{"paper_id":"c3e216fd-862c-4f97-93ed-27291a10b7ac","body_text":"Submit Manuscript | http://medcraveonline.com\nIntroduction\nThe gonadotropin-releasing hormone (GnRH) antagonists are \nmolecules that act as competitive inhibitors of the GnRH receptors \n(GnRHR) in the adenohypophysis, against endogenous GnRH, and \nonce they bind to this receptor, they cause the immediate suppression \nof the hypothalamic-pituitary-gonadal (HPG) axis, with a rapid and \nsustained decline in gonadotropin and sex hormones levels, via \ndownregulation, preventing premature luteinizing hormone (LH) \nsurges.1–3 These may be used during any time of the follicular phase. 4 \nThe suppression of the HPG axis is dose-related, with lower doses \nachieving a partial suppression, and higher doses, a full suppression.3 \nAntagonists have also shown to behave as agonists in peripheral \ntissues, an observation that has led to believe that GnRHRs may \nacquire varying conformations in the different cell types where they \nare expressed, activating different intracellular signaling pathways, as \nwell.5 As a matter of fact, the synthesis of the first-generation GnRH \nantagonists was based on multiple amino acid substitutions, with an \nintricate structural complexity, and their most deleterious effects, \nsuch as anaphylactic reactions and edematogenic effects, were related \nto histamine release; fortunately, this has changed with the new \ngeneration antagonists.1,3,4\nGnRH antagonists induce a rapid onset of clinical effects, \nwithout the flare-up effect that is seen with agonists, 6,7 and have \nimmediate therapeutic effects, - 24 to 72 hours -, and once this \ntreatment concludes, the hormonal suppression rapidly ceases, with \nnormalization of gonadal function within a few days, guaranteeing \nan increase of GnRH concentration. The use of GnRH antagonists \nhas been destined for the treatment of pathological conditions, such \nas endometriosis, adenomyosis, uterine fibroids, dysmenorrhea, \nmenorrhagia, female infertility, and precocious puberty (PP).1–4,8 \nThe objective of the present manuscript is to review and analyze \nthe use of GnRH antagonists in different gynecological pathologies, \nincluding endometriosis, adenomyosis, non-menstrual pelvic pain, \nuterine fibroids, infertility, and PP, based on their pharmacokinetics, \npharmacodynamics, advantages, efficacy, and safety on recently held \nclinical trials for the aforementioned pathologies, to compartmentalize \ntheir effects in one complete and extensive narrative review. \nMethods\nThe information used to write this manuscript was obtained \nduring a three-month period, between October and May 2022, from \nspecialized literature, written in English and Spanish, related to the \nuse and potential applications of GnRH antagonists in medicine, \nmainly published during the last five years, using journals found in the \nmost relevant medical digital archives, including PubMed, SciELO, \nGoogle Scholar, Cochrane, and Elsevier. Among the keywords used \nfor obtaining this updated information were gonadotropin-releasing \nhormone (GnRH) antagonists; GnRH receptors (GnRHR); elagolix; \nrelugolix; cetrorelix; linzagolix; hypothalamic-pituitary-gonadal \n(HPG) axis; endometriosis; adenomyosis; pelvic pain; uterine fibroids; \nleiomyomas; infertility; precocious puberty; PP; and central PP. \nThe inclusion criteria were articles published between 2015-2022; \npublished clinical trials about the medical uses of GnRH antagonists; \nObstet Gynecol Int J. 2022;13(4):226‒238. 226\n©2022 Martínez-Núñez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, \nwhich permits unrestricted use, distribution, and build upon your work non-commercially.\nGynecological uses of GnRH antagonists: review \narticle\nVolume 13 Issue 4 - 2022\nElizabeth Natalia Martínez-Núñez,1 Daniel \nErnesto Carvallo-Ruiz,1 José Núñez-\nTroconis2\n1Hospital Vargas de Caracas, Faculty of Medicine; Universidad \nCentral de Venezuela, Caracas, Venezuela.\n2Professor, Department of Obstetrics and Gynecology, \nUniversidad del Zulia, Maracaibo, Venezuela.\nCorrespondence: Daniel Ernesto Carvallo Ruiz, Hospital \nVargas de Caracas, Faculty of Medicine, Universidad Central \nde Venezuela, Caracas, Hospital Vargas de Caracas, Urb. San \nJosé de Cotiza, Postal Code 1030, Caracas, Venezuela, T el \n+584141130019, Email \nReceived: July 18, 2022 | Published: August 01, 2022\nAbstract\nAim: to review and analyze the use of gonadotropin-releasing hormone (GnRH) antagonists \nin endometriosis, adenomyosis, non-menstrual pelvic pain, uterine fibroids, prostate cancer, \nfemale infertility, and precocious puberty.\nMethods: the information used to write this manuscript was obtained during a three-month \nperiod, between October and May 2022, from specialized literature, written in English and \nSpanish, related to the use and potential applications of GnRH antagonists in medicine, \nmainly published during the last five years, using journals found in the most relevant medical \ndigital archives, including PubMed, SciELO, Google Scholar, Cochrane, and Elsevier. \nAmong the keywords used for obtaining this updated information were gonadotropin-\nreleasing hormone (GnRH) antagonists; GnRH receptors (GnRHR); elagolix; relugolix; \ncetrorelix; linzagolix; hypothalamic-pituitary-gonadal (HPG) axis; endometriosis; \nadenomyosis; pelvic pain; uterine fibroids; leiomyomas; infertility; precocious puberty; PP; \nand central PP. \nResults: GnRH antagonists induce a rapid onset of clinical effects, without the flare-up \neffect that is seen with agonists, and have immediate therapeutic effects; once treatment \nconcludes, hormonal suppression rapidly ceases, with normalization of gonadal function \nwithin a few days, guaranteeing an increase of GnRH concentration, controlling non-\nmenstrual pelvic pain and heavy menstrual bleeding, and serving as part of the treatment of \ninfertility and precocious puberty. \nConclusion: even though the aforementioned gynecological pathologies can be treated \nwith the use of multiple drugs, GnRH antagonists have shown to be potential first lines of \ntreatment, as long as their administration protocols are followed correctly.\nKeywords: adenomyosis; elagolix; endometriosis; infertility; leiomyoma; pelvic pain; \nprecocious puberty.\nObstetrics & Gynecology International Journal\nReview Article\n Open Access\n\n\nGynecological uses of GnRH antagonists: review article\n227\nCopyright:\n©2022 Martínez-Núñez et al.\nCitation: Martínez-Núñez EN, Carvallo-Ruiz DE, Núñez-Troconis J. Gynecological uses of GnRH antagonists: review article. Obstet Gynecol Int J. \n2022;13(4):226‒238. DOI: 10.15406/ogij.2022.13.00654\nand articles related to new uses of GnRH antagonists in gynecology. \nAmong the exclusion criteria were articles published more than 10 \nyears ago; manuscripts that were not related to the use of GnRH \nantagonists; and articles published in non-reliable sources and with \nquestionable outcomes. \nA summary of the different studies that were included in the \nanalysis of this manuscript can be seen in Table 1.\nDiscussion\nHypothalamic-pituitary-gonadal axis\nThe processes of regulation of fertility, normal sexual function, \nhuman reproduction, and expression of sexual characteristics are \ndirectly dependent on an intricate neuroendocrine network system \nknown as the HPG axis. This axis is activated during the fetal and \nneonatal life, remaining in a quiescent state during childhood, and \nreactivating during puberty through adulthood. 