Riscos e benefícios do uso a longo prazo de análogos do GnRH e terapia add back em mulheres com endometriose

Uterine fibroids, smooth muscle tumours of the uterus, are found in at least 25 to 35% of women over the age of 35 years. Although some of these tumours are asymptomatic, up to 50% cause symptoms severe enough to warrant therapy and surgery is the standard treatment. Fibroid growth is stimulated by oestrogen and gonadotropin releasing hormone agonists (GnRHa) which induce a state of hypoestrogenism have been investigated as a potential treatment. GnRHa treatment causes fibroids to shrink but cannot be used long term because of unacceptable symptoms and bone loss. Therefore, GnRHa may be useful pre-operatively both to reduce fibroid and uterine volume and control bleeding. The objective of this review is to evaluate the role of pre-treatment with gonadotropin releasing hormone (GnRH) analogues prior to a major surgical procedure, either hysterectomy or myomectomy, for uterine fibroids. Electronic searches for relevant randomised controlled trials of the Cochrane Menstrual Disorders and Subfertility Group Register of Trials, MEDLINE, EMBASE, PsychLIT, Current Contents, Biological Abstracts, Social Sciences Index and CINAHL were performed. Attempts were also made to identify trials from citation lists of review articles. In most cases, the first author of each included trial was contacted for additional information. The inclusion criteria were randomised comparisons of GnRH analogue treatment versus placebo, no treatment, or other medical therapy prior to surgery, either myomectomy or hysterectomy, for uterine fibroids. Nineteen RCTs were identified that fulfilled the inclusion criteria for this review. The reviewers extracted the data independently and odds ratios for dichotomous outcomes and weighted mean differences for continuous outcomes were estimated from the data of twelve trials where GnRH analogue treatment was compared with no pre-treatment and five trials where GnRH analogue treatment was compared with placebo (two trials are awaiting assessment). No RCTs of GnRH analogue treatment versus other medical therapy were identified. Results from pre-operative outcomes were combined for both types of surgery but results from intra- and post-operative outcomes were reported separately for myomectomy and hysterectomy. Subgroup analysis was performed according to type of control group, no pre-treatment or placebo, and for some outcomes there were additional subgroup analyses according to size of the uterus in gestational weeks. Pre- and post-operative haemoglobin (Hb) and haematocrit (HCT) were significantly improved by GnRH analogue therapy prior to surgery, and uterine volume, uterine gestational size and fibroid volume were all reduced. Pelvic symptoms were also reduced but some adverse events were more likely during GnRH analogue therapy. Hysterectomy appeared to be easier after pre-treatment with GnRH analogue therapy; there was reduced operating time and a greater proportion of hysterectomy patients were able to have a vaginal rather than an abdominal procedure. Duration of hospital stay was also reduced. Blood loss and rate of vertical incisions were reduced for both myomectomy and hysterectomy. Evidence of increased risk of fibroid recurrence after GnRH analogue pre-treatment in myomectomy patients was equivocal and no data were available to assess change in post-operative fertility. The increased costs associated with GnRH analogue therapy were not assessed. The use of GnRH analogues for 3 to 4 months prior to fibroid surgery reduce both uterine volume and fibroid size. They are beneficial in the correction of pre-operative iron deficiency anaemia, if present, and reduce intra-operative blood loss. If uterine size is such that a mid-line incision is planned, this can be avoided in many women with the use of GnRH analogues. For patients undergoing hysterectomy, a vaginal procedure is more like

There was low or moderate quality evidence that tibolone, raloxifene, estriol and ipriflavone help to preserve bone density and that MPA and tibolone may reduce vasomotor symptoms. Larger uterine volume was an adverse effect associated with some add-back therapies (MPA, tibolone and conjugated estrogens). For other comparisons, outcomes of interest were not reported or study findings were inconclusive.

