Regulation of Gonadotropins

2019 ◽  
Author(s):  
Daniel J. Bernard ◽  
Yining Li ◽  
Chirine Toufaily ◽  
Gauthier Schang
Keyword(s):  
Pituitary Gland ◽  
Granulosa Cells ◽  
Positive Feedback ◽  
Sex Steroids ◽  
Somatic Cells ◽  
Inhibin B ◽  
Dependent Manner ◽  
Α Subunit ◽  
Theca Cells ◽  
The Brain

The gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), are glycoproteins produced by gonadotrope cells of the anterior pituitary gland. The two hormones act on somatic cells of the gonads in both males and females to regulate fundamental aspects of reproductive physiology, including gametogenesis and steroidogenesis. In males, LH stimulates testosterone production and sperm maturation. FSH also regulates spermatogenesis, though the importance of the hormone in this process differs across species. In females, FSH stimulates ovarian follicle maturation. Follicles are structures composed of oocytes surrounded by two types of somatic cells, granulosa and theca cells. FSH stimulates granulosa cells to proliferate and to increase their production of the aromatase enzyme. LH stimulates theca cells to make androgens, which are converted into estrogens by aromatase in granulosa cells. A surge of LH also stimulates ovulation of mature follicles. Gonadotropin-releasing hormone (GnRH) from the brain is the principal stimulator of gonadotropin synthesis and secretion from the pituitary. The sex steroids (androgens and estrogens) that are produced by the gonads in response to the gonadotropins feedback to the brain and pituitary gland. In the brain, these hormones usually slow the release of GnRH through a process called negative feedback, which in turn leads to decreases in FSH and LH. The steroids also modulate the sensitivity of the pituitary to GnRH in addition to directly regulating expression of the genes that encode the gonadotropin subunits. These effects are gene- and species-specific. In females, estrogens also have positive feedback actions in the brain and pituitary in a reproductive cycle stage-dependent manner. This positive feedback promotes GnRH and LH release, leading to the surge of LH that triggers ovulation. The gonadotropins are dimeric proteins. FSH and LH share a common α-subunit but have hormone-specific subunits, FSHβ and LHβ. The β subunits provide a means for differential regulation and action of the two hormones. In the case of FSH, there is a second gonadal feedback system that specifically regulates the FSHβ subunit. The gonads produce proteins in the transforming growth factor β (TGFβ) family called inhibins, which come in two forms (inhibin A and inhibin B). The ovary produces both inhibins whereas the testes make inhibin B alone. Inhibins selectively suppress FSH synthesis and secretion, without affecting LH. The pituitary produces additional TGFβ proteins called activins, which are structurally related to inhibins. Activins, however, stimulate FSH synthesis by promoting transcription of the FSHβ subunit gene. Inhibins act as competitive receptor antagonists, binding to activin receptors and blocking activin action, and thereby leading to decreases in FSH. Together, GnRH, sex steroids, activins, and inhibins modulate and coordinate gonadotropin production and action to promote proper gonadal function and fertility.

scholarly journals Bone morphogenetic protein-6 enhances gonadotrophin-dependent progesterone and inhibin secretion and expression of mRNA transcripts encoding gonadotrophin receptors and inhibin/activin subunits in chicken granulosa cells

Reproduction ◽  
2007 ◽  
Vol 134 (2) ◽  
pp. 293-306 ◽  
Author(s):  
Sara L Al-Musawi ◽  
Richard T Gladwell ◽  
Philip G Knight
Keyword(s):  
Bone Morphogenetic Protein ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Cell Function ◽  
Dependent Manner ◽  
Cell Type ◽  
Inhibin A ◽  
Theca Cells ◽  
Subunit Mrna ◽  
Morphogenetic Protein

