Current approaches to overcome the side effects of GnRH analogs in the treatment of patients with uterine fibroids.

Uterine Fibroids are benign monoclonal neoplasms of the Myometrium and represent the most common tumors in women worldwide. Unfortunately, there has been no long-term non-invasive treatment option that exists for these hormone-dependent tumors. Several reported risk factors are involved in UFs pathogenesis, the most important and frequent one is race, specifically, the African American race. Other risk factors include old age; obesity, vitamin D deficiency, pre-menopausal state; non-parity, family history of UFs and frequent consumption of Soybean milk. Available hormonal therapies are to control uterine bleeding and tumor growth based on regulation of estrogen and progesterone levels/effects. However, some of these hormonal therapies have the potential to interfere with endometrial development and implantation and therefore cannot be used while pursuing pregnancy. Initially, oral contraceptive pills were used to stop excessive uterine bleeding for short-term considering their cost-effectiveness, however their effect on tumor size was controversial and limits their long-term use. Similarly, levonorgestrel intrauterine devices have been used but limited with being expelled with tumors, especially submucosal ones. SPRMs such as UPA were attractive to medical community following approval in several countries worldwide including Europa, Canada, and Australia. These oral compounds showed promising treatment outcome in terms of tumor size shrinking and controlling bleeding based on their tissue-specific mixed agonist/antagonist effects on progesterone receptors on endometrium and UFs. However, later their use has been restricted following reports of liver failure and need for hepatic transplantation. Studies on other SPRM Vilaprisan were also discontinued, as there were cases of toxicity in animal studies. Elagolix was developed by AbbVie for management of hormone-dependent reproductive disorders in women. Subsequently, In July 2018, the US FDA approved elagolix tablets (ORILISSA ™ ) for management of moderate to severe pain associated with endometriosis. In May 2020, FDA approved ORIAHNN ™ (Elagolix, estradiol, and norethindrone acetate capsules; Elagolix capsules) as the first oral medication for the management of heavy menstrual bleeding due to UFs in pre-menopausal women as One capsule (elagolix 300 mg, E2 1 mg, NETA 0.5 mg) in the morning and one capsule (elagolix 300 mg) in the evening for up to 24 months [ 46 , 65 , 82 ]. Recently, In May 2021, Myovant Sciences and Pfizer Inc. announced that the US.FDA has approved MYFEMBREE® (relugolix 40 mg, E2 1 mg, and NETA 0.5 mg) as the first once-daily treatment for the management of heavy menstrual bleeding associated with UFs in premenopausal women, with a treatment duration of up to 24 months [ 47 ]. These drugs approvals relied on results from large phase 3 clinical trials that showed GnRH antagonist, either elagolix or relugolix, in combination with ABT showed significant efficacy while marinating good safety profile as regards to hypoestrogenic side effects as compared to placebo, permits them to be used for 24 months [ 44 , 68 , 83 , 84 ]. Linzagolix is still under studies and results showed that it reduced uterine and fibroid volumes and improved pain and hemoglobin levels in women with UFs, according to multiple analyses of two phase 3 clinical trials [ 85 ]. In addition, recent case report study showed that linzagolix significantly reduced lesion size and improved quality of life in a patient with severe adenomyosis, who was previously nonresponsive to treatment with UPA [ 86 ]. Remarkably, GnRH analog therapy is associated with severe hypoestrogenism which negatively affect the patients since it contributes to BMD loss with subsequent osteoporosis with prolonged treatment [ 39 , 87 ]. Therefore, patients administer GnRH analogs combined with ABT to reduce these climacteric symptoms. For example, medroxyprogesterone acetate was used and shown to improve patient symptoms but exerted a negative impact on tumor mass reduction [ 88 ]. Interestingly, systematic review showed that low to moderate quality evidence confirmed that tibolone, raloxifene, estriol and selected flavones assisted in preserving BMD and that medroxyprogesterone acetate and tibolone might reduce vasomotor symptoms while contribute to UFs mass [ 89 ]. The other important issue about the use of GnRH agonist in the therapy of UFs is fibroid regrowth and recurrence of symptoms following treatment discontinuation [ 90 – 92 ]. According to the study by Schlaff et al., uterus and lesions reapproaches their pretreatment