Inhibition of Follicle-Stimulating Hormone-Induced Preovulatory Follicles in Rats Treated with a Nonsteroidal Negative Allosteric Modulator of Follicle-Stimulating Hormone Receptor (original) (raw)
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Molecular Human Reproduction, 1996
This review summarizes observations on the background and potential clinical significance of interference with follicle stimulating hormone (FSH) regulation of human ovarian function. This interference may occur at the level of the pituitary by the secretion of FSH isoforms with reduced or absent bioactivtty. In addition, interference with FSH may occur in the circulation, or within the ovarian follicular compartment. Although the full range of its significance remains to be elucidated, there are distinct indications that these mechanisms may be involved in normal ovarian physiology, as well as in abnormal response of the ovary to stimulation by endogenous FSH or by exogenously-administered gonadotrophin preparations. Moreover, recent advances in the determination of the structure-function relationship of FSH and FSH-receptor interaction, in combination with new developments in recombinant DNA technology, will allow the production of modified FSH-or FSH receptor-like molecules with altered bioactivrty. The availability of FSH agonists and antagonists in the near future should provide a challenge for clinicians to improve treatment outcome and to find new indications for the use of these compounds.
Journal of Physiology and Biochemistry, 2010
Rat ovaries stimulated with human folliclestimulating hormone (hFSH) overexpress a factor that attenuates the LH surge in the rat: the putative gonadotropin surge-attenuating factor (GnSAF). A reduced gondadotrope progesterone receptor (PR) phosphorylation/activation is likely to be the main causative factor involved in GnSAF bioactivity on LH release. Besides, GnSAF reduces LH synthesis as well as LH secretion, and it is not known whether PR is involved in the inhibitory action of GnSAF on LH synthesis. Thus, the purpose of the present work was to evaluate the involvement of PR in the inhibitory effects of GnSAF on LH synthesis in cycling rats. To this end we used a specific radioimmunoassay and reverse transcription-polymerase chain reaction (RT-PCR) to study the effect on LH pituitary content and LHβ mRNA expression of PR occupancy with P (3 mg/0.2 ml oil in diestrus) on the inhibitory effects of hFSH (0, 0.1, 1, and 10 IU) in metestrus (day 2) and diestrus (day 3) on LH synthesis on proestrus in intact and on day 4 in day 2 ovariectomized (OVX) rats injected with 5 and 10 μg of estradiol benzoate (EB) on days 2 and 3, respectively. Results showed that (1) hFSH decreased pituitary LH content in intact, but not in OVX rats injected with EB, without affecting LHβ mRNA levels, and (2) PR occupancy with P annulled the inhibitory action of hFSH on pituitary LH content. These results indicate that PR is involved in ovarian GnSAF effect on LH content probably at a post-transcriptional level.
Frontiers in Endocrinology, 2021
An increasing number of pollutants with endocrine disrupting potential are accumulating in the environment, increasing the exposure risk for humans. Several of them are known or suspected to interfere with endocrine signals, impairing reproductive functions. Follicle-stimulating hormone (FSH) is a glycoprotein playing an essential role in supporting antral follicle maturation and may be a target of disrupting chemicals (EDs) likely impacting female fertility. EDs may interfere with FSH-mediated signals at different levels, since they may modulate the mRNA or protein levels of both the hormone and its receptor (FSHR), perturb the functioning of partner membrane molecules, modify intracellular signal transduction pathways and gene expression. In vitro studies and animal models provided results helpful to understand ED modes of action and suggest that they could effectively play a role as molecules interfering with the female reproductive system. However, most of these data are potenti...
Effect of Adrenal and Ovarian Androgens on Type 4 Follicles Unresponsive to FSH in Immature Mice
Endocrinology, 2001
The present study investigates the physiological significance of dehydroepiandrosterone, dehydroepiandrosterone sulfate, T, androstenedione (⌬ 4), dihydrotestosterone (DHT), estrone (E1), and E2 on recombinant human FSH-(rhFSH) resistant type 4 follicles obtained from immature mice. Type 4 follicles of a diameter of 100-120 m with one or two granulosa cell layers around the oocyte and an intact basal lamina with theca cells were isolated from the ovaries of 11-d-old BDF-1 mice and cultured with medium alone (control) or with dehydroepiandrosterone, dehydroepiandrosterone sulfate, T, ⌬ 4 , DHT, E1, or E2 at concentrations ranging from 1 ؋ 10 ؊11 to 1 ؋ 10 ؊7 M for 4 d. We examined the mean diameters of type 4 follicles, levels of immunoreactive (IR)-inhibin, and E2 and progesterone in the culture media on day 4. In addition, we evaluated follicular cell proliferation by immunofluorescence staining with 5-bromo-2-deoxyuridine. All tested androgens significantly increased the diameter of type 4 follicles in a dose-dependent manner without the production of IR-inhibin and E2. The nuclei of granulosa cells in type 4 follicles cultured with all tested androgens exhibited intense 5-bromo-2deoxyuridine-positive staining, compared with those of controls. In contrast, neither E1 nor E2 had any stimulatory effects. The stimulatory effects of T, ⌬ 4 , or DHT were inhibited by an AR antagonist in a dose-related fashion but not by an aromatase inhibitor. Furthermore, all tested androgens had a synergistic effect with rhFSH on follicular growth and the production of IR-inhibin and E2. These results demonstrated that neither adrenal nor ovarian androgens are arteriogenic but that they stimulate type 4 follicles unresponsive to rhFSH and augment the responsiveness of these follicles to rhFSH.