The aims were to examine ovarian expression of bone morphogenetic protein (BMP) ligands/receptor mRNAs in the chicken and to test the hypothesis that theca-derived BMP(s) modulates granulosa cell function in a paracrine manner. RT-PCR revealed expression of multiple BMPs in granulosa and theca cells from prehierarchical and preovulatory follicles with greater expression in theca cells; both cell types expressed BMP receptors-IA, -IB and -II consistent with tissue responsiveness. Preovulatory granulosa cells (F1, F2 and F3/4) were cultured with BMP-6 (expressed by theca but not granulosa) in the presence/absence of LH, FSH or 8-Br-cAMP. BMP-6 increased ‘basal’ and gonadotrophin-induced inhibin-A and progesterone secretion by each cell type but did not enhance the effect of 8-Br-cAMP. This indicates that the observed synergism between BMP-6 and gonadotrophin might involve BMP-induced up-regulation of gonadotrophin receptors. In support of this, BMP-6 alone increased LH-receptor (LHR) mRNA in F1 cells and FSH-receptor (FSHR) mRNA in F1, F2 and F3/4 cells. BMP-6 also enhanced LH/FSH-induced LHR transcript amount in each cell type but did not raise FSHR transcript amounts above those induced by BMP-6 alone. To further explore BMP-6 action on inhibin-A secretion, we quantified inhibin/activin subunits (α, βA, βB) mRNAs. Consistent with its effect on inhibin-A secretion, BMP-6 enhanced ‘basal’ expression of α- and βA-subunit mRNA in F1, F2 and F3/4 cells, and βB-subunit mRNA in F3/4 cells. BMP-6 markedly enhanced FSH/LH-induced expression of α-subunit in all follicles and FSH-induced βA-subunit in F2 and F3/4 follicles but not in F1 follicles. Neither BMP-6 alone, nor FSH/LH alone, affected ‘basal’ βB mRNA abundance. However, co-treatment with gonadotrophin and BMP-6 greatly increased βB-subunit expression, the response being lowest in F1 follicles and greatest in F3/4 follicles. Collectively, these results support the hypothesis that intraovarian BMPs of thecal origin have a paracrine role in modulating granulosa cell function in the chicken in a preovulatory stage-dependent manner.

Expression of inhibin α,βA and βB messenger ribonucleic acids in the normal human ovary and in polycystic ovarian syndrome

1994 ◽  
Vol 143 (1) ◽  
pp. 127-137 ◽  
Author(s):  
T-A Jaatinen ◽  
T-L Penttilä ◽  
A Kaipia ◽  
T Ekfors ◽  
M Parvinen ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Cellular Localization ◽  
Polycystic Ovarian Syndrome ◽  
Human Ovary ◽  
Α Subunit ◽  
Ribonucleic Acids ◽  
Theca Cells ◽  
Subunit Mrna ◽  
Normal Human ◽  
Ovarian Syndrome

Abstract We studied the cellular distribution of inhibin α, βA and βB mRNAs in the normal human ovary and in polycystic ovarian syndrome (PCOS) by in situ hybridization. Our results show that human granulosa cells express inhibin α, βA and βB subunit mRNAs, and theca cells express inhibin α and βA subunit mRNAs. The co-localization of α and βA mRNAs in theca cells supports the hypothesis that inhibin also has an autocrine function in these cells. We did not detect any inhibin subunit mRNA in the granulosa cells of atretic follicles, while theca cells also expressed α subunit mRNA in those follicles. The present findings suggest that the expression of inhibin subunits is regulated differently in human follicular granulosa and theca cells. It has been speculated that inhibin may be involved in the development of PCOS. Our results show that the cellular localization of inhibin subunit mRNAs is not disturbed in PCOS ovaries. Journal of Endocrinology (1994) 143, 127–137

Control of inhibin production by primate granulosa cells

1989 ◽  
Vol 123 (1) ◽  
pp. 65-73 ◽  
Author(s):  
S. G. Hillier ◽  
E. J. Wickings ◽  
P. T. K. Saunders ◽  
A. F. Dixson ◽  
S. Shimasaki ◽  
...  
Keyword(s):  
Granulosa Cell ◽  
Granulosa Cells ◽  
Follicular Development ◽  
Common Marmoset ◽  
Dependent Manner ◽  
Stimulatory Action ◽  
Α Subunit ◽  
Luteal Tissue ◽  
Ovarian Inhibin

