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Ovulation induction with pulsatile gonadotropin releasing hormone: missing in action

2018; Elsevier BV; Volume: 109; Issue: 4 Linguagem: Inglês

10.1016/j.fertnstert.2018.01.023

1556-5653

Marco Filicori, Graçiela Estela Cognigni,

Sexual Differentiation and Disorders

The identification and characterization of gonadotropin releasing hormone (GnRH; also known as luteinizing hormone-releasing hormone, LHRH) represents one of the most consequential reproductive medicine discoveries of the 20th century. Roger Guillemin and Andrew Schally were awarded the 1977 Nobel Prize in Physiology or Medicine for their pioneering work on GnRH, and soon thereafter GnRH and its superactive analogs became available for treatment of human reproductive disorders. Nevertheless, initial studies failed to identify a clear clinical role for these substances. The seminal work of Ernst Knobil and coworkers (1Belchetz P.E. Plant T.M. Nakai Y. Keogh E.J. Knobil E. Hypophysial responses to continuous and intermittent delivery of hypothalamic gonadotropin-releasing hormone.Science. 1978; 202: 631-633Crossref PubMed Scopus (1078) Google Scholar) soon demonstrated that lack of therapeutic efficacy of GnRH and GnRH agonists depended on insufficient understanding of the critical role of the pulsatile nature of GnRH secretion; in primates (monkeys and humans alike) only pulsatile GnRH administration will result in sustained gonadotropin secretion and normal gonadal function, while continuous GnRH infusion (or the use of superactive GnRH agonists) fails to persistently stimulate, and eventually will further suppress, endogenous gonadotropin secretion. Thus, by the early 1980s pulsatile GnRH administration became a suitable clinical option for the management of anovulation and hypogonadotropic conditions in both women (2Filicori M. Flamigni C. Meriggiola M.C. Cognigni G. Valdiserri A. Ferrari P. et al.Ovulation induction with pulsatile gonadotropin-releasing hormone: technical modalities and clinical perspectives.Fertil Steril. 1991; 56: 1-13Abstract Full Text PDF PubMed Google Scholar) and men (3Pitteloud N. Hayes F.J. Dwyer A. Boepple P.A. Lee H. Crowley W.F. Predictors of outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic hypogonadism.J Clin Endocrinol Metab. 2002; 87: 4128-4136Crossref PubMed Scopus (160) Google Scholar); conversely, at about the same time, GnRH agonists started being applied in conditions where endogenous gonadotropin suppression was the clinical goal of treatment (e.g., in precocious puberty, prostate cancer, endometriosis, uterine leiomyoma). Pulsatile GnRH administration will restore normal gonadotropin secretion in profound hypogonadotropic hypogonadism due to absent or severely reduced endogenous GnRH secretion, in both men and women. In most male hypogonadotropic patients receiving exogenous pulsatile GnRH, gonadotropin secretion rapidly increased to normal adult range levels; testosterone achieved normal concentrations in 93% of subjects (3Pitteloud N. Hayes F.J. Dwyer A. Boepple P.A. Lee H. Crowley W.F. Predictors of outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic hypogonadism.J Clin Endocrinol Metab. 2002; 87: 4128-4136Crossref PubMed Scopus (160) Google Scholar). Spermatogenesis was successfully induced in 77% and 82% of subjects by 12 and 24 months of treatment, respectively. It is notable that in these subjects conception can occur even when sperm count is relatively low. When applied to anovulatory female patients, pulsatile GnRH will recreate all the critical endocrine features of the spontaneous menstrual cycle, including an early follicular phase follicle-stimulating hormone (FSH) rise, progressive luteinizing hormone increments in the mid and late follicular phase (paralleled by FSH decline), and a physiological mid cycle gonadotropin surge preceded by a normal estradiol peak; when pulsatile GnRH is continued throughout the luteal phase, normal estrogen and progesterone secretion also ensues (2Filicori M. Flamigni C. Meriggiola M.C. Cognigni G. Valdiserri A. Ferrari P. et al.Ovulation induction with pulsatile gonadotropin-releasing hormone: technical modalities and clinical perspectives.Fertil Steril. 1991; 56: 1-13Abstract Full Text PDF PubMed Google Scholar). Pituitary negative and positive feedback mechanisms are fully restored so that mid-late follicular phase estrogen increments are mirrored by FSH decrements and the midcycle gonadotropin surge occurs at peak follicle maturity conditions. Thus, just like in the spontaneous menstrual cycle, initial multiple follicle recruitment is followed by the selection of a single dominant follicle that develops until ovulation. This endocrine and ovarian pattern dramatically contrasts with the outcome of exogenous gonadotropin administration. With the latter, a counter-physiological prevalence of high FSH levels up to the late follicular phase can result in markedly elevated estrogen levels and brisk folliculogenesis; risks of ovarian hyperstimulation syndrome (OHSS) development and multiple conceptions are higher as human chorionic gonadotropin (hCG) is used to trigger ovulation. To induce ovulation, GnRH is usually administered through a portable infusion pump at 60-120 min intervals, at dosages ranging between 2.5 and 20.0 μg per bolus. When the intravenous route of administration (vs. subcutaneous) is chosen, the lower