Introduction ON JUNE 24, 1971, Andrew V. Schally announced the determination of the primary structure of porcine GnRH at The Endocrine Society Meeting in San Francisco. This announcement was followed by publications by Matsuo et al. (1, 2) and Baba et al. (3) on the proposed amino acid sequence for porcine GnRH and its synthesis and by Burgus et al. (4) who characterized ovine GnRH and found the sequence to be identical with that of porcine GnRH. The physiological and therapeutic importance attributed to the discovery of the new substance was greatly increased by the prospect of the design of potent and long acting GnRH agonists and antagonists. Since that time more than 2000 analogs of GnRH have been synthesized. The impact of research of GnRH and its analogs on clinical medicine recently led Ziporyn (5) to note, “There's almost no subspecialty of medicine that will be left untouched by the [research] advances associated with LHRH or its analogs.” It is the intent of this article to provide a historical ...

Gonadotropin-releasing hormone analog design. Structure-function studies toward the development of agonists and antagonists: rationale and perspective.

In the healthy endometrium, progesterone and estrogen signaling coordinate in a tightly regulated, dynamic interplay to drive a normal menstrual cycle and promote an embryo-receptive state to allow implantation during the window of receptivity. It is well-established that progesterone and estrogen act primarily through their cognate receptors to set off cascades of signaling pathways and enact large-scale gene expression programs. In endometriosis, when endometrial tissue grows outside the uterine cavity, progesterone and estrogen signaling are disrupted, commonly resulting in progesterone resistance and estrogen dominance. This hormone imbalance leads to heightened inflammation and may also increase the pelvic pain of the disease and decrease endometrial receptivity to embryo implantation. This review focuses on the molecular mechanisms governing progesterone and estrogen signaling supporting endometrial function and how they become dysregulated in endometriosis. Understanding how these mechanisms contribute to the pelvic pain and infertility associated with endometriosis will open new avenues of targeted medical therapies to give relief to the millions of women suffering its effects.

https://www.mdpi.com/1422-0067/20/15/3822/pdf

Progesterone and Estrogen Signaling in the Endometrium: What Goes Wrong in Endometriosis?

Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist.

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder of uncertain aetiology, which affects between 6 and 10% of women of the reproductive age. The heterogeneity of both the ovarian morphology and clinical findings in women with polycystic ovaries has been well recognized since Stein & Leventhal’s (1935) first report and gradually led to the establishment of the term polycystic ovary syndrome. The many features of this syndrome can be broadly divided into three categories: clinical, endocrine and metabolic. The clinical features include menstrual abnormalities, hirsutism, acne, alopecia, anovulatory infertility and recurrent miscarriages. The endocrine features include elevated androgens, luteinizing hormone, oestrogen and prolactin levels. The metabolic aspects of this syndrome include insulin resistance, obesity, lipid abnormalities and an increased risk for impaired glucose tolerance and type 2 diabetes mellitus (type 2 DM). Controversy persists regarding the criteria used for PCOS diagnosis. Currently, the recommended diagnostic criteria for PCOS are hyperandrogenism and ovulatory dysfunction with the exclusion of specific disorders, such as nonclassic adrenal 21hydroxylase deficiency, Cushing’s syndrome, hyperprolactinaemia and androgen-producing tumours. This clinical definition reflects a 1990 National Institutes of Health–National Institute of Child Health and Development Consensus Conference (Zawadeski & Dunaif, 1992) in which there was poor agreement among the 58 specialists who completed a questionnaire on the diagnostic criteria for PCOS, with no single criterion endorsed as ‘definite or probable’ by more than 64% of respondents. Interestingly, the conclusion of this meeting was that the polycystic ovary morphology is consistent with, but not essential for, the diagnosis of the syndrome. Sonographic criteria for polycystic ovaries have been refined with advances in technology (Fox, 1999; Atiomo et al ., 2000) and transvaginal ultrasound is currently the gold standard for diagnosing polycystic ovaries. Using the most conservative criteria based on transabdominal ultrasound, the presence of 10 or more cysts, 2–8 mm in diameter, arranged either peripherally around a dense core of stroma or scattered throughout an increased amount of stroma (Adams et al ., 1985), up to 23% of normal volunteer women meet the sonographic criteria for polycystic ovaries (Clayton et al ., 1992). On the other hand, many investigators have maintained that ovaries from women with PCOS may be sonographically normal (Hann et al ., 1984; Timor-Tritsch & Rottem, 1998). Thus, the ovarian morphological changes must be distinguished from the endocrine syndrome of PCOS and be considered as a sign rather and not a disease.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2265.2003.01842.x

The pathophysiology of polycystic ovary syndrome

Most clinicians working in in vitro fertilization (IVF) centers worldwide have taken for granted for more than a decade the paradigm of so-called 'controlled' ovarian hyperstimulation, using maximum stimulation by exogenous gonadotropins, together with the gonadotropin-releasing hormone (GnRH) agonist long-protocol. Potential detrimental effects of this approach with regard to oocyte quality, corpus luteum function and endometrial receptivity have been largely ignored. These factors might by themselves have a major impact on IVF outcome and should therefore be considered seriously. The recent introduction of GnRH antagonists along with the current emphasis on the need for transfer of a reduced number of embryos enables a careful re-evaluation of current IVF strategies. We can now render stimulation protocols simpler, starting with a spontaneous menstrual cycle, allowing for more subtle interference with single dominant follicle selection. Here, we discuss recent approaches to ovarian stimulation, the induction of oocyte maturation, and effects of these altered follicular phase interventions on corpus luteum function following ovarian stimulation.

https://www.cell.com/trends/endocrinology-metabolism/pdf/S1043-2760(03)00075-4.pdf

Reproductive biology and IVF: ovarian stimulation and luteal phase consequences.