size within 6 months of therapy discontinuation [ 90 ]. That is why this form of treatment must be carefully and individually implemented. According to expert opinions, patients who will derive benefit of this therapy are those with menorrhagia, these women will experience a significant blood loss reduction. Women with larger uteri or lesions might also benefit of this therapy as these drugs will increase the likelihood of a transverse abdominal incision or laparoscopic or vaginal entry. Guttmann et al. believe that the one of the most relevant indication for preoperative use of those GnRH analogs appears in patients with submucous fibroids as they might be significantly easier to resect these way [ 80 ]. Since GnRH analogs especially the oral antagonists seem the key pharmacological treatment of UFs related bleeding in the near future and considering they cannot be used alone due to their hypoestrogenic side effects, it’s important for researcher to develop strategies to overcome their side effects such as combination with ABT. Exploring new regimens and dosage forms of ABT might add benefits for such treatment modalities. Also, it is important to bear in mind that these drugs’ effects are reversible when treatment ends, and hormones and tissues will return to pretreatment levels soon after treatment is stopped with symptoms going back. Currently, GnRH antagonists are approved for 24 months only. Knowing that uterine and fibroid tissues will not shrink when ABT is included, therefore women with bulking symptoms due tumor mass will be unlikely to benefit. Only patients whose main concern are UF related bleeding will benefit from such combination. Utility of natural compounds such as vitamin D, green tea and others might help those patients with minimal side effects [ 93 , 94 ] with taking their hormonal therapy. Today, many women are looking for alternative methods in the treatment of UFs. They are especially interested in pharmacotherapy which allows to reduce the clinical symptoms and size of the fibroid [ 95 ]. Some of the available medications allow physicians to avoid surgery or postpone it. A recent study from Finland has shown that the number of hysterectomies has fallen over a period of about 20 years [ 96 ]. The above dependence probably results from the greater awareness of both patients and doctors that the treatment of UFs is in most cases a treatment improving the quality of life, not saving it [ 97 ]. Therefore, in many cases, pharmacological treatment of UFs can and should be attempted. In a large proportion of patients, such treatment may result in relief or reduction of symptoms. Undertaking rushed surgical treatment without proper preparation of patients in many cases may unnecessarily increase the risk of complications and the suboptimal scope and effect of the surgery [ 98 ]. In their paper, Guttmann et al. described both advantages and disadvantages of GnRH analogs use in patients with UFs [ 80 ]. According to these authors, definitive advantages of this therapy are anemia resolution, volume reduction, reduction in pelvic and abdominal symptoms and higher chance of mini-invasive route of surgery. Less important and possible advantages are reduction in operative time and blood loss, reduction in hospital stay after surgery and reduction in adhesion formation. On the other hand, there is still a risk of disadvantages. The definite disadvantages are side effects and decrease in bone mineral density, risk of delaying treatment for malignancy or increased risk of lesions recurrence (secondary to missing the smaller changes at primary surgery due to their drug-related volume reduction). Finally, recent study employed real-world data from the National Health and Nutrition Examination Survey and longitudinal data from the elagolix phase III clinical trials in models across a wide age range, and other covariates [ 99 ]. Interestingly, Body mass index (BMI) and race (i.e., Black) were significant predictors indicating that patients with high BMI or Black race experience a relatively lower BMD loss. Such study utilizing model- informed drug development (MIDD) approach is able to predict the magnitude of change in BMD and fracture risk due to medical treatments over time to inform the risk- benefit evaluation of new therapies. Table 2 summarizes published information about Elagolix and ABT for women with UFs. In summary, Elagolix and relugolix are recently approved oral GnRH antagonists for the treatment of heavy menstrual bleeding associated with UFs for 24 months with promising results. However, use of low-dose hormonal ABT in combination is essential to reduce hypoestrogenic side effects especially bone mineral density loss.