3,9,10 Its principal \nregulator is gonadotrophin-releasing hormone (GnRH), a decapeptide \nhormone synthetized for the first time in 1971. GnRH is constituted \nby 10 amino acids and produced by a few parvocellular neurons,- \n10-30%, or less than 2000-, in the arcuate nucleus and hypothalamic \npreoptic area, extending all the way to the infundibular nucleus, to \nthe lamina terminalis and, from that point, to the median eminence, \nwhich serves as a functional and anatomical link between the \nhypothalamus and the pituitary gland, thus allowing the GnRH to pass \nto the adenohypophysis through the hypophyseal portal system. This \nallows the GnRH to reach the pituitary gonadotropes and to stimulate \nits specific receptors or GnRHR. 1,3,5,9 GnRH controls and regulates \nthe pituitary gonadotrophins hormones secretion, LH and follicle-\nstimulating hormone (FSH), which induce spermatogenesis and the \nproduction of testosterone (T), in the case of men, and stimulate \ngametogenesis in the ovaries and the production of the ovarian sex \nsteroid hormones, estrogen (E 2) and progesterone (P), in the case of \nwomen.1,3,9 \n In women, the control of the reproductive cycle depends on \nan intricate interrelationship between GnRH, LH, FSH and ovarian \nsteroids, which will also determine the release of GnRH, mainly from \nthe arcuate nucleus, via feedback effects and loops that may be long, \nshort or ultra-short. The first one takes place in, both, the hypothalamus, \nand the adenohypophysis, targeting the circulating levels of those \nhormones; the second one consists of a negative-feedback process \nthat LH and FSH apply over their own secretion, most probably from \nan inhibitory effect from the hypothalamic releasing hormones; and, \nfinally, the third one consists of an inhibition by the hypothalamic \nreleasing hormones over their secretion. The regulation of the GnRH \nrelease also depends on the stimulatory or inhibitory actions of \nneurosignals or neurotransmitters such as dopamine, norepinephrine, \nepinephrine, endorphin, serotonin, melatonin, neuropeptide Y , \nkisspeptins, interleukin-1, gonadotropin-inhibitory hormone, as well \nas gonadal steroids, inhibin, activin, follistatin and environmental \nfactors, such as stress and changes in energy stores.1 \nThe secretion and release of GnRH follow two modes: pulsatile and \nsurge, with the last one only taking place in females. The former refers \nto the secretion and episodic releases of the hormone, in a pulsatile \nmanner, approximately every 30 to 120 minutes, into the hypophyseal \nportal system. 5,9–12 The adenohypophysis and GnRH neurons have \nan intrinsic pulsatile pattern. This pulsatile secretion depends on the \nhypothalamic expression of the GnRH-I gene. 1 Also, GnRH has the \nparticularity that, apart from having a very short half-life, -2 to 4 \nminutes,1,3,13 it is not quantifiable outside of the hypophyseal portal \nsystem. But LH and FSH do enter the peripheral circulation, so these \nhormones can be measured in venous blood.14\nThe pulsatility rate of release of GnRH is mainly controlled by \na variety of hypothalamic neurons, especially those located on the \narcuate nucleus; but, it may also be controlled by the neurons in \nthe infundibular region, the preoptic area and/or the anteroventral \nperiventricular nucleus,3 and it has a physiological importance, since \nit avoids the downregulation of GnRHR in the pituitary gonaotropes; \nwhereas, when GnRH is administered in a pulsatile way, there is an \nupregulation of the receptors. It is important to consider that LH and \nFSH are also secreted in a pulsatile manner, as well as the ovarian \nsteroid hormones. FSH secretion is a product of low-frequency \nGnRH pulses, as opposed to LH secretion, which depends on high-\nfrequency pulses. During the follicular phase of the menstrual cycle, \nthe elevation of serum E2 levels induces an activation of the HPG axis, \nwhich traduces itself in a higher GnRH pulse frequency secretion and, \nthus, augments the secretion levels of LH. However, when there are \nnormal levels of E 2 and P, that pulsatility is negatively regulated, - \nwith a downregulation of receptor numbers -, by those hormones, \ncausing a maintenance of the basal levels of serum LH. Nevertheless, \nwhen the hormone levels have decreased, there is a lower GnRH \npulse frequency secretion, causing an elevation of FSH levels. So, the \neffects induced by E2 over GnRH pulsatility rate will be stimulatory or \ninhibitory, depending on the stage of the menstrual cycle, influencing \nthe development of sex functions. More specifically, the LH pulse \nmean amplitude, on the early follicular phase, is of 6.5 IU/L, with a \npulse mean frequency of 90 minutes; during the midfollicular phase, \nof 5 IU/L; during the late follicular phase, of 7.2 IU/L, with a pulse \nmean frequency of 60 to 70 minutes; during the early luteal phase, \nof 15 IU/L, with a pulse mean frequency of 100 minutes; during the \nmidluteal phase, of 12.2 IU/L; and, on the late luteal phase, of 8 IU/L, \nwith a pulse mean frequency of 200 minutes. On the other hand, P has \nan inhibitory action over the secretion of GnRH, especially over pulse \nfrequency; nonetheless, it increases pulse amplitude during the luteal \nphase.1,3,5,10,15\nGonadotropin-releasing hormone receptor (GnRHR)\nThe GnRHR is a rhodopsin-like G protein-coupled receptor 16 that \nhas seven transmembrane domains, an extracellular amino-terminal \ndomain with 35 amino acids and two glycosylation sites. This protein \ncontains 328 amino acids and it is genetically encoded by 4q13, a gene \nlocated on the chromosome 4 that has three exons and two introns.3,5,10 \nThis receptor is not only found in the adenohypophysis–specifically \nin gonadotrophs, thyrotrophs and somatotrophs –, but also, on a \nmultisystemic level, including the placenta, ovarian corpus luteum and \ngranulose cells, epithelial ovarian carcinoma, endometrial, ovarian, \nand mammary cancer/carcinoma cell lines, prostatic tissue, and other \norgans, such as kidneys, liver, heart, skeletal muscle and mononuclear \nblood cells10 There are a variety of GnRHRs, but GnRHR-1 is the only \none expressed in mammals.17\n There are certain differences between the GnRHRs located in \nthe pituitary cells, -particularly in the gonadotrophs -, and those found \nin peripheral reproductive tissues. GnRHRs in the gonadotrophs \nare coupled to the Gαq/11 intracellular signaling pathway. Once \nGnRH binds to this receptor, phospholipase-Cβ1 is activated; \nthus, diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP3) \nare formed. This leads to the activation of protein kinase C (PKC) \nand increase of intracellular calcium levels, due to its release from \nendoplasmic reticulum, inducing the generation of action potentials \nthat facilitate the biosynthesis, secretion, and release of gonadotropins. \nIt is important to take into consideration that PKC also activates \nmitogen-activated protein kinase (MAPK) cascades, phospholipase D \n\nGynecological uses of GnRH antagonists: review article\n228\nCopyright:\n©2022 Martínez-Núñez et al.