A potent GnRH antagonist, [Ac-delta 3-Pro1,p-F-D-Phe2,D-Trp3,6]GnRH (4F-Antag), was used as a probe to determine the relative dependency of ovarian cyclicity on pulsatile gonadotropin secretion. 4F-Antag was administered in a dose of 80 micrograms/kg sc twice a day for 3 consecutive days during different phases of the menstrual cycle. This treatment resulted in a prompt attenuation of pulsatile gonadotropin secretion in all women studied. Maximal suppression of gonadotropin levels, expressed as percent change from baseline, averaged 48% for LH and 22% for FSH. The reduced pulsatile gonadotropin release induced by 4F-Antag administration during the early follicular phase resulted in a significant decrease in serum estradiol levels during the period of treatment and was followed by a prolongation of follicular phase (2.4 days) and cycle length (3.5 days), but no alteration of subsequent cyclic ovarian steroid profiles compared to control cycles. Treatment initiated during the midfollicular phase 4-6 days before the expected LH surge resulted in a more dramatic decline in serum estradiol levels and prolongation of follicular phase length by 5-6 days compared to control cycles. Normal luteal function was preserved. These alterations were compatible with induction of the demise of the dominant follicle followed by the reinitiation of follicular recruitment. Administration of 4F-Antag during the midluteal phase resulted in rapid falls in serum estradiol and progesterone levels and the onset of menstrual bleeding in all women. The luteolytic effect of 4F-Antag was completely negated by the administration of hCG. These data indicate that 4F-Antag interferes with ongoing cyclic ovarian function by reducing pulsatile gonadotropin stimulation, which disrupts folliculogenic processes and induces the demise of the corpus luteum. From these findings we infer that the functional integrity of ovarian cyclicity is remarkably sensitive to brief (3 days) and partial reduction in pulsatile gonadotropin secretion.

The dependency of folliculogenesis and corpus luteum function on pulsatile gonadotropin secretion in cycling women using a gonadotropin-releasing hormone antagonist as a probe.

The inhibitory effect of a GnRH antagonist, [AC-delta 2-Pro1, p-F-D-Phe 2, D-Trp3,6]GnRH (4F-Antag), on gonadotropin secretion was determined by four sequential studies in five hypergonadotropic postmenopausal women. In response to an iv (80 micrograms/kg) dose of 4F-Antag, a progressive decline in basal gonadotropin levels with a marked attenuation of pulse amplitude was observed. Mean serum LH and FSH concentrations were maximally reduced by 46% and 26%, respectively, 4 and 9 h after the iv bolus. A similar pattern of suppression was found with sc and im routes of administration, with maximal effects occurring at 6.0 h for LH and 8.5 h for FSH. This was followed by the resumption of pulsatile release and a return to basal levels between 10 and 24 h for both gonadotropins. When 4F-Antag was superimposed during an iv infusion of GnRH (0.2 micrograms/min) at the time (2 h) of maximal LH release (231% above basal values), a 47.1% decrease in GnRH-stimulated LH levels and a 15.8% decrease in FSH values occurred at 1.75 h. A positive linear correlation was found between basal and exogenous GnRH-stimulated LH and FSH concentrations and the inhibitory effect of the 4F-antagonist. The dynamics of the antagonistic effect demonstrated by this analog provide an important reference for future investigations of endogenous GnRH control of gonadotropin secretion as well as for exploring contraceptive potential.

The dynamics of gonadotropin inhibition in women induced by an antagonistic analog of gonadotropin-releasing hormone.

The Dependency of Folliculogenesis and Corpus Luteum Function on Pulsatile Gonadotropin Secretion in Cycling Women Using a Gonadotropin-Releasing Hormone Antagonist as a Probe

Inhibition of gonadotropin secretion in women by an antagonistic analog of gonadotropin releasing hormone

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The dependency of folliculogenesis and corpus luteum function on pulsatile gonadotropin secretion in cycling women using a gonadotropin-releasing hormone antagonist as a probe.

The dynamics of gonadotropin inhibition in women induced by an antagonistic analog of gonadotropin-releasing hormone.

The Dependency of Folliculogenesis and Corpus Luteum Function on Pulsatile Gonadotropin Secretion in Cycling Women Using a Gonadotropin-Releasing Hormone Antagonist as a Probe

Inhibition of gonadotropin secretion in women by an antagonistic analog of gonadotropin releasing hormone