A scientific working group advocated for the use of suitable add-back therapy in conjunction with GnRH agonist treatment to ameliorate hypoestrogenic symptoms, prevent pre-cancerous endometrial changes and perhaps prolong the duration of medication beyond 6 months while maintaining therapeutic efficacy [ 58 , 59 ]. Earlier and following the results of randomized controlled trials in women with endometriosis, the FDA approved progestin NETA, also known as norethisterone acetate, at a daily dose of 5 mg in combination with a synthetic GnRH agonist (leuprolide acetate), as an add-back therapy in women with endometriosis. NETA has profound tissue-specific progestogenic, estrogenic or antiestrogenic, and androgenic actions, where, the average conversion ratio of NETA to ethynyl estradiol (E2) by aromatization is 0.7 percent to 1% at 5 mg NETA dosages. It is believed that the estrogenic action of NETA may explain its beneficial effect on BMD. Low dosages of E2 1 mg coupled with NETA 0.5 mg have been shown to prevent bone loss in endometriosis patients receiving GnRH agonist treatment [ 60 ]. Consequently, this combination are being used for women with UFs who are on long-term GnRH antagonist therapy. Moreover, earlier clinical study examined the use of ovestin to overcome the adverse effects of GnRH agonists goserelin. Twelve individuals were given GnRH analogues without ovestin cream (Control group). Another twelve individuals were administered a combination of vaginal ovestin and GnRH analogues goserelin. The results showed that ovestin group had a significant less side effects than the control group regarding cervicovaginal symptoms. These results indicated that goserelin can improve the tolerance to GnRH analogues [ 61 ]. A clinical review on elagolix showed that the most prevalent side effects were mild to moderate nausea and hot flashes, with the highest incidence of hot flashes occurring in women receiving a dosage of at least 200 mg twice day. Spotting was also observed by seven participants in a phase 1 investigational study [ 62 , 63 ]. In a phase II trial of endometriosis patients, both elagolix 150 mg and 250 mg groups exhibited a substantial reduction in bone mineral density (BMD) where a substantial dose-dependent decline in lumbar BMD was seen in both groups following six months of therapy [ 64 ]. Additionally, phase III trial showed an elagolix-related rise in low-density and high-density lipoprotein cholesterol, as well as triglycerides [ 63 ]. In another clinical study, it was found that the adverse reactions appeared in women treated with elagolix plus addback therapy resulted in therapy discontinuation in some of them. The most common reported side events were nausea, headache, alopecia, metrorrhagia, menorrhagia, and hot flushes (reported in 1% each). Add-back treatment reduced elagolix’s hypoestrogenic effects, particularly BMD loss, but hot flushes and metrorrhagia occurred considerably more frequently than placebo [ 65 ]. A Clinical study was conducted on premenopausal women with a mean age of 41.8 years and having UFs and heavy menstrual bleeding to examine the safety and efficacy of elagolix vs placebo vs elagolix / low dose ABT. The low dose ABT was 0.5 mg of E2 + 0.1mg of NETA. Another group administered ABT of E2 1mg + cyclical P 200mg. The most prevalent adverse effect was a hot flush (in elagolix alone group showed 45.5 to 62.5 %; in placebo group showed 12.0%; and in add-back regimens showed 18.5 to 26.5%). It was concluded that, flushing was significantly decreased by low-dose add-back regimens [ 66 ]. Recent study was conducted to explore potetial pharmacokinetic interaction between elagolix and low-dose hormonal ABT, both oral and transdermal, using two multiple-dose, open-label, single-sequence, non-randomized studies and results showed that no dose adjustments were recommended when elagolix is co-administered with oral or transdermal low-dose ABT [ 67 ]. Importantly in the same study, authors found that number of treatment-emergent adverse events (TEAEs) in both studies of oral/transdermal E2/NETA alone and in combination with elagolix were similar. The tested regimens were generally well tolerated with no clinically significant changes in vital signs, electrocardiograms, or laboratory measurements [ 67 ]. Another recent spin-off study from ELARIS fibroid trials that explored efficacy and safety of elagolix (300 mg twice a day) with ABT (1 mg E2/0.5 mg NETA once a day) in reducing heavy menstrual bleeding associated with UFs in various subgroups of women over 6 months of treatment, TEAEs were assessed by subgroup and the overall pooled study population and results showed that proportions of women treated with elagolix with ABT reporting at least 1 adverse event were similar among all subgroups, and most adverse events were classified as mild or moderate [ 68 ]. Finally, an interesting simulation study utilized validated quantitative systems pharmacology (QSP) model showed that elagolix 150 mg once daily dosing for 24 months is predicted to result in −0.91% change from baseline in lumbar spine BMD. These results contributed to evidences supported