Central precocious puberty (CPP) is defined as an early pubertal development that occurs before the age of 9 years in boys and 8 years in girls. It results from premature activation of the hypothalamic-pituitary-gonadal axis. Gonadotropin-releasing hormone agonists (GnRHa) have been the gold standard therapy for CPP for more than 30 years. These compounds have a high affinity for the pituitary LHRH receptor and are resistant to enzymatic degradation. Through continuous stimulation, GnRHa inhibit the pulsatile secretion of gonadotropin, resulting in hormonal suppression, cessation of pubertal development, and normalization of growth and skeletal maturation rates. The goal of therapy is to halt pubertal progression and delay epiphyseal maturation that leads to improvement of final adult height. There are no widely accepted guidelines for how long to continue treatment with a GnRHa for CPP, and individual practice varies widely. Furthermore, conflicting results have been published on the long-term effects of GnRHa therapy in patients with CPP. Therefore, we reviewed the current literature focusing our attention on the long-term effects and the significant adverse drug reactions (ADRs) observed during treatment with GnRHa in patients with CPP. Our review may provide the necessary data to enable clinicians to administer GnRHa in the safest and most appropriate way. Further studies are necessary to identify the mechanisms of development of potential adverse drug reactions related to GnRHa therapy in CPP. (www.actabiomedica.it)

The rationale underlying the use of gonadotropin-releasing hormone analogues (GnRHa) to treat patients with central precocious puberty is reviewed. GnRHa are now considered the treatment of choice for patients with central precocious puberty, but the adult heights that these patients attain often fall short of what would be expected according to their genetic potential. This has led to investigations of whether adding growth hormone to GnRHa therapy can improve adult height. The results of recent combination trials are presented and analyzed.

Several lines of investigation suggest a direct modulatory role for gonadotrophin-releasing hormone (GnRH) on granulosa cell functions. Also, GnRH and its analogues (GnRHa) have been implicated in the resumption of meiosis, both in vivo and in vitro. Despite the presence of specific receptors for GnRH on human granulosa and luteal cells, very little is known about the possible effects of this hormone on the ovary. The use of GnRHa for long periods of time in patients undergoing in vitro fertilization (IVF) may influence granulosa cell function and/or oocyte maturation. We describe our clinical and experimental data in which we have searched for evidence of a direct action of GnRHa on the ovary. We have found that the retrieval of higher numbers of oocytes in women treated with GnRHa is correlated with oocytes of lower quality, manifested by a decreased fertilization and implantation rate. This impairment seems to be the consequence of oocyte immaturity, as ascertained by cytogenetic analysis of unfertilized oocytes in which an increase in diploidy, as well as prematurely condensed sperm chromosomes of the G1 phase, was observed in women with an excessive response to the stimulating drugs. Follicular atresia was not increased in women treated with GnRHa. Thus, there was no evidence for a direct effect of GnRHa on the human oocyte. Rather, the observations reflect the harmful effect of pushing follicles in early stages of development using this stimulation protocol. We have also searched for possible effects of GnRHa on granulosa-luteal cells obtained at ovum collection. In vitro culture of these cells has shown that the steroidogenic pathway is affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Steroidogenesis in vitro of human granulosa-luteal cells pretreated in vivo with gonadotropin-releasing hormone analogs

Gonadotropin-releasing hormone analogues (GnRH-a) have been used preoperatively before hysteroscopic myomectomy to decrease the size and vascularization of the myomas, but evidence to support this practice is weak. Our objective was to analyze the use of GnRH-a in the reduction of submucous fibroid as a facilitator for surgical hysteroscopy from published clinical trials. Studies from electronic databases (Pubmed, Scielo, EMBASE, Scopus, PROSPERO), published between 1980 and December 2018. The keywords used were fibroid, GnRH analogue, submucous, histeroscopy, histeroscopic resection and their correspondents in Portuguese. The inclusion criteria were controlled trials that evaluated the GnRH-a treatment before hysteroscopic resection of submucous myomas. Four clinical trials were included in the meta-analysis. Two review authors extracted the data without modification of the original data, using the agreed form. We resolved discrepancies through discussion or, if required, we consulted a third person. The present meta-analysis included a total of 213 women and showed no statistically significant differences in the use of GnRH-a compared with the control group for complete resection of submucous myoma (relative risk [RR]: 0.94; 95% confidence interval [CI]: 0.80-1.11); operative time (mean difference [MD]: - 3.81; 95%CI : - 3.81-2.13); fluid absorption (MD: - 65.90; 95%CI: - 9.75-2.13); or complications (RR 0.92; 95%CI: 0.18-4.82). The present review did not support the routine preoperative use of GnRH-a prior to hysteroscopic myomectomy. However, it is not possible to determine its inferiority when compared with the other methods due to the heterogeneity of existing studies and the small sample size.