\nCitation: Martínez-Núñez EN, Carvallo-Ruiz DE, Núñez-Troconis J. Gynecological uses of GnRH antagonists: review article. Obstet Gynecol Int J. \n2022;13(4):226‒238. DOI: 10.15406/ogij.2022.13.00654\nand A2, all of which are in charge of phosphorylating and activating \na group of transcription factors that participate in the biosynthesis \nof gonadotropins. Also, it is known that GnRHR can be coupled to \nthe Gαs/adenyl cyclase (AC) intracellular signaling pathway, which \ninduces an increase of cyclic adenosine monophosphate (cAMP) \nlevels and activates protein kinase A (PKA).1,5,10,18–20\n In the peripheral reproductive tissues, particularly those in \nthe female anatomy, the GnRHRs are coupled to Gαi intracellular \nsignaling pathway. Once this pathway is triggered, a decrease of cAMP \nlevels take place, activating protein kinase A (PKA). This will result \nin the activation of several other intracellular pathways, including, but \nnot limited to, MAPK/ERK kinase, phosphoinositide 3-kinase (PI3K) \nand extracellular signal-regulated kinase 1/2 (ERK 1/2), which will \ninhibit cell proliferation, downregulate gene transcription and produce \nproapoptotic effects.5\nIn order for the GnRHR to be activated, there must be a hypothalamic \npulsatile GnRH secretion, 3,18 whose frequency, width and shape will \ndiffer and vary, depending on the physiological conditions or menstrual \ncycle stage taking place at the moment. 21 Following the activation of \nthis receptor, GnRHR internalizes slowly; plus, it does not undergo a \nfast desensitization.5 However, when this receptor is not sufficiently \nstimulated – meaning that there is a decline on its stimulation-, the \nnumber of GnRHRs decreases, causing an induction and restoration \nof their initial number, via calcium mobilization, in case there is a \nsubsequent stimulation to these receptors. This process is known as \nupregulation. But, when it is continuously stimulated, the number of \nGnRHRs will be downregulated, which will inhibit the synthesis and \nsecretion of gonadotropins, a process known as desensitization.10 \nEndometriosis and adenomyosis\nEndometriosis is a chronic, estrogen-dependent, inflammatory \ndisease, characterized by implantation, abnormal growth, and \npresence of endometrium-like tissue epithelium and stroma outside \nof the uterus, 2,22–24 mainly on the ovaries, uterine tubes, uterosacral \nligaments, rectouterine or vesicouterine pouch, bladder, and/or \nintestines, and rarely on the diaphragm, umbilicus, lungs and pleura, \npericardium, and brain. 2,3,23,24 The patient may present mild, severe, \nor intense symptoms, or even be asymptomatic, with dysmenorrhea, \nchronic non-menstrual pelvic pain, and dyspareunia being the \nmost prevalent. Other infrequent symptoms are dysuria, dyschezia, \nconstipation, and pain at ovulation. Endometriosis may also lead to \nsubfertility and infertility, decreasing ovarian reserve and gamete \ntransport.2,22–26\nAdenomyosis, one of the leading causes of abnormal uterine \nbleeding, is another common gynecologic, chronic, inflammatory, \nestrogen-dependent, and benign uterine disorder in women of \nreproductive age, 27–29 particularly between the ages of 40 and 50, \nwhere heterotopic and non-neoplastic endometrial glands and stroma \ncan be found in the myometrium, at a depth of more than 2.5mm, with \nsurrounding fibrotic, hypertrophic and hyperplastic smooth muscle, \ncausing the enlargement of the uterus. 27,29 It is characterized by the \npresence of heavy menstrual bleeding, dysmenorrhea, dyspareunia, \npelvic pain, metrorrhagia, and infertility.27,28\nOral GnRH antagonists have proven to be a potential alternative \nfor the treatment of these estrogen-dependent conditions, allowing a \ndose-dependent control of estradiol (E 2) levels,22 including elagolix, \nan oral, nonpeptide GnRH antagonist, with a half-life of 4 to 6 \nhours,4,8 and a rapid onset of action. Since its approval by the FDA \nin July 2018, elagolix has become the first GnRH antagonist used for \nthe management and treatment of moderate to severe endometriosis-\nassociated pelvic pain and dysmenorrhea, as well as dyspareunia, \ndue to its high binding affinity for GnRHR, decreased interactions \nwith hepatic P450 enzymes, avoidance of the flare-up effect of the \nGnRH agonists, and its efficacy in suppressing LH, FSH and E 2 \nlevels.2,22–25,28,30–32 \nElagolix is given at doses of 150mg once a day during a 24 month-\nperiod, causing partial estrogen suppression, and 200 mg twice a \nday for 6 months, resulting in full estrogen suppression, allowing an \nadequate and individual control of hypoestrogenic side effects. 4,22,32 \nThe tablet should be taken at approximately the same time, every day, \nwith or without food. Neither the regularity of the menstrual cycles \nnor the patient’s body mass determines the efficacy of this GnRH \nantagonist.32 It may potentially cause dose-dependent changes in \nmenstrual patterns; increase risks of spontaneous abortions; decrease \nbone mineral density; increase transaminase levels; hot flushes; mood \nswings, among other mild side effects. 22,24,31 However, the use of \nthis GnRH antagonist has proven to be significantly safe and well-\ntolerated, with prominent and sustained results that may arise after 4 \nweeks of treatment (Table 1).2,3,31,33–36\nT able 1 Summary of clinical trials and studies regarding the use of GnRH antagonists in different gynecological conditions\nAuthors, \nyear, \ncountry\nStudy design Subjects Intervention Results\nDiamond \net al.,33\nPhase II, randomized, \ndouble-blind, placebo-\ncontrolled, parallel \ngroup study.\nn = 155 women with laparoscopically \nconfirmed endometriosis within 8 \nyears of screening (ages 18-49 years); \nComposite Pelvic Signs and Symptoms \nScore ≥ 6, moderate dysmenorrhea ≥ 2, \nmild non-menstrual pelvic pain ≥ 1.\n-Subjects randomized \nto placebo, elagolix \n150 mg or elagolix 250 \nmg once daily for 12 \nweeks.\n- Elagolix: acceptable efficacy and safety \nprofile.\n- Placebo group: \nrerandomized to \nelagolix.\n- Monthly mean (standard error of the \nmean) reductions: not statistically different \nbetween placebo (-0.88 ± 0.18), elagolix \n150 mg (-1.19 ± 0.18) and elagolix 250 mg \n(-1.25 ± 0.18); although, slightly greater in \nboth elagolix groups.\n- Elagolix (150 and 250 \nmg) group: continue \ndosing for 12 more \nweeks.\n- Monthly mean dysmenorrhea and non-\nmenstrual pelvic pain scores reductions: \ngreater in elagolix group, at 8 and 12 \nweeks (p < 0.05).\n\nGynecological uses of GnRH antagonists: review article\n229\nCopyright:\n©2022 Martínez-Núñez et al.\nCitation: Martínez-Núñez EN, Carvallo-Ruiz DE, Núñez-Troconis J. Gynecological uses of GnRH antagonists: review article. Obstet Gynecol Int J. \n2022;13(4):226‒238. DOI: 10.15406/ogij.2022.13.00654\nAuthors, \nyear, \ncountry\nStudy design Subjects Intervention Results\n- Posttreatment \nfollow-up period after \n24 weeks, for 6 more \nweeks.\n- Adverse effects: headaches, nausea, \nanxiety and hot flushes (elagolix 150 mg: \n62.7%; elagolix 250 mg: 51.9%); minimal \nbone mineral density changes.\nCarr et \nal.,34\nPhase II, randomized, \ndouble-blind, \nmulticenter, placebo-\ncontrolled, parallel \ngroup study.\nn = 155 women with laparoscopically \nconfirmed endometriosis within 8 \nyears of screening (ages 18-49 years); \nComposite Pelvic Signs and Symptoms \nScore > 6, moderate dysmenorrhea > 2, \nmild non-menstrual pelvic pain > 1.\n- Data collection for \n8 weeks, establishing \nbaseline pelvic pain.\n- Elagolix: generally well-tolerated.\n- Double-blind \nplacebo-controlled \ntreatment period for 8 \nmore weeks.\n- Monthly mean dysmenorrhea, non-\nmenstrual pelvic pain, and dyspareunia \nreductions, at week 8: statistically greater \nin elagolix group, compared with placebo \n(-1.13 ± 0.11, p < 0.05; -0.47 ± 0.07, p < \n0.05; -0.61 ± 0.1, p < 0.05, respectively), \nwith similar results at the end of the \nopen-labeled period, and statistically \ngreater than those at the end of week 30.\n- Open-label \ntreatment period for \n16 weeks: elagolix 150 \nmg for all patients \nonce daily.\n- Statistical improvement of quality-of-life \nmeasures.\n- Posttreatment \nfollow-up period for 6 \nmore weeks.