the approved duration of elagolix therapy [ 69 ]. A phase II randomized, double-blind, placebo-controlled trial tested oral relugolix 10, 20, and 40 mg administered once daily for 12 weeks, the incidence of adverse effects like metrorrhagia, menorrhagia, headache and hot flush was higher by 10% in the 20 and 40 mg groups compared to the control group; with mild to moderate severity [ 70 ]. Same group later ran a phase III clinical trial to compare the efficacy and safety of oral relugolix 40 mg administrated once-daily to placebo in reducing pain experienced in Japanese women with UFs, results showed that the incidence of adverse effects was higher in the relugolix group than in the placebo group; however, most of them were mild to moderate in intensity in both groups. These side effects included hot flushes, metrorrhagia, hyperhidrosis, and menorrhagia which all are related to relugolix’s mode of action [ 70 ]. In two more clinical studies, women were given 40 mg relugolix with ABT (1 mg E2 + 0.5 mg NETA once daily). The percentage of patients achieved the primary goal (menstrual blood loss of 80 mL or a decrease of more than 50% from baseline) were 73.4% and 71.3%, respectively. Amenorrhea responders were 52.3 and 50.4%, respectively, with spine BMD loss of −0.36 and −0.13 %. Furthermore, the outcomes of a three oral GnRH antagonists (elagolix, relugolix, linzagolix) in phase 3 clinical trials have showed effective control of fibroid-related heavy menstrual bleeding and proven that the reduction in monthly bleeding is sustained when ABT is used with the antagonists, and BMD loss is mitigated [ 71 ]. Linzagolix is a new oral GnRH antagonist currently in phase 3 clinical studies. Linzagolix showed to cause a limited bone loss (below 2%) at 100 mg dose, potentially eliminating the need for add-back medication [ 72 ]. Clinical study was conducted to compare the safety and bleeding pattern effects of high-dose linzagolix in healthy women using combined versus delayed hormonal add-back treatment (ABT). The add-back treatment (ABT) administered was E2 1mg/ NETA 0.5 mg. The study included 32 randomized women 1:1 in which a group received a once daily dose of linzagolix 200mg/ABT for 10 weeks, and the other received linzagolix 200mg alone for 4 weeks followed by linzagolix 200mg/ABT for 6 weeks. The results showed that the treatment began with a combination linzagolix/ABT regimen resulted in improved bleeding control, no hot flushes, and lower median E2 levels than a “Delayed-ABT” regimen [ 73 ]. A Cochrane Review indicated that there was low to moderate evidence that estriol, tibolone, ipriflavone, and raloxifene maintained bone density and that medroxyprogesterone and tibolone improve vasomotor symptoms. However, the ABT medroxyprogesterone, tibolone, and conjugated estrogens were associated with increased uterine volumes as a side effect [ 74 ]. A comprehensive evaluation was carried out to assess the efficacy and safety of ABT, which compared the conjunction of GnRH analogues with progesterone, tibolone, raloxifene, or estrogen-progestogen to a GnRH analogue only. The conclusion showed that adding tibolone, progestogen, or raloxifene to GnRH analogues can suppress menopausal symptoms and bone loss, although the combination does not appear to improve or reduce treatment effectiveness [ 75 ]. It worth mentioning that a clinical trial conducted to compare the efficacy of different add-back regimens on hypoestrogenic side effects during GnRH agonist treatment in endometriosis patients. The study included 71 young women in reproductive age from which 57 completed the study. All the subjects administered GnRH agonist leuprorelin acetate 3.75 mg for 6 cycles (6 months). From the 57 patients, 16 patients administered E2 alone, 14 administered tibolone, 13 administered combination of E2 1 mg and drospirenone 2 mg, and 14 administered combination of E2 1 mg and NETA 0.5 mg. Study findings revealed that E2 and NETA regimen was found to be highly beneficial in improving quality of life, menopausal symptoms, and BMD [ 76 ]. In a clinical study including 133 women with relapse of endometriosis-related pain after previous endometriosis surgery to demonstrate the effect of ABT, 44 women administered GnRH analogue alone, 46 women GnRH analogue with ABT, and 43 women received estroprogestin for 12 months. The GnRH analogue was leuprolide acetate, the ABT was transdermal E2 25 ug + oral norethindrone 5 mg, and the estroprogestin was ethinyl estradiol E2 30 ug + gestodene 0.75 mg. The results revealed that when compared to GnRH analogue alone or oral contraceptive, ABT allowed women to be treated for a longer period of time with less BMD loss, improved management of pain symptoms, and greater quality of life [ 77 ]. A clinical study comparing the difference between low dose-back therapy effect versus regular dose-back therapy during postoperative GnRH agonist treatment. The study included 120 patient women from which 107 competed the study. The study was over 24 weeks of treatment, and 12 weeks follow up. The treatment groups were as follow: GnRH agonist leuprolide acetate (3.75 mg) intramuscularly