GnRH dosages (2.5–5.0 μg/bolus) and shorter intervals (60-90 min) are preferable. Ovulation usually occurs within two weeks of treatment onset and exogenous hCG is not needed to trigger final follicle and oocyte maturation, though it can be later used to replace pulsatile GnRH for the support of corpus luteum function. When no hCG is administered at midcycle, moderate or severe OHSS never occurs. In a limited number of cycles, multiple folliculogenesis and thus multiple conception is possible. Usually this occurs when pretreatment pituitary gonadotropin reserve is elevated as in cases of secondary normogonadotropic amenorrhea, and when multifollicular and polycystic ovaries are present; nevertheless, overall occurrence of multiple gestations after pulsatile GnRH is well below 5% and approaches a physiologic 1.4% in patients with profound hypogonadotropic hypogonadism (e.g., Kallmann Syndrome) or when pituitary gonadotropin reserve is reduced before treatment with the administration of a GnRH agonist (4Filicori M. Flamigni C. Dellai P. Cognigni G. Michelacci L. Arnone R. et al.Treatment of anovulation with pulsatile gonadotropin-releasing hormone: prognostic factors and clinical results in 600 cycles.J Clin Endocrinol Metab. 1994; 79: 1215-1220Crossref PubMed Scopus (76) Google Scholar). Pulsatile GnRH can also be used to induce ovulation in polycystic ovary syndrome patients, through less effectively. In anovulatory patients pregnancy rates after pulsatile GnRH are comparable to natural conception rates in normal subjects. Intrauterine insemination is not indispensable, but can be resorted to when sperm quality is suboptimal in male partners. Miscarriage rates after pulsatile GnRH are generally similar to what reported in spontaneous conception, though elevated in patients with polycystic ovary syndrome (4Filicori M. Flamigni C. Dellai P. Cognigni G. Michelacci L. Arnone R. et al.Treatment of anovulation with pulsatile gonadotropin-releasing hormone: prognostic factors and clinical results in 600 cycles.J Clin Endocrinol Metab. 1994; 79: 1215-1220Crossref PubMed Scopus (76) Google Scholar). In this issue of Fertility and Sterility, Tranoulis and coworkers (5Tranoulis A. Laios A. Pampanos A. Yannoukakos D. Loutrdis D. Michala L. Efficacy and safety of pulsatile gonadotropin-releasing hormone therapy amongst patients with idiopathic and functional hypothalamic amenorrhea; a systematic review of the literature and a meta-analysis.Fertil Steril. 2018; 109: 708-719Abstract Full Text Full Text PDF Scopus (7) Google Scholar) in their review and metanalysis of more than 1,000 patients in 35 studies have confirmed that ovulatory rates following pulsatile GnRH in hypogonadotropic patients are elevated (85% and 79% in primary and secondary hypothalamic amenorrhea, respectively). Though not significant, intravenous therapy appeared to be slightly more effective than subcutaneous pulsatile GnRH administration (89% vs. 78%). Pregnancy and live birth rates per ovulatory cycle were elevated at 39% and 35%, respectively. Considering its excellent efficacy and safety (no severe OHSS risk and few multiple conceptions), then why is pulsatile GnRH not always applied as a first line treatment of anovulatory infertility? Of course, continuously wearing a pump for at least two weeks is less practical than single, daily subcutaneous gonadotropin injections and requires elevated patient and health care provider motivation. Septic complications related to the indwelling catheter used for chronic subcutaneous or intravenous GnRH administration are theoretically possible (though they were never reported) (5Tranoulis A. Laios A. Pampanos A. Yannoukakos D. Loutrdis D. Michala L. Efficacy and safety of pulsatile gonadotropin-releasing hormone therapy amongst patients with idiopathic and functional hypothalamic amenorrhea; a systematic review of the literature and a meta-analysis.Fertil Steril. 2018; 109: 708-719Abstract Full Text Full Text PDF Scopus (7) Google Scholar). This treatment is also more burdensome (due to infusion pump logistics) and less financially rewarding for pharmaceutical companies in this field. On the whole, however, it is likely that the greatest asset of pulsatile GnRH is also its greatest liability. While greatly efficacious to manage anovulatory infertility, the unique capacity of pulsatile GnRH to almost invariably induce monofolliculogenesis makes it unsuitable as a treatment modality for in-vitro fertilization, where moderate ovarian hyperstimulation and multiple folliculogenesis until the end of stimulation are a desirable goal. This feature greatly reduces the therapeutic range of this ovulation induction modality. Hopefully, future developments in infusion device technology will make pulsatile GnRH even more user-friendly and, once again, a viable therapeutic tool for the management of anovulatory infertility and the treatment of male and female hypogonadotropic hypogonadism. Efficacy and safety of pulsatile gonadotropin-releasing hormone therapy among patients with idiopathic and functional hypothalamic amenorrhea: a systematic review of the literature and a meta-analysisFertility and SterilityVol. 109Issue 4PreviewTo systematically review and appraise the existing evidence in relation to the efficacy and safety of pulsatile gonadotropin-releasing hormone (pGnRH) for the treatment of women with hypothalamic amenorrhea (HA). Full-Text PDF