including adenomyosis and UF. A bonus and important clinical advantage of the LNG-IUS is the minimal to no systemic effect and lack of impact on ovarian function. Today, many international guidelines recommend LNG-IUS as a first-line treatment option for heavy menses. It is important to note that despite its widespread use in this capacity, the use of LNG-IUS for treating heavy menses due to structural pathology is still considered an off-label use (
The need for effective treatments for patients with contraindications to or refusal of hormonal therapies, procedural options (UF embolization [UFE]), and surgical options (hysterectomy, myomectomy, ablation) as well as treatment options that would not preclude pregnancy were an additional driving force behind the quest to develop new drugs for UF treatment. Different groups of great experts made substantial efforts to develop innovative medical options for treating symptomatic UF. Regrettably, despite these efforts, to date, no fully curative pharmacological treatment has been developed yet (
). The therapeutic efficacy and a milder adverse effect profile of these drugs were confirmed in high-quality studies. They are characterized by a rapid onset of action and dose-dependent effect without a full suppression of circulating estrogens (
) found that elagolix reduced heavy menstrual bleeding symptoms in patients with UF. Optimal results were obtained using the dose of 300 mg twice daily. According to Schlaff et al (2020), the double-blind, randomized, placebo-controlled, ELARIS Uterine Fibroids 1 and 2 [UF-1 and UF-2] trials demonstrated that elagolix with add-back therapy was effective in reducing heavy menstrual bleeding in women with uterine fibroids. Those studies showed that the hypoestrogenic effects of elagolix were attenuated with add-back therapy. Another antagonist, relugolix, is also believed to be a well-tolerated and noninvasive pharmacological option for UF patients. Relugolix induces a concentration-dependent decrease in HMB. LIBERTY 1 and LIBERTY 2 studies conducted in women with fibroid-derived heavy menstrual bleeding explored a combination therapy of relugolix with estrogen and norethindrone acetate or relugolix monotherapy followed by relugolix combination therapy. The treatment was found effective in comparison with the placebo control group. It was also added that relugolix had a longer half-life which allowed for once-daily administration (
Linzagolix with and without hormonal add-back therapy for the treatment of symptomatic uterine fibroids: two randomised, placebo-controlled, phase 3 trials.
). Very recently, the third antagonist, ie, linzagolix, was also approved for the treatment of UF. The preliminary results of double-blind phase 3 trials (PRIMROSE 1 and PRIMROSE 2) revealed its efficacy in treating heavy menstrual bleeding related to such lesions. In both studies, the response rate at week 24 was significantly higher in the linzagolix group than in the placebo group, and the risk for osteoporosis was not significant (
Linzagolix with and without hormonal add-back therapy for the treatment of symptomatic uterine fibroids: two randomised, placebo-controlled, phase 3 trials.
The developments and advancements in GnRH analogs after the FDA rejection and mandated limited use of SPRMs, as summarized in this section, represent a proverbial "rise like a phoenix from the ashes" for GnRH analogs in UF treatment. Today, the antagonists are naturally on the rise because of very encouraging results and a high safety profile. However, we are eagerly awaiting other substances, drug combinations, or treatment regimens, with the goal of broadening treatment options and ensuring the maximum effectiveness of the therapy with minimal associated risks.
Future direction
To date, the results regarding the efficacy of new-generation oral GnRH antagonists are more than promising and offer a potential solution for some UF-derived issues. However, we must still remember that these antagonists should mostly be combined with hormonal add-back therapy to minimize the hypoestrogenic side effects such as hot flashes or bone loss (
Notably, linzagolix is the only GnRH antagonist developed for fibroid related heavy menses that allows for the separation of add-back estrogen and progestin. According to experts, the use of such a drug may be beneficial for patients who refuse treatments that contain estrogens (
Linzagolix with and without hormonal add-back therapy for the treatment of symptomatic uterine fibroids: two randomised, placebo-controlled, phase 3 trials.
). In these cases, the benefits of partial suppression with lower doses of linzagolix (100 mg) without add-back therapy versus full suppression (200 mg) with add-back therapy may be acceptable. Donnez et al. (
Linzagolix with and without hormonal add-back therapy for the treatment of symptomatic uterine fibroids: two randomised, placebo-controlled, phase 3 trials.
) noted that a higher incidence of fibroids might often be correlated with a higher prevalence of risk factors for complications related to add-back therapy. Again, for these pateients, linzagolix without hormonal therapy would be a preferred therapeutic option. Certainly, the availability of additional drugs with similar safety profiles and administration options will be attractive for patients and will influence drug price and availability. Apart from the issue of add-back therapy, we need further studies in larger numbers for longer periods to gain additional information about the efficacy, tolerability, and compliance of available antagonists.
The transition from the injection of agonists to oral antagonists was a milestone. What will be the next milestone in the treatment of UF? Will it include GnRH analog-releasing systems other than injections? Looking with envy at the great success of levonorgestrel-releasing systems in the treatment of abnormal bleeding and for contraception (
), one can dream of new carriers for the GnRH antagonist analogs. Perhaps, we could develop a special system for local administration, e.g., intrauterine, long-term release of GnRH analogs. Such drug administration would bypass certain critical points or organs and avoid the exposure of the patient to specific side effects associated with systemic drug administration.
In addition to the modulation of the hormonal microenvironment as a target for emerging therapies in the future, we must strongly consider that a deepened understanding of the discreet molecular pathways regulating the growth of UF can play a critical role in the development of innovative therapies (
). A classic example of this idea is the development of treatment options that target the extracellular matrix. The extracellular matrix is abundant and disorganized in UF and is affected by growth factors, including transforming growth factor [TGF]-B, cytokines (tumor necrosis factor [TNF]-a), steroid hormones, and microRNAs. Nonhormonal therapies that modulate—inhibit, or down-regulate any of these growth factors may broaden therapeutic options for UF treatment in the future and should be investigated (
Beyond an idea and great willingness, the development of novel therapies for UF treatment in the future will require strategic planning and collaborative efforts by engineers, scientists, physicians, and pharmacists. However, as history indicates, we are up to the task. As millions of patients wait for help, we must remain committed to innovation and motivated to overcome any barriers that may preclude success.
References
Kramar C.
Baud C.A.
Lagier R.
Presumed calcified leiomyoma of the uterus. Morphologic and chemical studies of a calcified mass dating from the Neolithic period.
Linzagolix with and without hormonal add-back therapy for the treatment of symptomatic uterine fibroids: two randomised, placebo-controlled, phase 3 trials.
S.O.M-L has nothing to disclose. M.C. has nothing to disclose. A. A-H. reports support from Bayer AG, Berlin, Germany, for the submitted work; grants from National Institutes of Health; consulting fees from AbbVie, Bayer, ObsEva, and Myovant Sciences; patent for novel diagnostics and therapeutics for uterine sarcoma US Patent No. 9,790,562 B2 outside the submitted work.
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