ABSTRACT In-vitro data from experiments on rats implicate granulosa cells as primary sites of hormone-dependent ovarian inhibin biosynthesis, but no equivalent data exist for primates. We have used the common marmoset (Callithrix jacchus) to investigate inhibin biosynthesis in primate granulosa cells in vitro and to determine its relationship to preovulatory follicular development. To relate the production of immunoactive inhibin to follicular maturity, we studied primary granulosa cell cultures from follicles at progressive stages of preovulatory development. Granulosa cells from 'large' (≥2·0 mm diameter) follicles expressed high rates of inhibin production and steroidogenesis (progesterone), and were positively regulated by human (h)LH in vitro. Less mature granulosa cells from 'medium' (1·1–1·9 mm) and 'small' (≤ 1·0 mm) follicles expressed proportionately lower rates of inhibin production and steroidogenesis, but each parameter was stimulated in a dose- and time-dependent manner by hFSH in vitro. The stimulatory action of hFSH on immunoactive inhibin was augmented by the presence of testosterone or oestradiol; testosterone (but not oestradiol) also augmented the steroidogenic response to hFSH. Marmoset luteal tissue also produced inhibin in vitro and expressed an ∼1·5 kb inhibin α-subunit mRNA, confirming the corpus luteum as a source of ovarian inhibin in primates. These results provide direct experimental evidence that primate granulosa cells produce inhibin. They suggest that production of inhibin by immature granulosa cells is initially induced by FSH and subject to modulation by follicular steroids. During advanced preovulatory development, granulosa cell inhibin production becomes directly responsive to LH, thereby indicating a role for LH in the control of peri- and postovulatory inhibin secretion by the primate ovary. Journal of Endocrinology (1989) 123, 65–73

Cytokine modulation of inhibin secretion in cultured rat granulosa cells

1996 ◽  
Vol 151 (3) ◽  
pp. 449-457 ◽  
Author(s):  
M Imai ◽  
M Yamoto ◽  
H Otani ◽  
R Nakano
Keyword(s):  
Enzyme Immunoassay ◽  
Granulosa Cells ◽  
Dependent Manner ◽  
Inhibin A ◽  
Α Subunit ◽  
Cytokine Modulation ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Factor Α ◽  
Dose Dependent

Abstract In the present study, we examined the effects of tumour necrosis factor α (TNFα) and interleukin-1β (IL-1β) on inhibin secretion by cultured rat granulosa cells using immunoblotting and two-site enzyme immunoassay for inhibin A (α-βA dimer). FSH stimulated the secretion of the inhibin α-βA dimer (32 kDa) by the cells in a dose-dependent manner. In addition to the predominant 32 kDa inhibin α-βA dimer staining, staining of minor immunoreactive bands was also enhanced by FSH. TNFα alone did not have any effect on inhibin secretion. Immunoblot analyses using an antiserum against α-subunit and an antiserum against βA-subunit revealed a dose-dependent inhibition by TNFα of FSH-stimulated secretion of inhibin by rat granulosa cells. Similarly, TNFα inhibited in a dose-dependent manner FSH-stimulated inhibin secretion when measured using a two-site enzyme immunoassay. IL-1β alone did not exert any effect on inhibin secretion but it inhibited FSH-stimulated inhibin release in a dose-dependent manner (using both immunoblotting and a two-site assay for inhibin A). The present observations suggest that TNFα and IL-1β inhibit gonadotrophin-stimulated inhibin production by cultured rat granulosa cells. Journal of Endocrinology (1996) 151, 449–457

CONVERSION OF PROGESTERONE TO 5α- AND 5β-REDUCED METABOLITES IN THE BRAIN OF THE HEN AND ITS POTENTIAL ROLE IN THE INDUCTION OF THE PREOVULATORY RELEASE OF LUTEINIZING HORMONE

1980 ◽  
Vol 86 (3) ◽  
pp. 459-464 ◽  
Author(s):  
P. J. SHARP ◽  
R. MASSA
Keyword(s):  
Luteinizing Hormone ◽  
Pituitary Gland ◽  
Positive Feedback ◽  
Potential Role ◽  
Laying Hen ◽  
Feedback Effect ◽  
Lh Release ◽  
The Brain ◽  
Positive Feedback Effect

In the laying hen, progesterone was shown to be converted in vitro in the pituitary gland and the hypothalamus to 5β-pregnane-3,20-dione (5β-DHP), 5β-pregnan-3α-ol-20-one (5β,3α-ol) and 5α-pregnane-3,20-dione (5α-DHP) and in the hyperstriatum dorsale to 5β-DHP and 5β,3α-ol. The conversion of progesterone to 5β-reduced metabolites was greater in the hyperstriatum dorsale than in the hypothalamus (P<0·001) and greater in the hypothalamus than in the pituitary gland (P <0·01). The conversion of progesterone to 5β-reduced metabolites was greater than its conversion to 5α-DHP in the pituitary gland (P <0·01) and the hypothalamus (P < 0·001). The possibility was investigated that 5α-DHP and 5β-DHP may act as metabolic intermediaries in the mechanism by which progesterone exerts a positive feedback effect on LH release. Progesterone, 5α-DHP and 5β-DHP were injected into laying hens at doses of 0·05,0·25 and 1·25 mg/kg and the changes in the concentration of plasma LH were followed for 4 h thereafter. Secretion of LH was stimulated after treatment with progesterone or 5α-DHP but not 5β-DHP. Progesterone stimulated LH release more effectively than did 5α-DHP, since an increase in the concentration of plasma LH was observed after 0·25 mg progesterone/kg but not after the same dose of 5α-DHP. It was concluded that in the hen 5α-DHP is unlikely to play a role in the induction of the preovulatory release of LH.