Maintaining surplus captive male antelope in bachelor groups can result in aggression in some species, leading to injury or death. Suppressing endogenous testosterone using gonadotropin‐releasing hormone (GnRH) analogs has been used in primates to control aggressive behavior, but little information is available on the use of GnRH analogs in nondomestic ruminant species. The aim of this study was to investigate the effect of a slow‐release GnRH agonist (deslorelin) on circulating hormone concentrations, semen and sperm characteristics and behavior in male gerenuk, dorcas gazelle, and scimitar horned oryx. Body weight, testicular volume, circulating hormone concentrations, ejaculate traits, and behavior were recorded before and during deslorelin treatment. A GnRH challenge (with serial blood sampling) was administered to gerenuk and dorcas gazelles before and during GnRH analog treatment. Quantitative behavioral data were collected for gerenuk and dorcas gazelles for 30 min three times a week, starting 1 month before deslorelin treatment, and the mean incidence of combined aggressive behaviors (supplanting, foreleg kicking, sparring, marking, and mounting) was compared before and during deslorelin treatment. No statistical difference (P>0.05) in body weight, semen volume, sperm concentration, percent sperm motility, percent sperm plasma membrane integrity, or percent normal sperm morphology was found before or during deslorelin treatment. The characteristic rise in luteinizing hormone (LH), occurring ∼10 min following administration of a GnRH challenge in untreated males, was not evident during deslorelin treatment, although tonic LH concentrations were maintained. No differences (P>0.05) in the mean incidence of any aggressive behavioral traits in gerenuk or dorcas gazelle were detected before and during deslorelin. The absence of a GnRH‐induced increase in serum LH in treated males indicated that deslorelin suppressed pituitary responsiveness to endogenous GnRH, but that the continued tonic production of LH was sufficient to maintain testosterone production, aggressive behavior, and subsequent semen production. Zoo Biol 21:435–448, 2002. © 2002 Wiley‐Liss, Inc.

Studies of the use of gonadotropin-releasing hormone analogs (GnRHa) to protect ovarian function have shown mixed results. To determine whether administering GnRHa during chemotherapy in premenopausal women with breast cancer can reduce ovarian impairment. This randomized clinical trial, conducted at the Shanghai Jiao Tong University Affiliated Shanghai Sixth People's Hospital and Zhejiang Cancer Hospital in China, was an open-label trial involving premenopausal women aged 18 to 49 years with operable stage I to III breast cancer for which treatment with adjuvant or neoadjuvant cyclophosphamide-containing chemotherapy was planned in 2 parallel groups: treatment with chemotherapy with or without GnRHa. Enrollment occurred from September 2015 to August 2017, and follow-up ended December 2020. The data were analyzed in March 2021. A total of 405 patients were enrolled in the study, among whom 27 patients (6.7%) quit participation voluntarily, 33 (8.1%) did not meet the inclusion criteria and were excluded, and 15 (3.7%) were lost to follow-up. Ultimately 330 patients were included in the primary analysis, including 29 patients with baseline anti-Müllerian hormone levels less than 0.5ng/ mL. Eligible patients were randomly assigned (1:1) to receive chemotherapy with (n = 165) or without (n = 165) GnRHa. In patients randomized to receive GnRHa, 3.6 mg of goserelin or 3.75 mg of leuprorelin was injected subcutaneously once every 28 days from 1 to 2 weeks before the first cycle of chemotherapy to 4 weeks after the last cycle of chemotherapy. The primary end point was the rate of premature ovarian insufficiency (POI) at 12 months after chemotherapy. Premature ovarian insufficiency was defined as anti-Müllerian hormone levels of less than 0.5 ng/mL in this study. The secondary end point was overall survival (OS) and tumor-free survival (TFS). A total of 330 eligible patients could be evaluated with complete data, among whom 301 patients (91.2%; GnRHA group: mean [SD] age, 40.6 [6.7] years; control group: mean [SD] age, 40.2 [5.9] years) were eligible for primary end point analysis. At 12 months after the completion of chemotherapy, the POI rate was 10.3% (15 of 146) in the GnRHa group and 44.5% (69 of 155) in the control group (odds ratio, 0.23; 95% CI, 0.14-0.39; P < .001). Anti-Müllerian hormone resumption in the GnRHa group was significantly better than that in the control group (15 of 25 vs 6 of 44; odds ratio, 4.40; 95% CI, 1.96-9.89; P < .001). After a median follow-up of 49 months (range, 25-60 months), the differences in 4-year OS and TFS between the 2 groups were not significant. A post hoc analysis showed that in patients younger than 35 years, the TFS was higher in the GnRHa group than in the control group (93% vs 62%; P = .004; hazard ratio, 0.15; 95% CI, 0.03-0.82; P = .03). This randomized clinical trial found that administering GnRHa in treatment with chemotherapy for premenopausal patients with breast cancer reduces the risk of POI, which promotes the recovery of ovarian function. ClinicalTrials.gov Identifier: NCT02518191.