\n- Adverse effects: headache, nausea, and \nhot flushes (9.9% of patients, each).\nTaylor et \nal.,35\nT wo phase III, double-\nblind, randomized \ntrials (ELARIS EM-I \nand ELARIS EM-II).\nn = 872 women with laparoscopically \nconfirmed endometriosis within 10 \nyears of screening (ages 18-49 years), \nwith moderate or severe endometriosis-\nassociated pain.\n- Subjects randomized \nto elagolix 150 mg \nonce daily or elagolix \n200 mg twice daily, \ncompared with a \nplacebo group.\n- Elagolix: acceptable efficacy and safety \nprofile.\n- Clinical response to \ndysmenorrhea and to \nnon-menstrual pelvic \npain: measured after 3 \nmonths and 6 months, \nrespectively, studying \nthe possible decrease \nin the pain score and \nin the use of rescue \nanalgesic agents. \n- ELARIS EM-I: clinical response to \ndysmenorrhea at 3 months: elagolix 150 \nmg group (46.4%) and elagolix 200 mg \ngroup (75.8%) vs. placebo group (19.6%); \nclinical response to non-menstrual pelvic \npain at 3 months: elagolix 150 mg group \n(50.4%) and elagolix 200 mg group (54.5%) \nvs. placebo group (36.5%); sustained \nresponses at 6 months.\n- ELARIS EM-II: clinical response to \ndysmenorrhea at 3 months: elagolix 150 \nmg group (43.4%) and elagolix 200 mg \ngroup (72.4%) vs. placebo group (22.7%); \nclinical response to non-menstrual pelvic \npain at 3 months: elagolix 150 mg group \n(49.8%) and elagolix 200 mg group (57.8%) \nvs. placebo group (36.5%); sustained \nresponses at 6 months.\n- Adverse effects: hot flushes, higher level \nof serum lipids, and loss of bone mineral \ndensity.\nSurrey et \nal.,36\nT wo phase III, double-\nblind, randomized \ntrials (ELARIS EM-III \nand ELARIS EM-IV).\nn = 569 women from the ELARIS EM-I \nand ELARIS EM-II trials.\n- Evaluation of 6 \nadditional months \nfrom the ELARIS EM-I \nand ELARIS EM-II \ntrials, for a grand total \nof 12 months. \n- Elagolix: acceptable efficacy and \nconsistent safety profile, with sustained \nreductions in dysmenorrhea, non-\nmnestrual pelvic pain and dyspareunia.\nTable Continued...\n\nGynecological uses of GnRH antagonists: review article\n230\nCopyright:\n©2022 Martínez-Núñez et al.\nCitation: Martínez-Núñez EN, Carvallo-Ruiz DE, Núñez-Troconis J. Gynecological uses of GnRH antagonists: review article. Obstet Gynecol Int J. \n2022;13(4):226‒238. DOI: 10.15406/ogij.2022.13.00654\nAuthors, \nyear, \ncountry\nStudy design Subjects Intervention Results\n- Clinical response \nto dysmenorrhea, \nnon-menstrual pelvic \npain, and dyspareunia, \nmeasured after 6 \nmonths studying the \npossible decrease in \nthe pain score and \nin the use of rescue \nanalgesic agents, after \na total of 12 months.\n- ELARIS EM-I: clinical response to \ndysmenorrhea at 3 months: elagolix \n150 mg group (52.1%) and elagolix 200 \nmg group (78.1%); clinical response to \nnon-menstrual pelvic pain at 3 months: \nelagolix 150 mg group (67.8%) and \nelagolix 200 mg group (69.1%); clinical \nresponse to dyspareunia: elagolix 150 mg \ngroup (45.2%) and elagolix 200 mg group \n(60.0%).\n- ELARIS EM-II: clinical response to \ndysmenorrhea at 3 months: elagolix \n150 mg group (50.8%) and elagolix 200 \nmg group (75.9%); clinical response to \nnon-menstrual pelvic pain at 3 months: \nelagolix 150 mg group (66.4%) and \nelagolix 200 mg group (67.2%); clinical \nresponse to dyspareunia: elagolix 150 mg \ngroup (45.9%) and elagolix 200 mg group \n(58.1%).\n- Reduced estrogen levels.\nMuneyyirci-\nDelale et \nal.,37\nT wo phase III, double-\nblind, randomized, \nplacebo-controlled \ntrials (ELARIS UF-I \nand ELARIS UF-II).\nn = 790 premenopausal women (18-51 \nyears) with heavy menstrual bleeding \n(> 80 ml menstrual blood loss per \ncycle), uterine fibroids and coexisting \nadenomyosis, diagnosed by magnetic \nresonance imaging and/or ultrasound at \nbaseline.\n- Subjects randomized \nto placebo, elagolix \n300 mg twice daily or \nelagolix 300 mg twice \ndaily + 1 mg estradiol / \n0.5 mg norethindrone \nacetate once daily.\n- Elagolix 300 mg BID + 1 mg estradiol / \n0.5 mg norethindrone acetate: prominent \nresults for the reduction of heavy \nmenstrual bleeding; further studies \nrequired.\n- Clinical response \nto heavy menstrual \nbleeding: measured \nafter 6 months, \nstudying the possible \ndecrease in the pain \nscore.\n- Clinical response to heavy menstrual \nbleeding at 6 months: elagolix 300 mg BID \n+ 1 mg estradiol / 0.5 mg norethindrone \nacetate group (76.8%) vs placebo group \n(12.1%) (p < 0.05).\n- Adverse effects: hot flushes, headache, \nnausea, and night sweats. \nMuneyyirci-\nDelale et \nal.,38\nT wo phase III, double-\nblind, randomized, \nplacebo-controlled \ntrials (ELARIS UF-I \nand ELARIS UF-II).\nn = 786 premenopausal women (18-51 \nyears) with heavy menstrual bleeding \n(> 80 ml menstrual blood loss per \ncycle), uterine fibroids, with and without \ncoexisting adenomyosis, diagnosed by \nmagnetic resonance imaging and/or \nultrasound at baseline.\n- Subjects randomized \nto placebo, elagolix \n300 mg twice daily or \nelagolix 300 mg twice \ndaily + 1 mg estradiol / \n0.5 mg norethindrone \nacetate once daily.\n- Elagolix 300 mg BID + 1 mg estradiol \n/ 0.5 mg norethindrone acetate: \nprominent results for the reduction of \nheavy menstrual bleeding in patients \nwith uterine fibroids and coexisting \nadenomyosis.\n- Clinical response \nto heavy menstrual \nbleeding: measured \nafter 6 months, \nstudying the possible \ndecrease in the pain \nscore.\n- Clinical response to heavy menstrual \nbleeding at 6 months in patients with \nadenomyosis (n = 126; 16%): elagolix \n300 mg BID + 1 mg estradiol / 0.5 mg \nnorethindrone acetate group (77.1%) vs \nplacebo group (12.2%).\n- Adverse effects: hot flushes, nausea, and \nnight sweats.\nTable Continued...\n\nGynecological uses of GnRH antagonists: review article\n231\nCopyright:\n©2022 Martínez-Núñez et al.\nCitation: Martínez-Núñez EN, Carvallo-Ruiz DE, Núñez-Troconis J. Gynecological uses of GnRH antagonists: review article. Obstet Gynecol Int J. \n2022;13(4):226‒238. DOI: 10.15406/ogij.2022.13.00654\nAuthors, \nyear, \ncountry\nStudy design Subjects Intervention Results\nOsuga et \nal.,40\nPhase II, multicenter, \nrandomized, double-\nblind, placebo-\ncontrolled study.\nn = 487 premenopausal women, with \nregular menstrual cycles (25-38 days), \nwith confirmed endometriosis via \nlaparoscopy, laparotomy or magnetic \nresonance imaging, within 5 years \nof screening (ages 20-50 years); \ndysmenorrhea and/or pelvic pain.\n- Subjects randomized \nto placebo, relugolix \n10 mg once daily, \nrelugolix 20 mg \nonce daily, relugolix \n40 mg once daily, \nor leuprorelin 3.75 \nmg as a monthly \nsubcutaneous \ninjection.\n- Relugolix, orally administered: well-\ntolerated, prominent effects in the \nreduction of pelvic pain.\n- Clinical response \nto pelvic pain, \ndysmenorrhea, and \ndyspareunia, in mean \nvisual analog scale \nscore, during 28 days \nbefore the end of the \n12-weeks treatment. \n- Mean changes from baseline in mean \nvisual analog scale score for pelvic pain: \nplacebo group: -3.8 mm; relugolix 10 mg \ngroup: -6.2 mm; relugolix 20 mg group: \n-8.1 mm; relugolix 40 mg group: -10.4 \nmm; and leuprorelin group: -10.6 mm (p < \n0.05). After the first month of treatment: \nsaid score started diminishing in a dose-\nresponse fashion, as well as in the case \nof dysmenorrhea. Regarding dyspareunia, \nresults were not consistent.\n- Estradiol, LH, FSH and progesterone: \ndecrease in a dose-response fashion in \nrelugolix groups. \n- Adverse effects: hot flushes, \nmetrorrhagia, menorrhagia, and bone \nmineral density decrease.