scholarly journals Activin A reduces luteinisation of human luteinised granulosa cells and has opposing effects to human chorionic gonadotropin in vitro

2008 ◽  
Vol 199 (2) ◽  
pp. 201-212 ◽  
Author(s):  
Michelle Myers ◽  
Sander van den Driesche ◽  
Alan S McNeilly ◽  
W Colin Duncan
Keyword(s):  
Corpus Luteum ◽  
Chorionic Gonadotropin ◽  
Granulosa Cells ◽  
Human Chorionic Gonadotropin ◽  
Activin A ◽  
Cell Phenotype ◽  
Dependent Manner ◽  
Α Subunit ◽  
Opposing Effects

The transition of the dominant follicle into the corpus luteum is of fundamental reproductive importance. Luteinisation involves disparate changes in the gene expression of follicular granulosa cells that differentiate into the granulosa-lutein cells of the corpus luteum after the gonadotrophin surge. We have shown that activin and human chorionic gonadotropin (hCG) have opposing effects during luteolysis. Therefore, we hypothesised that activin A was an inhibitor of luteinisation that was blocked during the pre–ovulatory gonadotrophin surge. Ovarian tissue and cells were collected from women with regular cycles having hysterectomy and women undergoing oocyte retrieval for assisted conception. Genes that changes during luteinisation were investigated in primary cultures of luteinised granulosa cells exposed to activin A and hCG in vitro. hCG promotes a luteinised granulosa cell phenotype, while activin A promotes a more follicular phenotype in luteinised cells by upregulating granulosa cells markers such as FSHR, HSD11B2 and downregulating LHCGR. In addition, activin A blocked hCG upregulation of STAR, HSD3B1 and HSD11B1 and downregulation of oestrogen receptor α. Activin A antagonised hCG effects in a dose-dependent manner and could block the hCG-stimulated molecular inhibitors of activin action (inhibin α-subunit, follistatin and TGFBR3). These studies show that hCG and activin A have opposing effects on luteinised granulosa cells and some effects of activin are seen only in the presence of hCG. While hCG can inhibit activin action in granulosa cells to facilitate luteinisation, activin A can promote an unluteinised phenotype in luteinised granulosa cells. This confirms the importance of adequate activin withdrawal during luteinisation in women.

206. Differential regulation of activin and inhibin production by interleukin 1 (IL1), transforming growth factor β1 (TGFβ1) and protein kinase C (PKC) in the Sertoli cell and granulosa cell

2008 ◽  
Vol 20 (9) ◽  
pp. 6 ◽  
Author(s):  
V. Eede ◽  
J. A. Muir ◽  
A. E. O. 'Connor ◽  
W. R. Winnall ◽  
A. E. Drummond ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Sertoli Cell ◽  
Granulosa Cells ◽  
Sertoli Cells ◽  
Activin A ◽  
Inhibin B ◽  
Inhibin A ◽  
Α Subunit ◽  
Subunit Mrna ◽  
Subunit Expression

Activin and inhibin are gonadal regulatory proteins comprising an α-subunit and either a βA-subunit or βB-subunit (inhibin A or B), or two βA-subunits (activin A). Synthesis of the α-subunit, and the inhibins, is regulated by FSH via cAMP/protein kinase A. Regulation of the β-subunits in the gonads is less well defined, but the IL1/MAP kinase, TGFβ /Smad and PKC pathways have been implicated. Sertoli cells and granulosa cells were isolated from 18–22 day-old Sprague-Dawley rats under standard conditions and cultured with IL1, TGFβ1 and the PKC agonists, gonadotrophin releasing hormone (GnRH) or phorbol myristate acetate (PMA). Activin A, inhibin A and inhibin B were measured in culture medium (at 48h) by ELISA. Subunit mRNA expression was measured in cell extracts (at 4 h and 8h) using quantitative RT–PCR. IL1 stimulated βA-subunit and activin A production and inhibited α-subunit and βB-subunit expression and inhibin B production in Sertoli cells, but had no effect in granulosa cells. TGFβ1 stimulated activin A in both cell types, as well as the inhibins in granulosa cells. Surprisingly, TGFβ1 had no effect on Sertoli cell α-subunit or βA-subunit mRNA expression, but did cause a slight reduction of βB-subunit expression. GnRH increased activin A and inhibin A, but not inhibin B, production by granulosa cells and had no effect on Sertoli cells, which lack the GnRH receptor. However, direct activation of PKC by PMA stimulated βA-subunit mRNA expression and activin A production and decreased βB-subunit and inhibin B production by Sertoli cells, with marginal effects on inhibin A. These results indicate that activation of the TGFβ or PKC signalling pathways preferentially stimulates βA-subunit expression and/or translation, leading to increased activin A secretion by Sertoli cells and both activin A and inhibin A secretion by granulosa cells. The ability of IL1 to stimulate activin A is confined to the Sertoli cell.