every 4 weeks, GnRH agonist plus an oral combination of (estradiol valerate 1 mg / medroxyprogesterone acetate 2.5 mg) once per day (low dose-back therapy), or GnRH agonist plus an oral combination of (estradiol valerate 1 mg / medroxyprogesterone acetate 2.5 mg) twice per day (regular dose-back therapy). The results showed that low-dose ABT could successfully alleviate hypoestrogenic adverse effects while maintaining GnRH agonist treatment’s therapeutic efficacy more than regular dose although the difference is not significant (e.g, hot flashes (19.2% for low dose versus 21.8% for regular dose, p = 0.741), that recommended low-dose add-back therapy as a therapeutic option during postoperative GnRH agonist management [ 78 ]. Moreover, users of GnRH antagonists for the treatment of UFs may be encouraged to take calcium and/or vitamin D supplements concurrently to avoid or reduce the potential influence on BMD [ 79 ]. Notably, the side effects related to hypoestrogenism may occur in even 90% of women treated with GnRH agonists. Symptoms like hot flushes, insomnia, headaches, and vaginal dryness may result in high dropout rates in clinical studies, and low number of patients wishing to continue with long-term GnRH agonist use [ 80 ]. For example, in the study by Friedman et al. of the 51 women involved, only 27 completed 2 full years of treatment. Most of the patients declared that they are discontinuing the study, because of lack of self-reported effect or adverse medication-related effects or other personal reasons [ 81 ]. Various regimens including estrogen, progestogens, estrogen‐progestogen, tibolone or raloxifene have been described to limit these outcomes [ 50 ].

The main component of all pathways contributing to the development of UFs is the transformation of a normal myometrial cell into an abnormal tumor cell capable of undergoing clonal divisions [ 18 ]. Subsequently, it further divides, and the tumor grows [ 18 , 19 ]. According to currently available studies, most pathophysiological processes occurring in UFs depend on steroid hormones. Uterine fibroids are hormonal-dependent, because almost no prepubertal cases have been described in the literature, and postmenopausal UFs are rare [ 4 , 20 ]. Poor evidence quality suggests that UFs do not change their volume, or slightly enlarge during pregnancy (hyperestrogenic state) and subsequently reduce in size during puerperium [ 21 ]. According to the latest analyses, UFs are more common in women who are obese or with a high percentage of the adipose tissue [ 22 , 23 ], which also indirectly indicates the role of estrogens in this area. Uterine fibroids are characterized by the overexpression of the estrogen receptor (ER) gene compared to the normal myometrium. UF cells demonstrated overactivity in response to estrogens compared to the normal myometrium [ 20 ]. The proliferative potential of UFs may be acquired by the tumorous tissue via stimulation with estrogens, which make UF cells more active when dividing [ 20 ]. Despite those data, it was stated that the reduced apoptotic potential along with the increased proliferative potential were more associated with the progestogen component [ 18 , 24 ]. Notably, UFs also produce some amounts of estrogens via the aromatization of circulating androgens, which promote other divisions and the increase of UFs in situ [ 25 ]. Such a mechanism may be corroborated by the clinical use of aromatase inhibitor letrozole which was shown to reduce UF size even by half during a 3-month treatment [ 26 , 27 ]. Experimental research showed that the growth of UFs was even more stimulated by progesterone [ 18 , 24 ]. Two isoforms of the progesterone receptor (PR) may be distinguished: PR-A and PR-B. Uterine fibroids are characterized by a larger quantity of both types of those receptors compared to the normal myometrium [ 28 ]. A considerable increase in the number of myometrial cell divisions is observed in the second phase of the cycle. The process was also noted in UFs. The phenomenon was associated with the deceleration of apoptosis and the overexpression of a variety of genes determining tumor growth [ 29 ]. The luteal phase is also related to the increased amount of progestogen receptors in tissues [ 24 ]. Progesterone influences the development and growth of UFs by a number of growth factors which belong to the regulators of growth, differentiation, apoptosis and tissue remodeling [ 6 ]. Those factors are secreted and act directly on the fibroid in an autocrine like fashion. These factors which may directly influence the pathogenesis of UFs include: transforming growth factor, insulin-like growth factors, vascular growth factors, platelet rich plasma, interleukins and other proinflammatory factors [ 6 ]. Transforming growth factor beta seems to play a particular role [ 30 ]. A positive influence of progesterone on the growth of UFs was confirmed indirectly via the use of its antagonists in the treatment. The use of selective progesterone receptor modulators (SPRM), e.g. ulipristal acetate (UPA) and causes a reduction of tumors and related manifestations in women with UFs [ 8 , 31 ].