\nOsuga et \nal.,41\nA phase III, \nmulticenter, \nrandomized, double-\nblind, double-dummy, \nactive-controlled \nstudy\nn = 454 premenopausal women, with \nregular menstrual cycles (25-38 days), \nwith at least one of the following \ndiagnostics: confirmed endometriosis \nvia laparoscopy or laparotomy within 5 \nyears of screening; clinical endometriosis \nwith restricted uterine mobility; \novarian endometrioma confirmed via \nultrasonography or magnetic resonance \nimaging, within 1 year of screening; pelvic \npain; and/or induration of the Douglas \ncavity (ages 20-50 years); dysmenorrhea \nand/or pelvic pain.\n- Subjects randomized \nto placebo, relugolix \n40 mg once daily, \nor leuprorelin 3.75 \nor 1.88 mg as a \nmonthly subcutaneous \ninjection.\n- Efficacy for treating pelvic pain: relugolix \nhas a similar efficacy than leuprorelin, \nconfirming the results of the phase II trial.\n- Clinical response \nto pelvic pain, \ndysmenorrhea, and \ndyspareunia, in mean \nvisual analog scale \nscore, during 28 days \nbefore the end of the \n24-weeks treatment.\n- Mean changes from baseline in mean \nvisual analog scale score for pelvic pain: \nrelugolix 40 mg group: -52.6 ± 1.3; and \nleuprorelin group: -57.5 ± 1.4; with a \ndecrease of ovarian endometrioma of: \n12.26 ± 17.52 cm3 (relugolix group) and \n14.10 ± 18.81 cm3 (leuprorelin groups). \nDysmenorrhea and dyspareunia had \nconsistently similar results.\n- Adverse effects: hot flushes, \nmetrorrhagia, headache, and genital \nhemorrhage.\nDonnez et \nal.,22\nPhase IIb, \nmultinational, \nmulticenter, double-\nblind, randomized, \nparallel-group, \nplacebo-controlled, \ndose-ranging trial \n(EDELWEISS trial).\nn = 328 premenopausal women, with \nsurgically confirmed endometriosis within \n10 years of screening, and endometriosis-\nassociated pain (ages 18-45 years).\n- Subjects randomized \nto placebo, linzagolix \n50 mg, linzagolix 75 \nmg, linzagolix 100 mg \nor linzagolix 200 mg, \nor a titrated-dose \ngroup (75 mg initially) \nonce daily for 24 \nweeks.\n- Linzagolix: well-tolerated, acceptable \nefficacy and safe profile, particularly in the \nreduction of endometriosis-associated \npain and bone mineral loss and increase of \nquality of life.\nTable Continued...\n\nGynecological uses of GnRH antagonists: review article\n232\nCopyright:\n©2022 Martínez-Núñez et al.\nCitation: Martínez-Núñez EN, Carvallo-Ruiz DE, Núñez-Troconis J. Gynecological uses of GnRH antagonists: review article. Obstet Gynecol Int J. \n2022;13(4):226‒238. DOI: 10.15406/ogij.2022.13.00654\nAuthors, \nyear, \ncountry\nStudy design Subjects Intervention Results\n- Placebo group (12 \nweeks): rerandomized \nto linzagolix 100 mg \ngroup for another 12 \nweeks.\n- Decrease in pelvic pain at 12 weeks: \nplacebo group (34.5%); linzagolix 75 mg \ngroup (61.5%); linzagolix 100 mg group \n(56.4%); and linzagolix 200 mg group \n(56.3%), effects that were maintained up \nto 24 weeks. \n- Tritrated-dose group: \n75 mg once daily for \n12 weeks; 50, 75 or \n100 mg for the next \n12 weeks.\n- Decrease in dysmenorrhea and non-\nmenstrual pelvic pain: IDEM.\n- Clinical response \nto pelvic pain, non-\nmenstrual pelvic \npain, dysmenorrhea, \namenorrhea, quality of \nlife and bone mineral \ndensity. \n- Statistical improvement of quality-of-life \nmeasures.\n- Bone mineral density loss: less than \n1% in linzagolix 50 and 75 mg groups, \nincreasing dose-dependently up to 2.6% in \nlinzagolix 200 mg group.\nOsuga et \nal.,52\nPhase III, multicenter, \nrandomized, double-\nblind, double-dummy, \nparallel-group, \nnoninferiority study. \nn = 429 premenopausal women, \nregular menstrual cycles (25-38 days), \nwith confirmed noncalcified uterine \nleiomyomas with no prior surgical \ntreatment, and heavy menstrual bleeding \n(at least 120 points on the pictorial blood \nloss assessment chart) for minimum three \nconsecutive days. \n-Subjects randomized \nto placebo, oral \nrelugolix 40 mg once \ndaily, or leuprorelin \nacetate 3.75 or 1.88 \nmg as a monthly \nsubcutaneous \ninjection, for 24 weeks.\n- Relugolix in the improvement of heavy \nmenstrual bleeding: well-tolerated \nand noninferior to monthly injected \nleuprorelin.\n- Posttreatment \nfollow-up period after \n24 weeks, for 4 more \nweeks.\n- Mean pictorial blood loss assessment \nchart score at baseline: relugolix group \n(254.3) and leuprorelin group (263.7). \n- Clinical response \nto menstrual blood \nloss, myoma and \nuterine volumes, and \nhemoglobin levels.\n- Weeks 6-12: % patients with said chart \nscore of less than 10 was of 82.2% in \nthe relugolix group, and 83.1% in the \nleuprorelin group (noninferiority margin: \n15%; p < 0.05). Relugolix: earlier effect on \nmenstrual bleeding (chart score of less \nthan 10: 64.2% vs 31.7%); faster recovery \nafter treatment discontinuation (37 days \nvs 65 days).\n- Myoma and uterine volumes reduced, \nhemoglobin levels increased.\nHoshiai et \nal.,51\nPhase II, randomized, \ndouble-blind, placebo-\ncontrolled study.\nn = 216 women, with confirmed uterine \nleiomyomas and heavy menstrual bleeding \n(at least 120 points on the pictorial blood \nloss assessment chart).\n-Subjects randomized \nto oral relugolix 10 \nmg, 20 mg, or 40 mg \nonce daily, for 12 \nweeks.\n- Relugolix: well-tolerated and significant \ndose-dependent decreases in heavy \nmenstrual bleeding.\n- Clinical response to \nmenstrual blood loss, \namenorrhea, myoma \nand uterine volumes.\n- Points on the pictorial blood loss \nassessment chart score of less than 10 \n(weeks 6-12): relugolix 10 mg group \n(20.8%), 20 mg group (43.6%), and 40 mg \ngroup (83.6%).\n- Relugolix 40 mg group: achievement \nof amenorrhea and dose-dependent \ndecrease in myoma and uterine volumes.\n- Adverse effects: mild-to-moderate \nheadaches, menorrhagia, metrorrhagia and \nhot flushes.\nTable Continued...\n\nGynecological uses of GnRH antagonists: review article\n233\nCopyright:\n©2022 Martínez-Núñez et al.\nCitation: Martínez-Núñez EN, Carvallo-Ruiz DE, Núñez-Troconis J. Gynecological uses of GnRH antagonists: review article. Obstet Gynecol Int J. \n2022;13(4):226‒238. DOI: 10.15406/ogij.2022.13.00654\nAuthors, \nyear, \ncountry\nStudy design Subjects Intervention Results\nArcher et \nal.,53\nPhase IIa, multiple-\ncohort, proof-of-\nconcept, dose-ranging \nstudy.\nn = 271 women (mean age: 41.8 years), \nwith regular menstrual cycles (24-35 \ndays), with confirmed uterine leiomyomas \nvia pelvic ultrasound, and heavy menstrual \nbleeding (> 80 ml menstrual blood loss \nper cycle).\n- Subjects randomized \nto placebo (elagolix \n600 mg once daily), \nelagolix 100 mg twice \ndaily, elagolix 200 mg \ntwice daily, elagolix \n300 mg twice daily, \nelagolix 400 mg once \ndaily, or elagolix 200 \nmg twice daily + \ncontinuous low-dose \n0.5 mg estradiol / 0.1 \nmg norethindrone \nacetate, elagolix 300 \nmg twice daily + 1 mg \nestradiol continuously \nand 200 mg cyclical \nprogesterone, for 3 \nmonths.\n- Elagolix: well-tolerated and significant \nreduction in heavy menstrual bleeding in \nwomen with uterine fibroids; low-dose \nadd-back regimes: decrease in flushing.\n- Clinical response \nto heavy menstrual \nbleeding: least-mean \npercentage changes of \nmenstrual blood loss \nmeasured at the end \nof treatment.\n- Mean percentage changes of menstrual \nblood loss: higher with elagolix (72-98%; \ngreater with 300 mg), compared with \nplacebo (8-41%); add-back regimes (80-\n85%).\n- Adverse effects: hot flushes; lower with \nplacebo (56%) and add-back regimes \n(55.6-70.6%).\nCarr et \nal.,54\nPhase IIb, double-\nblind, randomized, \nplacebo-controlled, \nparallel-group study\nn = 571 premenopausal, nonpregnant \nwomen (43±5 years), with regular \nmenstrual cycles (less than 38 days), with \nconfirmed uterine leiomyomas and heavy \nmenstrual bleeding (> 80 ml menstrual \nblood loss per month).