In the debate about preserving fertility for patients treated with chemotherapy, more is known about inducing gonadal toxicity than is known about avoiding gonadal toxicity. Controversy over how best to advise patients facing a medical decision will commonly occur when inadequate data are available on which to base a sound opinion. The debate becomes passionate when emotionally charged issues such as cancer and fertility preservation are involved, as evidenced by the two reviews in this issue of The Oncologist [1, 2]. Premature ovarian failure is the most common significant long-term toxicity of chemotherapy in premenopausal women. While chemotherapy-induced ovarian ablation is potentially beneficial for some individuals, such as those with hormone receptor–positive breast cancer, it is an unwanted side effect for others. Adverse consequences of premature menopause include hot flashes, mood changes, genitourinary dysfunction, osteoporosis, and infertility. The choices of chemotherapy drug, dose, duration, and schedule are important risk factors for gonadal failure. Alkylating agents are well known to result in ovarian failure, but anthracyclines and taxanes contribute as well [3, 4]. The age of the patient at exposure to the drug also affects ovarian function outcome. The younger the patient and the lower the dose of exposure, the greater the potential for preserving ovarian function. It is important to note, however, that preservation of ovarian function does not equal fertility, which in turn may not result in live births. Potential interventions to preserve ovarian function and/or fertility have not yet been subjected to rigorous scientific assessment. For patients strongly desiring preservation of fertility or ovarian function, the debate centers on whether it is appropriate to offer gonadotropin-releasing hormone (GnRH) analogue coadministration with curative-intent chemotherapy outside of a clinical trial. Based on biologic plausibility and clinical data from single-arm or suboptimally controlled studies, Blumenfeld [1] supports the potential for cotreatment with a GnRH analogue and chemotherapy to reduce the gonadal toxicity of chemotherapy. On the other hand, Oktay et al. [2] point out the failure of these studies to demonstrate superior fertility with GnRH analogue coadministration. Furthermore, Oktay et al. [2] discuss mechanisms whereby GnRH analogue cotreatment might be not only ineffective, but also potentially detrimental to ovarian function. Both papers support participation in ongoing randomized clinical trials assessing this method for ovarian function preservation. Oktay et al. [2] offer three requirements “for a new medical treatment to be proven effective.” The authors then provide a rationale to support their view that GnRH analogues do not meet these criteria. Certainly, there are no prospective, randomized, controlled trials showing consistent preservation of ovarian function during and after chemotherapy exposure (point 2). Oktay et al. [2] question the plausibility of GnRH analogues to have the desired effect of protecting the ovaries from cytotoxic agents. In the presentation of their detailed analysis it becomes clear that most, if not all, studies of GnRH analogue coadministration with chemo-

It is demonstrated that gonadotropin-releasing hormone (GnRH) analogs can directly inhibit the proliferation of reproductive tissue cancer cells, but the poor pharmacokinetic properties still restrict their application in treating hormone-dependent diseases. Modifications in position 6 and 10 of natural GnRH can improve the metabolic stability. In order to study the effect of incorporation Cys6 substitution with C-terminal Pro9-NHEt modification and dimerization of linear peptides on metabolic stability and antiproliferative activity of GnRH analogs, two new GnRH analogs [l-Cys6, desGly10, Pro9-NHEt]-GnRH (1) and [d-Cys6, desGly10, Pro9-NHEt]-GnRH (2), and their corresponding dimer derivatives ([l-Cys6, desGly10, Pro9-NHEt]-GnRH)2 (3) and ([d-Cys6, desGly10, Pro9-NHEt]-GnRH)2 (4) were synthesized. Incubation of these analogs with human serum was carried out to evaluate their metabolic stability, and direct growth inhibitory effect of the two dimer derivatives 3 and 4 on MCF-7 human breast cancer cell line was examined by MTT assay. The metabolic stability of dimer derivatives 3 and 4 was remarkably improved in comparison with natural GnRH. The d-Cys6 substituted dimer derivative 4 exhibited higher inhibitory effect (29.6–39.7% growth reduction) on cell growth than its corresponding counterpart 3 (21.8–26.2% growth reduction) at concentration range of 50, 100 and 200 μΜ. The cell growth inhibition of leuprolide was 16.4–27.2% at the tested concentrations. The dimer derivative 4 was the most stable and active GnRH analog in this study and has the potential for future preclinical investigations as promising antitumor drug candidate.