New GnRH antagonists are oral, non-peptide, gonadotropin-releasing hormone receptor antagonist. Elagolix and relugolix are approved for the treatment of heavy menstrual bleeding associated with UFs. Use of low-dose hormonal ABT has shown efficacy in reducing hypoestrogenic side effects. Therefore, all approved drugs are in combination with ABT of estradiol and norethindrone acetate.

Uterine fibroids (UFs, AKA leiomyoma) are currently the most common benign tumors in the reproductive age women. Their incidence increases during the reproductive age to reach even 60–70% in the perimenopausal population [ 1 , 2 ]. Uterine fibroids may be solitary, but very often several of them or conglomerate masses are observed. The vast majority of those lesions do not produce any manifestations, but in approximately 30% of cases they may contribute to a whole range of disorders. UF-triggered manifestations may be grossly divided into 3 main groups, i.e. symptoms associated with abnormal bleeding from the reproductive tract, those related to the presence of a pathological mass in the minor pelvic cavity and/or abdominal cavity, and ones related to reproductive dysfunctions [ 3 , 4 ]. Abnormal uterine bleeding which seems to be the most common manifestation may occur in a variety of forms, from spotting, through prolonged menorrhagia, to life-threatening hemorrhages which cause severe anemia. Bleeding problems occur most commonly in patients with fibroids adjacent to the endometrium, but lesions located nearby may also disrupt the bleeding pattern [ 5 ]. It is due to the fact that UFs are also biologically active tissues that influence the endometrium in a paracrine manner [ 6 , 7 ]. Symptoms associated with UFs may negatively impact daily living and the quality of life, and in numerous cases they constitute an indication to the immediate implementation of treatment [ 8 ]. UFs are the main reason for hysterectomy and hospitalization due to gynecological conditions in the USA. Based on various estimates, the total UF-related financial burden in the USA may even exceed 34 billion dollars annually [ 9 ]. Health care administration and payers involved in the organization of the treatment of women with UFs should be aware of the amount of public expenditures required to meet such needs [ 9 – 11 ]. Regrettably, new data obtained in population studies indicated that the basis for calculations is usually incomplete, as many women may be undiagnosed [ 11 ]. The problems associated with the off-label use of pharmacologic therapies and the still performing high percentage of hysterectomies (with their highest complication rates) for clinically symptomatic UFs suggest a need for effective approved non-invasive treatment alternatives [ 12 ]. Available therapies do not optimize future fertility and are associated with various medical complications [ 8 ]. Research revealed that currently available evidence is insufficient and its quality is too low to recommend any medical treatment in the management of UFs [ 13 ]. Therefore, the therapy should be individually chosen to obtain the best possible outcomes for each patient. For many years, hysterectomy has been the preferred surgical option for symptomatic UFs treatment. Currently, it is observed that the modalities involving radical treatment are becoming less popular, which translates into the reduction in the number of hysterectomies [ 14 , 15 ]. Such a trend was visible in research conducted previously. In 2013 Borah et al. demonstrated that the majority of affected women seeking treatment for symptomatic UFs preferred therapies that did not involve a surgery (79%) and preserved the uterus (51%) [ 16 ]. It is partially due to the fact that numerous women decide to delay maternity (beyond the age of 30–35 years) in order to pursue professional development beforehand. This postponement of motherhood is often associated with difficulty achieving a successful pregnancy [ 17 ]. Therefore, hysterectomy cannot be accepted in those women. That is why we need access to early treatment and effective non-surgical options. In this article we will cover Gonadotropin releasing hormone (GnRH) analogs, the current pharmacological treatment for UFs associated bleeding, with focus on their side effects and the studies performed in attempt to overcome these side effects. First, we will briefly discuss the pathophysiology of UFs and highlight their hormonal dependence to maintain tumor growth which GnRH analogs disrupt as a mechanism to stop tumor growth and relieve their resultant symptoms.