\n- Subjects randomized \nto elagolix 300 mg \nonce daily or 600 \nmg once daily, for 6 \nmonths.\n- Elagolix (with add-back regime + without \nadd-back regime): well-tolerated and \nsignificant reduction in heavy menstrual \nbleeding in women with uterine \nfibroids; add-back regime: reduction in \nhypoestrogenic effects in bone mineral \ndensity. \n- Elagolix 300 mg \ngroup: placebo, elagolix \nalone, elagolix + 0.5 \nmg estradiol / 0.1 mg \nnorethindrone acetate, \nand elagolix + 1 mg \nestradiol / 0.5 mg \nnorethindrone acetate.\n- Heavy menstrual bleeding reduction: \nelagolix 300 mg group (placebo: 27%; \nelagolix alone: 92%; elagolix + 0.5 mg \nestradiol / 0.1 mg norethindrone acetate: \n85%; and elagolix + 1 mg estradiol / 0.5 mg \nnorethindrone acetate: 79%); elagolix 600 \nmg group (placebo: 32%; elagolix alone: \n90%; elagolix + 0.5 mg estradiol / 0.1 mg \nnorethindrone acetate: 73%; and elagolix \n+ 1 mg estradiol / 0.5 mg norethindrone \nacetate: 82%).\n- Elagolix 600 mg \ngroup: placebo, elagolix \nalone, elagolix + 0.5 \nmg estradiol / 0.1 mg \nnorethindrone acetate, \nand elagolix + 1 mg \nestradiol / 0.5 mg \nnorethindrone acetate.\n- Bone mineral density: reduction \nattenuated by the addition of elagolix + \n1 mg estradiol / 0.5 mg norethindrone \nacetate.\n- Clinical response to heavy menstrual bleeding, and changes in bone \nmineral density.\nTable Continued...\n\nGynecological uses of GnRH antagonists: review article\n234\nCopyright:\n©2022 Martínez-Núñez et al.\nCitation: Martínez-Núñez EN, Carvallo-Ruiz DE, Núñez-Troconis J. Gynecological uses of GnRH antagonists: review article. Obstet Gynecol Int J. \n2022;13(4):226‒238. DOI: 10.15406/ogij.2022.13.00654\nAuthors, \nyear, \ncountry\nStudy design Subjects Intervention Results\nSchlaff et \nal.,56\nT wo phase III, double-\nblind, randomized, \nplacebo-controlled \ntrials (ELARIS UF-1 \nand ELARIS UF-2).\nn = 412 premenopausal women (18-51 \nyears), with regular menstrual cycles \n(24-35 days), with confirmed uterine \nleiomyomas via ultrasonopgraphy, and \nheavy menstrual bleeding (> 80 ml \nmenstrual blood loss per cycle).\n- Subjects randomized \nto placebo, elagolix \nalone 300 mg twice \ndaily, or elagolix 300 \nmg twice daily + 1 \nmg estradiol / 0.5 \nmg norethindrone \nacetate once daily, for \n6 months. \n- Elagolix with add-back regime: well-\ntolerated and significant reduction in \nheavy menstrual bleeding in women with \nuterine fibroids.\n- Posttreatment \nfollow-up period, for \n12 more weeks.\n- Heavy menstrual bleeding reduction \nin ELARIS UF-1: placebo (8.7%), elagolix \nalone (84.1%), and elagolix + estradiol / \nnorethindrone acetate (68.5%).\n- Clinical response \nto heavy menstrual \nbleeding.\n- Heavy menstrual bleeding reduction \nin ELARIS UF-1: placebo (10%), elagolix \nalone (77%), and elagolix + estradiol / \nnorethindrone acetate (76.5%).\n- Adverse effects: hot flushes and \nmetrorrhagia, especially with the use \nof elagolix + 1 mg estradiol / 0.5 mg \nnorethindrone acetate.\n    \n- Bone mineral density: reduction \nattenuated by the addition of elagolix + \n1 mg estradiol / 0.5 mg norethindrone \nacetate.\nGnRH antagonists do not form part of the first line of treatment \nof adenomyosis. However, elagolix has been used in patients with \nuterine fibroids and adenomyosis at the baseline, with some consistent \nresults, particularly a significant reduction of the heavy menstrual \nblood loss (Table 1).37,38 In the first half of 2020, the first case report \nof a patient with adenomyosis, treated with elagolix, was published. \nThree months after the start of the treatment, at a dose of 150 mg once \ndaily, the pelvic pain had ceased. One month later, the uterine mass \nhad disappeared, with some diffusely distributed remnants. This case \nclearly shows the potential that elagolix may have in forming part of \nthe line of treatment of adenomyosis.39 \nRelugolix and linzagolix are other oral GnRH antagonists that \nare currently in the third phase of clinical trials for the treatment \nof endometriosis-associated pelvic pain. 2 Relugolix (TAK-385) is a \nnovel non-peptide, with a high affinity and a potent orally selective \nantagonist activity for human GnRHR. It can continuously and \nreversibly suppress the HPG axis. 3 The clinical trials have shown \nprominent results in the reduction of pelvic pain, after the oral \nadministration of relugolix at doses of 10, 20, and 40mg, once a day, \nfor 24 weeks, with some mild side effects, including metrorrhagia, \nmenorrhagia, and hot flushes, as well as a decrease in E 2 levels after \nthe administration of relugolix at higher doses. The third phase of \nongoing clinical trials (SPIRIT 1, SPIRIT 2, and SPIRIT extension) \nis studying the efficacy and safety of the daily co-administration of \n40 mg of this antagonist with 12 or 24 weeks of 1mg of estradiol and \n0.5mg of norethindrone acetate as add-back therapy, in patients with \nendometriosis-associated pelvic pain (Table 1).3,40–43\nLinzagolix, an antagonist with a half-life of 15 to 18 hours, has \nhad potentially positive results in the alleviation of dysmenorrhea and \nendometriosis-associated pelvic pain, after its daily administration, at \ndoses of 75, 100, and 200mg. Patients who presented with dyspareunia \nreceived higher doses (200mg), due to hypoestrogenic side effects. \nHowever, with that same high dose, bone mineral density loss would \nbe a more frequent side effect, in comparison with lower doses \n(100 mg). The most common adverse effects have been headaches \nand hot flushes; increases in LDL cholesterol, HDL cholesterol, and \ntriglyceride levels have not been commonly reported. It should be \ntaken into account that, even though a phase II trial demonstrated \nthe safety, efficacy and tolerance of linzagolix in the treatment of \nendometriosis, there are no definitive nor published results yet, \nconsidering that the EDELWEISS 3 phase III trial is still ongoing, and \nthat the EDELWEISS 2 trial was discontinued due to the COVID-19 \npandemic. Recently, it was shown that linzagolix may play a crucial \nrole in the treatment of adenomyosis, causing a regression in the \nadenomyotic lesions, and improving the patient’s quality of life. \nNevertheless, at the moment, linzagolix, as well as GnRH antagonists \nin general, are not included as tools in the treatment of adenomyosis \n(Table 1).2,27,44,45 \nAnother GnRH antagonist that is used for the treatment \nof endometriosis is cetrorelix acetate, a basic peptide that is \nsubcutaneously injected. 3,42 It has the capacity of inhibiting the \nproliferation of tumor necrosis factor-α (TNF-α)-induced cells, and \nthus reducing its levels, in endometrial stromal cells, 3,31 as well as \nreducing the stromal and glandular components of endometriotic \nlesions.17 In a recent clinical trial, 3mg of cetrorelix acetate were \nsubcutaneously injected, each week, for two months, to a group of \n15 patients with histologically diagnosed symptomatic endometriosis, \nshowing positive results to this antagonist, with almost no adverse \neffects. 60% of the sample showed regression of endometriosis-\nassociated lesions, making cetrorelix acetate a potential alternative \nfor the treatment of this condition.3,31,42 \nUterine fibroids\nUterine fibroids, or leiomyomas, constitute the most common \nsolid and benign gynecological tumors in women of reproductive \nTable Continued...\n\nGynecological uses of GnRH antagonists: review article\n235\nCopyright:\n©2022 Martínez-Núñez et al.