Does fertility preservation using gonadotrophin-releasing hormone (GnRH) analogues during chemotherapy act through a direct effect on the ovary or through inhibition of FSH secretion? The absence of FSH in vivo and the direct exposition of ovarian follicles to GnRH analogues in vitro did not prevent chemotherapy-induced ovarian damage. The potential mechanisms of action of GnRH analogues in protecting ovaries against chemotherapy damage remain poorly understood. We previously showed that GnRH analogues have a limited inhibitory effect on gonadotropin secretion and follicular growth in mice. Mouse models were developed to independently evaluate (i) the indirect effect of FSH depletion on chemotherapy-induced ovarian damage using Fshb-deficient (-/-) mice to mimic the profound inhibition of FSH secretion during GnRH analogues treatment and (ii) the direct in vitro effect of GnRH agonist and antagonist in follicles exposed to chemotherapy using a follicular culture system. To assess the indirect effect of GnRH analogues through FSH inhibition, Fshb-/- mice were treated with 1 IU pregnant mare serum gonadotropin (control group) or saline (study group) for 7 days and with cyclophosphamide (200 mg/kg) on Day 5. Ovaries were collected 48 h post-cyclophosphamide to evaluate ovarian reserve, cellular apoptosis and proliferation. To evaluate the direct effects of GnRH analogues on growing follicles, isolated preantral follicles from prepubertal mice were cultured in vitro for 13 days with 1 μM GnRH analogues and 20 μM of 4-hydroperoxycyclophosphamide or not at Day 4. Oocytes were matured by adding epidermal growth factor (EGF)/hCG on Day 12. Follicular development, follicular survival, oocyte maturation rates, cAMP production, and steroidogenesis were evaluated. To assess the direct GnRH analogues effects on follicular reserve, whole neonatal ovaries were cultured in vitro under the same conditions for 2 days. Ovaries were processed 24 h post-chemotherapy for ovarian reserve, cellular apoptosis and proliferation analysis. Cyclophosphamide induced a significant follicular loss of more than 50% in Fshb-/- mice regardless of previous treatment with gonadotropins and no difference was observed in cell proliferation or apoptosis. In vitro experiments on growing follicles showed that 4-hydroperoxycyclophosphamide significantly decreased preantral follicle survival and maturation rates (55% and 37%, respectively) and delayed follicular development, regardless of the presence of GnRH analogues. Chemotherapy reduced granulosa cell numbers in all groups, while no change in cAMP production/106 granulosa cells was observed. Similarly, 4-hydroperoxycyclophosphamide induced apoptosis and significant follicular loss in cultured neonatal ovaries irrespective of GnRH analogues exposure. As ovarian GnRH receptors expression differs in humans and mice, further studies are needed to validate our results in human ovaries. Our findings demonstrate that ovarian damage occurred even in the absence of FSH, suggesting that inhibition of the pituitary-gonadal axis is not involved in ovarian protection during GnRH analogues treatment. Using in vitro models, no evidence for direct protective effect of GnRH analogues against cyclophosphamide metabolite damage was observed. At present, clinical efficiency of GnRH analogues to prevent chemotherapy-induced ovarian damage remains highly debated and these experimental results reinforced the question as they did not bring evidence of direct or indirect mechanisms of protection. N/A. This work was supported by the Belgian FNRS, 'Le Fonds Emile DEFAY', and 'La Fondation Rose et Jean Hoguet'. Authors have no conflict of interest to declare.