Targeting the Follicle Stimulating Hormone Receptor (FSHR) To Treat Fertility Disorders
ACS medicinal chemistry letters, 2016
The invention in this patent application relates to 4-(1-piperazinyl)benzamides represented generally by formula (I). The compounds of formulas (I) possess activities as positive allosteric modulators of the follicle stimulating hormone receptor (FSHR) and may potentially provide useful treatment of fertility disorders. Gonadotropins constitute a family of glycoprotein polypeptide hormones. Members of this family include the follicle-stimulating hormone (FSH), the luteinizing hormone (LH), the thyroid-stimulating hormone (TSH), and the chorionic gonadotropin (CG).
Clinical Endocrinology, 2015
Objective To study the association between serum anti-M€ ullerian hormone (AMH) levels and follicular development and endocrine responses induced by increasing doses (5Á2-12Á1 lg/day) of a novel recombinant human FSH (rhFSH, FE 999049) in patients undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) in a GnRH antagonist protocol. Design Secondary analysis of a randomized controlled trial with stratified randomization according to AMH (lower stratum: 5Á0-14Á9 pmol/l; higher stratum: 15Á0-44Á9 pmol/l). Patients Infertile women of good prognosis (n = 265). Measurements Follicular development and endocrine parameters during controlled ovarian stimulation (COS) with rhFSH. Results Serum FSH levels increased with increasing rhFSH doses and steady-state levels for each dose were similar in both AMH strata. In the whole study population, significant (P < 0Á001) positive dose responses were observed for the number of follicles ≥12 mm, and serum levels of oestradiol, inhibin B, inhibin A and progesterone at end of stimulation. In comparison with the higher AMH stratum, patients in the lower AMH stratum had significantly different slopes of the dose-response curves for these hormones, and no clear dose-related increase was observed for the number of follicles in these patients. Conclusions Dose-response relationships between rhFSH and follicular development and endocrine parameters are significantly different for IVF/ICSI patients with lower and higher serum AMH levels at start of COS.
Reproductive Biology and Endocrinology, 2013
Background: Previous studies have demonstrated that pre-pubertal aryl hydrocarbon receptor knockout (AHRKO) mice have slow antral follicle growth and reduced capacity to produce estradiol compared to wild-type (WT) mice. Although previous studies have suggested that this is likely due to a reduced ability of the AHRKO follicles to respond to follicle-stimulating hormone (FSH), this possibility was not directly tested. Thus, the goal of these studies was to test the hypothesis that low FSH responsiveness is responsible for the slow growth and reduced estradiol production observed in pre-pubertal AHRKO versus WT antral follicles. Methods: Antral follicles from WT and AHRKO mice were cultured with varying amounts of FSH (0-15 IU/mL) for up to 7 days, and subjected to measurements of growth, FSH receptor and steroidogenic regulator expression, sex steroid hormone levels, and inhibin beta-A expression. General linear models (GLM) for repeated measures were used to compare follicle diameters over time among treatments. If the global tests from GLM were significant, Tukey's tests were used for pairwise comparisons. Remaining comparisons among groups were performed using one-way analysis of variance followed by Tukey's post hoc test.
Anti-Müllerian Hormone Attenuates the Effects of FSH on Follicle Development in the Mouse Ovary
Endocrinology, 2001
Although ovarian follicle growth is under the influence of many growth factors and hormones of which FSH remains one of the most prominent regulators. Therefore, factors affecting the sensitivity of ovarian follicles to FSH are also important for follicle growth. The aim of the present study was to investigate whether anti-Mü llerian hormone (AMH) has an inhibitory effect on follicle growth by decreasing the sensitivity of ovarian follicles to FSH. Furthermore, the combined action of AMH and FSH on ovarian follicle development was examined. Three different experiments were performed. Using an in vitro follicle culture system it was shown that FSH-stimulated preantral follicle growth is attenuated in the presence of AMH. This observation was confirmed by an in vivo experiment showing that in immature AMH-deficient females, more
Anti-Müllerian hormone versus antral follicle count for defining the starting dose of FSH
Reproductive BioMedicine Online, 2013
received her MD in 1996 and her Master's Degree in Clinical Embryology at the National University of Singapore in 1999. She was a member of the first IVF team in Vietnam in 1997. Since then, she has taken part in more than 15,000 IVF cycles. Currently, she works in the department of obstetrics and gynaecology, University of Medicine and Pharmacy, Ho Chi Minh City. She is now a PhD fellow in reproductive medicine. Her primary interests are individualized ovarian stimulation, luteal-phase support, use of antagonists in IVF, ovulation induction in polycystic ovary syndrome and in-vitro maturation.