\nCitation: Martínez-Núñez EN, Carvallo-Ruiz DE, Núñez-Troconis J. Gynecological uses of GnRH antagonists: review article. Obstet Gynecol Int J. \n2022;13(4):226‒238. DOI: 10.15406/ogij.2022.13.00654\nage, which arise from the myometrium, with the particularity of \nbeing steroid-hormone responsive and an unknown etiology, whose \nmonoclonal growth depends on the presence of E 2 and P, secreting \nan excessive, altered, and disorganized extracellular matrix of fibrous \nnature. Leiomyomas can be classified as subserosal, intramural and \nsubmucosal. These patients have a prevalence of abnormal and \nexcessive menstrual bleeding, intermenstrual bleeding, with or without \ndysmenorrhea, as well as a possible association with infertility and \nsubfertility; although, some women are asymptomatic.6,26,46 \n Cetrorelix acetate, ganirelix acetate, and Nal-Glu have been \nstudied for the treatment of leiomyomas, although these are not \ncommonly used. Their administration is via a subcutaneous injection \nevery 1 to 4 days. 46,47 The former has the potential of decreasing the \nuterine and the fibroids’ volume in pre-menopausal patients, causing \nmenorrhagia, the disappearance of pelvic pain, and a rapid return of \novarian function once the treatment has ceased. It is believed that it \nincreases apoptotic processes, inhibits the proliferating cell nuclear \nantigen, and decreases the production of some of the extracellular \ncomponents of leiomyomas, including collagen-1A, fibronectin and \nversican variant V0.7,48\n In January 2019, the use of relugolix for the treatment of \nuterine fibroids was approved in Japan. 43 This orally active non-\npeptide GnRH antagonist is capable of inhibiting the secretion of LH \nand FSH and, thus, E 2 and P, inducing amenorrhea. 43,49 With an oral \ndosage of 40mg and a half-life of 45.42 hours, this antagonist allows \nfaster recovery of the hormonal serum levels, inducing menstruation, \nafter it is discontinued. The recovery of fertility in these patients tends \nto be faster than in those that are treated with GnRH agonists, such as \nleuprorelin acetate.43,49,50 In a 2017 randomized, double-blind, phase II \ncontrol trial, Hoshiai et al. 51 concluded that amenorrhea and a dose-\ndependent reduction of the volume of the uterus and the uterine fibroids \ntend to be achieved by the majority of patients treated with a dose \nof 40mg of relugolix, in comparison with those treated with 10 and \n20mg, respectively, without presenting serious adverse effects. Osuga \net al. 52 concluded, as well, in the results of two separate phase III, \nrandomized clinical trials, published in March 2019 52 and November \n2019,49 respectively, that the use of 40mg of relugolix once a day to \ntreat heavy menstrual bleeding and pain symptoms associated with \nuterine fibroids is absolutely safe and well tolerated, with non-severe \nside effects. In both trials, more than 50% of their sample achieved \neither the lowest possible score of pain or its complete abolition, and \nmore than 80% presented a reduction of the volume of the uterus and \nthe uterine fibroids. Amenorrhea was achieved by more than 75% \nof the sample at the end of the trials, and menstruation returned to \npatients once the treatment was discontinued. Patients also presented \nhypoestrogenic effects and reduction of the levels of LH, FSH, and P, \nwhich returned to normality after the discontinuation of relugolix, a \nclear advantage that GnRH antagonists have over agonists, especially \nfor the restoration of fertility. At the moment, three international phase \nthree clinical trials are studying the efficacy and safety of the use of \n40mg relugolix co-administered, once a day, with add-back therapy \nwith low doses of estradiol and norethindrone acetate. These trials are \nLIBERTY 1, LIBERTY 2, and LIBERTY extension (Table 1).43,49\nIn 2017, Archer et al. 53 published the results of a phase II study, \ndemonstrating that the use of 200-600mg of elagolix alone in \npremenopausal women with uterine fibroids and heavy menstrual \nblood loss is similar than the use of elagolix with a low-dose hormonal \n(E2 and P) add-back therapy for the suppression of heavy menstrual \nbleeding and reductions of the sizes of the uterine cavity and fibroids. \nOn the other hand, Carr et al., 54 in 2018, demonstrated that the use \nof elagolix alone, - 300mg twice daily and 600mg once a day, - is \nsuperior for reducing profuse menstrual blood loss in women with \nleiomyomas, compared with elagolix with hormonal add-back \ntherapy (0.5mg of estradiol/0.1mg of norethindrone acetate and 1mg \nof estradiol/0.5mg of norethindrone acetate). Hypoestrogenic side \neffects, especially on bone mineral density, were reduced with the use \nof hormonal add-back therapy.54 The ELARIS Uterine Fibroids (UF) \n1 and 2 randomized, double-blind, placebo-control, phase III clinical \ntrials demonstrated that the reduction of mean menstrual blood loss \nvolume after one month of treatment, achievement of amenorrhea, \nand improvement of quality of life is completely significant in women \ntreated with elagolix and add-back therapy, with mild to moderate \nside effects.55–57 In the first half of 2020, the FDA approved the first \nand only oral treatment for heavy menstrual bleeding associated with \nuterine fibroids, marketed as Oriahnn, which consists of two capsules; \nthe first one contains 300mg of elagolix, 1 mg of estradiol and 0.5 mg \nof norethindrone acetate, which is taken in the morning; and the other \none contains elagolix alone, which is taken at night. This treatment \nshould be received for a maximum of 24 months, reducing heavy \nmenstrual bleeding, and decreasing hypoestrogenic side effects (Table \n1).58,59 \nFinally, even though more studies are required in the future, \nlinzagolix with add-back therapy may constitute the most appropriate \nregime for the treatment of sex-hormone-dependent diseases, \nincluding uterine fibroids with heavy menstrual bleeding, considering \nthat it has shown rapid, dose-dependent decreases in the serum levels \nof LH, FSH, and E 2. This was demonstrated by Pohl et al., 26 in 2019, \nwith a randomized, phase I clinical trial, that showed that the use of \ncoadjuvant add-back therapy may be necessary with the use of higher \ndoses of linzagolix, in order to avoid an increase in the patients’ \nbleeding patterns, E2 levels, and adverse effects. Although, the small \nsample of the study (n=32) may be a limitation and must be taken \ninto account. Overall, linzagolix has been well tolerated, with mild \nto moderate severe effects, especially hot flushes and bone mineral \nloss.26\nPrecocious puberty \nThe development of secondary sexual characteristics before \nthe expected age is what defines precocious puberty (PP), usually \ntaking place before the age of 8 in girls, and 9 in boys. PP can be \nGnRH-independent or peripheral (PPP), or GnRH-dependent or \ncentral (CPP). 60,61 PPP is a congenital or acquired consequence of \nsex steroid hormones secretion from the gonads, adrenal cortex, or \nectopic sources, characterized by an abnormally increased production \nof estrogens, and androgens. It is less common than CPP and it can \nsometimes lead to the pulsatile secretion of GnRH and secondary \ncentral PP.61,62 CPP can be caused by genetic mutations, injuries, \nmalformations, idiopathic, and different pathologies of the central \nnervous system. Its incidence is similar in girls and boys. 1,63 In girls, \nthe main indicator is breast development or an increase in the growing \nspeed; this can be accompanied by pubic hair development and an \nincrease in uterine volume. In boys, it usually presents as an increase \nin testicular volume; although, gonadarche can precede adrenarche in \nboys under the age of 6.1,64,65 \nEven though the treatment of CPP is usually based on GnRH \nagonists, recent studies have shown that the use of GnRH antagonists, \nsuch as relugolix, may be an effective treatment for this disorder. \nGnRH antagonists offer some advantages over agonists. 