Dear Dr. Papageorghiou, We applaud Vincent and Horne for clearly explaining the different mechanisms of endometriosis-associated pain, and for stating ‘there is already enough evidence that endometriosis-associated pain is similar in so many ways to other forms of chronic pain that we should feel confident in taking a pain-focussed approach’ [1] Accordingly, they advocate treatments targeted both at lesions for the nociceptive component of pain and at pain itself for the neuropathic-nociplastic component. Regarding nociceptive pain, the authors propose moving away from excisional surgery as the optimal primary choice and initiating hormonal treatment early instead [1]. However, they also emphasise that over 40% of patients reportedly fail to improve with medical therapy. When assessing the effect of any treatment, it is assumed that it has been correctly indicated and completed. As no surgeon is eager to publish poor results, the postoperative outcomes reported in meta-analyses may represent overestimates, reflecting the excellent technical capabilities of a few experts. We hypothesise that the opposite is true of hormonal therapies for endometriosis. These medications can be prescribed by all gynaecologists and GPs. As drugs are usually prepackaged and provided with approved administration schedules, specific experience may not be deemed necessary. However, we challenge the notion that findings from general clinical practice surveys reflect the true potential effect of hormonal treatment for endometriosis-associated pain. First-line medications include combined oral contraceptives (COCs) and progestogens, with gonadotropin-releasing hormone (GnRH) agonists and antagonists constituting second-line treatments. The choice of specific first-line components (e.g., ethinyl-oestradiol versus bioidentical 17β-oestradiol or oestetrol), doses (e.g., regular versus ultra-low-dose COCs) and the modality of use (e.g., cyclic vs. continuous use of COCs, or the adoption of tailored cycling regimens) may influence the outcome. The same applies to whether GnRH analogues are systematically used for patients who do not respond to or tolerate first-line medications. Notably, ‘hormonal therapy failure’ should not usually be concluded before amenorrhoea has been achieved or if a GnRH analogue has not been used, that is, if all the medical treatment options have not been tried. Before referring a patient to pain management services, referral to services specialising in medical treatments for endometriosis is recommended. Medical treatment experts could thus co-manage care, requesting consultations with pain management experts for non-responders to second-line drugs [2]. Patients may feel ‘abandoned’ when referred to a pain management service, as they may believe that the cause of their symptoms has been overlooked or that their condition has a particularly poor prognosis. This may increase anxiety, depression, and catastrophising, which could worsen nociplastic pain. Unfortunately, little evidence supports the pharmacological treatment of non-nociceptive pain in women with endometriosis. Vincent and Horne ask: ‘How do we identify those who may still benefit from a lesion-focused approach?’ [1]. To this end, we suggest conducting a 3-month GnRH analogue ex-juvantibus test, as non-responders are more likely to experience non-nociceptive pain and benefit most from a multidisciplinary approach [3]. This could also prevent the ‘scapegoat’, described by Hudelist et al. [4], of attributing pain to ectopic lesions when it is not caused by endometriosis. P.V. conceived the text and drafted the original version of the letter. V.B., N.S., P.Vi. and E.S. participated in conceiving and drafting part of the letter and critically revising it. All authors approved the final version of the letter. The authors have nothing to report. P.V. is a member of the Editorial Board of Human Reproduction Open, the Journal of Obstetrics and Gynaecology Canada and the International Editorial Board of Acta Obstetricia et Gynecologica Scandinavica; has received royalties from Wolters Kluwer for chapters on endometriosis management in the clinical decision support resource up-to-date; and maintains both a public and private gynaecological practice. P.Vi. is co-editor-in-chief of the Journal of Endometriosis and Uterine Disorders. E.S. is editor-in-chief of Human Reproduction Open; discloses payments from Ferring and Theramex for research grants and personal honoraria from Merck-Serono, Ibsa, and Gedeon-Richter; and maintains both a public and private gynaecological practice. V.B. and N.S. declare they have no Conflicts of Interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

A randomized trial comparing the 52-mg levonorgestrel system with combination oral contraceptives for treatment of heavy menstrual bleeding

It is now known that gonadotrophin-releasing hormone analogues (GnRHa) are extremely efficient at reducing uterine fibroid volume and reversing the related symptomatology. However, the fibroids tend to return to their pretreatment size about 6 months after discontinuing treatment. GnRHa treatment cannot be continued indefinitely due to its potential complications and high cost. It is therefore proposed that GnRHa treatment should be phase one of a two-phase treatment plan for uterine fibroids. The initial course of GnRHa should be followed by either menopause or surgery. Experience with presurgical GnRHa use indicates a definite treatment advantage and the use of GnRHa as adjuncts to surgery is well established. The value of GnRHa treatment as a alternative to surgery in pre-menopausal patients, however, remains to be established.