Gonadotropin-releasing hormone (GnRH) analogs have been one of the main pharmacological modalities in the treatment of UFs [ 8 , 32 ]. These analogs have been extensively used in clinical medicine since they were identified and synthesized in 1971 [ 33 ]. Those drugs are used in gynecology and oncology for the modulation of the pulsatile release of GnRH. They bind to the receptor of the frontal lobe of the pituitary gland inhibiting the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH are peptide hormones that regulate ovarian and testicular function and are essential for normal growth, sexual development, and reproduction. These pituitary gonadotropins are under the control of the above mentioned GnRH, which is produced in the hypothalamus and released in response to the circulating levels of estrogens and progesterone [ 34 ]. GnRH analogs are made of different peptides and are structurally related to GnRH. Very recently researchers have also obtained new small molecules (e.g. elagolix), which are structurally distinct (non-peptide) from and unrelated to GnRH analogs [ 35 ]. The majority of the above-mentioned substances present antigonadotropic properties. However, some may present pro-gonadotropic properties (e.g. gonadorelin), depending on whether they act to increase or decrease gonadotropin release [ 34 ]. As regards the mechanism of action, GnRH analogs act via the modulation of gonadotropin release which leads to desensitization, i.e., receptor downregulation. The use of GnRH agonists induces menopause-like effects, which may reduce the size and, consequently, the severity of symptoms in case of UFs [ 36 , 37 ]. Such a suppression of reproductive gland activity leads to the changes in the spectrum of blood flow in the vessels of the minor pelvic cavity and the decrease in the volume of blood flowing through the uterus. Regrettably, the majority of UFs regrow due to another gonadotropin release when GnRH agonists are discontinued [ 38 ]. GnRH analogs may be divided into two subgroups of drugs because of their influence on the pituitary gland: GnRH antagonists and agonists. The division is presented in Table 1 . GnRH agonists act mainly via the activation of the GnRH receptors which influences the secretion of gonadotropins. Originally, it was thought that GnRH agonists could be used as long-lasting stimulators of gonadotropin release, but it soon appeared that they caused only the initial stimulating action (also called “the flare effect”), which rapidly turned into downregulation due to profound hypogonadal effect achieved through receptor downregulation by the internalization of receptors. It resulted in the inhibition of the pituitary-gonadal axis. Such an action could be observed after several days in most cases and could be maintained when their use was continued for a longer period [ 33 , 39 ]. GnRH agonists are far more potent and have a longer half-life than human GnRH. They also slowly dissociate from the GnRH receptor [ 33 ]. GnRH agonists may be administered by injection, as an implant, or intranasally as a nasal spray. Injectable forms are available for daily, monthly, and quarterly use, whereas implants may last one month and longer [ 33 , 39 , 40 ]. The majority of side effects that occur in women during the use of GnRH agonists are related to sex hormone deficiency and include the symptoms of low estrogen levels, such as hot flashes, decreased libido, sexual dysfunction, vaginal atrophy, osteoporosis or infertility. It is due to the fact that GnRH agonist therapy is usually accompanied by severe hypoestrogenism. This state is often called “pseudo-menopause” or “medical oophorectomy” and may cause the resignation from a longer-lasting form of treatment [ 40 ]. Moreover, hypoestrogenism significantly contributes to bone mass loss, so prolonged treatment may lead to osteoporosis [ 41 ]. The other group, i.e., GnRH antagonists act in a slightly different way. Some GnRH antagonists are relatively similar in structure to natural GnRH, but have an antagonistic effect, while new GnRH antagonists (e.g., elagolix), are non-peptide and small-molecule compounds [ 35 ]. These agents can be used in the treatment of endometriosis and UFs. However, in the recent years they have mostly been used in female infertility in assisted reproduction, for the prevention of premature LH surge and endogenous ovulation in patients undergoing ovarian hyperstimulation