Gonadotropin-releasing hormone analogs: Mechanisms of action and clinical applications in female reproduction.

Extra-hypothalamic GnRH and extra-pituitary GnRH receptors exist in multiple human reproductive tissues, including the ovary, endometrium and myometrium. Recently, new analogs (agonists and antagonists) and modes of GnRH have been developed for clinical application during controlled ovarian hyperstimulation for assisted reproductive technology (ART). Additionally, the analogs and upstream regulators of GnRH suppress gonadotropin secretion and regulate the functions of the reproductive axis. GnRH signaling is primarily involved in the direct control of female reproduction. The cellular mechanisms and action of the GnRH/GnRH receptor system have been clinically applied for the treatment of reproductive disorders and have widely been introduced in ART. New GnRH analogs, such as long-acting GnRH analogs and oral nonpeptide GnRH antagonists, are being continuously developed for clinical application. The identification of the upstream regulators of GnRH, such as kisspeptin and neurokinin B, provides promising potential to develop these upstream regulator-related analogs to control the hypothalamus-pituitary-ovarian axis.

Adjuvant treatment strategies in ovarian stimulation for poor responders undergoing IVF: a systematic review and network meta-analysis.

BACKGROUND: Despite great advances in assisted reproductive technology, poor ovarian response (POR) is still considered as one of the most challenging tasks in reproductive medicine. OBJECTIVE AND RATIONALE: The aim of this systemic review is to evaluate the role of different adjuvant treatment strategies on the probability of pregnancy achievement in poor responders undergoing IVF. Randomized controlled trials (RCTs) comparing 10 adjuvant treatments [testosterone, dehydroepiandrosterone (DHEA), letrozole, recombinant LH, recombinant hCG, oestradiol, clomiphene citrate, progesterone, growth hormone (GH) and coenzyme Q10 (CoQ10)] were included. SEARCH METHODS: Relevant studies published in the English language were comprehensively selected using PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) until 11 July 2018. We included studies that investigated various adjuvant agents, including androgen and androgen-modulating agents, oestrogen, progesterone, clomiphene citrate, GH and CoQ10, during IVF treatment and reported subsequent pregnancy outcomes. The administration of GnRH analogs and gonadotrophins without adjuvant treatment was set as the control. We measured study quality based on the methodology and categories listed in the Cochrane Collaboration Handbook. This review protocol was registered with PROSPERO (CRD42018086217). OUTCOMES: Of the 1124 studies initially identified, 46 trials reporting on 6312 women were included in this systematic review, while 19 trials defining POR using the Bologna criteria reporting 2677 women were included in the network meta-analysis. Compared with controls, DHEA and CoQ10 treatments resulted in a significantly higher chance of clinical pregnancy [odds ratio (OR) 2.46, 95% CI 1.16 to 5.23; 2.22, 1.08-4.58, respectively]. With regard to the number of retrieved oocytes, HCG, oestradiol and GH treatments had the highest number of oocytes retrieved [weighted mean difference (WMD) 2.08, 0.72 to 3.44; 2.02, 0.23 to 3.81; 1.72, 0.98 to 2.46, compared with controls, respectively]. With regard to the number of embryos transferred, testosterone and GH treatment led to the highest number of embryos transferred (WMD 0.72, 0.11 to 1.33; 0.67, 0.43 to 0.92; compared with controls, respectively). Moreover, GH resulted in the highest oestradiol level on the HCG day (WMD 797.63, 466.45 to 1128.81, compared with controls). Clomiphene citrate, letrozole and GH groups used the lowest dosages of gonadotrophins for ovarian stimulation (WMD 1760.00, -2890.55 to -629.45; -1110.17, -1753.37 to -466.96; -875.91, -1433.29 to -282.52; compared with controls, respectively). CoQ10 led to the lowest global cancelation rate (OR 0.33, 0.15 to 0.74, compared with controls). WIDER IMPLICATIONS: For patients with POR, controlled ovarian stimulation protocols using adjuvant treatment with DHEA, CoQ10 and GH showed better clinical outcomes in terms of achieving pregnancy, and a lower dosage of gonadotrophin required for ovulation induction. Furthermore, high-level RCT studies using uniform standards for POR need to be incorporated into future meta-analyses.

Regulation of LH secretion by RFRP-3 - From the hypothalamus to the pituitary.

RFamide-related peptides (RFRPs) have long been identified as inhibitors of the hypothalamus-pituitary-gonad axis in mammals. However, less progress has been made in the detailed roles of RFRPs in the control of LH secretion. Recent studies have suggested that RFRP-3 neurons in the hypothalamus can regulate the secretion of LH at different levels, including kisspeptin neurons, GnRH neurons, and the pituitary. Additionally, conflicting results regarding the effects of RFRP-3 on these levels exist. In this review, we collect the latest evidence related to the effects of RFRP-3 neurons in regulating LH secretion by acting on kisspeptin neurons, GnRH neurons, and the pituitary and discuss the potential role of the timely reduction of RFRP-3 signaling in the modulation of the preovulatory LH surge.