66 As it was \npreviously mentioned, GnRH agonists may cause clinical symptoms \nrelated to an initial increase of gonadotropins and gonadal hormones; \n\nGynecological uses of GnRH antagonists: review article\n236\nCopyright:\n©2022 Martínez-Núñez et al.\nCitation: Martínez-Núñez EN, Carvallo-Ruiz DE, Núñez-Troconis J. Gynecological uses of GnRH antagonists: review article. Obstet Gynecol Int J. \n2022;13(4):226‒238. DOI: 10.15406/ogij.2022.13.00654\nthe antagonists, on the other hand, reduce these hormones, avoiding \nthe flare-up caused by the agonists, and therefore diminishing this side \neffect.67 One of these drugs is relugolix, a selective antagonist that \nis capable of reducing the levels of E 2, P, and T in a short period. 43 \nAnother advantage of relugolix is that, as a non-peptide antagonist, \nafter its withdrawal and discontinuation, the patient rapidly regains \ngonadal function, avoiding undesirable adverse effects. There are no \ndefinitive results regarding the use of relugolix in PP, as a first-line \ntreatment. This may serve as a prominent study in these patients in a \nnon-distant future.1\nInfertility \nSince the ‘90s, GnRH antagonists have been used to suppress \nhypophyseal activity and the HPG axis, preventing premature LH \nsurges,68 when used as comedication in IVF/intracytoplasmatic \nsperm injections procedures (IVF/ICSI).69 In comparison with GnRH \nagonists, the duration of treatment with GnRH antagonists is shorter. \nThere is a reduction of gonadotropin dose requirements and duration \nof its stimulation. There is less suppression in the early stages of the \nfollicular phase, benefiting women who are poor responders to these \ntreatment protocols. Considering that the levels of LH decrease during \nthe mid-follicular phase and finally start gradually ascending again in \nthe late follicular phase of the menstrual cycle, these protocols should \nbe applied during these phases of the menstrual cycle, due to its major \nrisk of a premature rise in the LH levels. However, the suppression of \nendogenous gonadotropin secretion is more complete with the use of \nantagonists than with the use of agonists. This treatment can also be \npostponed until the follicular development and the elevation of the E2 \nlevels have taken place, avoiding the emergence of hypoestrogenic \nside effects, approximately after 5 to 6 days posterior to gonadotropin \nstimulation. The use of GnRH antagonists diminishes the risk of \novarian hyperstimulation syndrome, development of follicular cysts, \nand cycle cancelation. However, patients have a risk of treatment \nfailure of around 0.34 and 8%, considering that the release of \nGnRH induced by endogenous E 2 is still preserved. Among the most \nprominent risk factors for these patients are senescence, diminished \novarian reserve, and a decreased response to gonadotropin.1,4,68\nSince 1995, cetrorelix and ganirelix have been used as comedication \nin ovarian stimulation for IVF. There are two forms of administration \nof these GnRH antagonists. The first one is the single-dose protocol, \nwhich consists of the injection of 3mg of cetrorelix once daily, during \nthe late phase of ovarian stimulation. And the second form is the \nmultiple-dose protocol, consisting of the administration of 0.25µg of \neither cetrorelix or ganirelix starting on the sixth day of stimulation. \nNonetheless, since the introduction of a flexible regimen starting \non day 7, which is based on the size of the follicle, the number of \ninjections and the duration of the treatment with these drugs have \ndiminished. Even though clinical trials in the past evidenced a small \nreduction in pregnancy rates, when GnRH antagonists were applied, \nprotocols used in the present day have not shown any difference in the \nrates of live births.4,69 Usually, there is no variation in terms of adverse \neffects differences between women using GnRH antagonists and \nthose using agonists.4 Embryonic side effects, as well as a decrease in \ntheir development and implantation potential, may arise if there is no \nincrease in the P secretion levels after the immediate suppression of \nthe LH by the GnRH antagonist.69\nLambalk et al.8 showed that GnRH antagonists regimes, compared \nwith agonists, especially in patients with polycystic ovarian syndrome, \nreduced by 2.5% the rate of ovarian hyperstimulation syndrome, with \na 3.6% of risk reduction in ongoing pregnancy rates, possibly due \nto inadequate suppression of the LH surges or to the lowering of the \noocyte yield, as a result of asynchronous follicular development in \nresponse to endogenous FSH secretion during the early follicular \nphase. But this sample was treated with GnRH antagonists and \nreceived an oral contraceptive pill pretreatment, 7 which might \nhave altered their results, considering that this pretreatment is \ncapable of reducing the chances of ongoing pregnancy and causing \nlower live-birth rate, demonstrated by Kolanska et al. 70,71 In recent \nyears, steroid pretreatments in IVF procedures, such as the luteal \nestradiol pretreatment, during the GnRH antagonist protocol, have \nbeen showing prominent results, by improving follicle stimulation, \nretrieving oocyte maturation, improving the response to the GnRH \nantagonists in the IVF cycles, and, even, clinical pregnancy and live \nbirth rates. Future clinical trials are needed to get better conclusions.72\nConclusion\nGnRH antagonists have proven to be promising alternatives in the \ntreatment of estrogen-dependent conditions, such as endometriosis, \nadenomyosis, and uterine fibroids, through the control of the non-\nmenstrual pelvic pain and heavy menstrual bleeding that arise from \nthese pathologies. Considering that these drugs have advantages over \nGnRH agonists, particularly the avoidance of the flare-up effects \nthat are experienced with the use of the agonists, as well as their \nimmediate therapeutic effects and the suppression of the premature \nsurges of LH levels, GnRH antagonists have shown great potential in \nthe treatment of endocrine pathologies, including PP. They have also \nbeen used in IVF/ICSI procedures, diminishing the risks of ovarian \nhyperstimulation syndrome, with a small or no reduction in pregnancy \nrates. These drugs have proven to be promising alternatives in the \ntreatment of these pathologies and may eventually be used as their \nfirst line of treatment, as long as they are administered following their \nadministration protocols correctly. In that sense, it is imperative to \nkeep enhancing and applying new clinical trials regarding the use of \nGnRH antagonists. \nAcknowledgments\nNone.\nContribution to authorship\nAll authors contributed to the conception of this narrative review, \nplanning, carrying out, data synthesis and interpretation, analysis, \nwriting and editing of the manuscript, and approval of the final version \nthat was ultimately submitted.\nFunding \nThe present manuscript did not receive any type of funding from \nany commercial company, charity, or government department.\nConflicts of interest \nThe authors declare that there is no conflict of interest regarding \nthe publication of this article.\nReferences\n1. Taylor HS, Pal L, Seli E. 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