with FSH in the preparation for in vitro fertilization [ 33 ]. The substances competitively and reversibly bind to GnRH receptors in the pituitary gland, blocking the release of gonadotropins from the anterior pituitary. It may even lead to 95% of estradiol and progesterone suppression [ 42 ]. Contrary to previously described medications, GnRH antagonists suppress pituitary gonadotropin by GnRH-receptor competition in a short-lasting manner. This fast action causes the avoidance of the initial stimulatory phase of the agonists. As their life-span is relatively short, the continuation of their use leads to a rapid and predictable recovery of the pituitary-gonadal axis [ 33 ]. Peptide GnRH antagonists are administered as a subcutaneous or intramuscular injection, whereas new antagonists (elagolix, linzagolix, relugolix) can be administrated orally [ 43 , 44 ]. Similarly to agonists, the use of GnRH antagonists is commonly associated with hormonal side effects [ 39 ]. Their subcutaneous administration may also cause injection-site reactions or allergic reactions [ 45 ]. Recently, elagolix and relugolix have been approved by FDA for treatment of heavy menstrual bleeding associated with UFs with a treatment duration for up to two years [ 46 , 47 ]. Notably, either of the approved drug is combined with hormonal add-back therapy (ATB) of estradiol (E2) and norethindrone acetate (NETA) to avoid the drug hypoestrogenic side effects as will be described below. To provide a broader perspective, it needs to be emphasized that both types of drugs may trigger common side effects related to hypogonadism, such as hot flashes, fatigue, weight gain, water retention, decreased libido. In case of prolonged treatment, the drugs may result in various metabolic abnormalities, diabetes destabilization and osteoporosis. According to the literature, the use of selected GnRH agonists was also associated with liver injury [ 39 ]. Various ABT methods have been used for a long time to avoid the side effects of analogs. This kind of therapy is not detrimental to the effective treatment with GnRH agonists. It was found to be commonly effective in preventing bone mineral loss. It also decreased the adverse effects of hypoestrogenism [ 48 ]. Some authors claimed that the choice of estrogen-progestin add-back therapy might be superior to the progestin-only add-back regimen if we considered uterine volumes, hemoglobin concentrations, bone mineral density measurements, or lipid profile [ 49 ]. According to available systematic reviews, there is low- or moderate-quality evidence that selected agents may help to preserve bone density and reduce hot flashes [ 50 ]. Until recently it had been believed that new generations of SPRM drugs, particularly UPA, would completely replace GnRH analogs in the treatment of UFs. Numerous studies revealed that the methods were much better tolerated and their effect on UFs was also strong, which resulted in considerable symptom and tumor volume reduction [ 8 , 51 , 52 ]. However, a broader use of those drugs was quite rapidly stopped because of repeated cases of drug-induced liver injury (DILI) [ 53 , 54 ]. Interestingly, available data on the physiochemical and pharmacokinetic properties of UPA did not suggest an apparent risk for DILI [ 54 ]. However, Gatti et al. (2020) demonstrated a significantly higher proportion of liver disorders for UPA than for mifepristone or leuprolide [ 55 ]. Therefore, in many countries prescribing the drug was suspended, and the revocation of its marketing authorization was recommended [ 54 , 56 ]. The situation was slightly different in case of Vilaprisan with all trials examining its utility for the treatment of UF being halted because of the cases of toxicity in animal studies [ 57 ]. Unfortunately, the above-mentioned events markedly limited the role of SPRMs in the therapy of UFs. The pharmaceutical market has not remained neutral. New non-peptide oral GnRH analogs, i.e. elagolix, linzagolix and relugolix, have been introduced and accepted by medical agencies. Numerous advocates of the pharmacological treatment of UFs are hopeful regarding those preparations. Therefore, it is necessary to show clinicians the various possibilities of the reduction of side effects associated with those drugs. Next, we are summarizing the studies explored utility of ABT in attempt to decrease the side effects of GnRH analogs in women gynecology.