scholarly journals ‘Free’ inhibin α subunit is expressed by bovine ovarian theca cells and its knockdown suppresses androgen production

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Mhairi Laird ◽  
Claire Glister ◽  
Warakorn Cheewasopit ◽  
Leanne S. Satchell ◽  
Andrew B. Bicknell ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Follicular Fluid ◽  
Unexpected Finding ◽  
Glycoprotein Hormones ◽  
Positive Role ◽  
Α Subunit ◽  
Theca Cells ◽  
Opposing Effects

AbstractInhibins are ovarian dimeric glycoprotein hormones that suppress pituitary FSH production. They are synthesised by follicular granulosa cells as α plus βA/βB subunits (encoded by INHA, INHBA, INHBB, respectively). Inhibin concentrations are high in follicular fluid (FF) which is also abundant in ‘free’ α subunit, presumed to be of granulosal origin, but its role(s) remains obscure. Here, we report the unexpected finding that bovine theca cells show abundant INHA expression and ‘free’ inhibin α production. Thus, theca cells may contribute significantly to the inhibin α content of FF and peripheral blood. In vitro, knockdown of thecal INHA inhibited INSL3 and CYP17A1 expression and androgen production while INSL3 knockdown reduced INHA and inhibin α secretion. These findings suggest a positive role of thecal inhibin α on androgen production. However, exogenous inhibin α did not raise androgen production. We hypothesised that inhibin α may modulate the opposing effects of BMP and inhibin on androgen production. However, this was not supported experimentally. Furthermore, neither circulating nor intrafollicular androgen concentrations differed between control and inhibin α-immunized heifers, casting further doubt on thecal inhibin α subunit having a significant role in modulating androgen production. Role(s), if any, played by thecal inhibin α remain elusive.

scholarly journals Influence of mutations affecting gonadotropin production or responsiveness on expression of inhibin subunit mRNA and protein in the mouse ovary

Reproduction ◽  
2004 ◽  
Vol 128 (1) ◽  
pp. 43-52 ◽  
Author(s):  
Rachel C Hirst ◽  
Margaret H Abel ◽  
Vivienne Wilkins ◽  
Christine Simpson ◽  
Phil G Knight ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Follicular Development ◽  
Inhibin B ◽  
Mrna Levels ◽  
Gene Encoding ◽  
Α Subunit ◽  
Lh Receptor ◽  
Protein Levels ◽  
Subunit Mrna ◽  
Major Cell Type

Measurement of inhibins A and B in the serum of normal cyclic rodents has implicated FSH in the regulation of these peptides within the ovary. To extend these observations we have used a panel of mutant mice carrying mutations which affect either the production of, or the ability to respond to, FSH and LH. As a consequence, the females are infertile and show different degrees of follicular development. The aim of this study was to measure inhibin gene transcription in the ovaries of these mutant females together with inhibin protein levels in ovaries and serum and to relate these to follicular development within the ovary. Comparison was made with a pool of normal/heterozygous females. In hpg females where lack of GnRH production results in the absence of gonadotropin synthesis, in FSHβ knockout (FSHβKO) females where disruption of the gene encoding FSHβ results in the absence of FSH production, and in FSH receptor knockout (FSHRKO) females which are unable to respond to circulating FSH, follicular development remains at the pre-antral stage in these three mutants. Only in the hpg females were common inhibin α subunit mRNA levels significantly lower than normal. In these three mutants, however, mRNA levels for both the βA and βB subunits were extremely low compared with normal mice. At the protein level, neither inhibin A nor B was detected in the serum of these three mutants; however inhibin B, albeit at very low levels, was detectable within the ovaries. These observations confirm a major role for FSH in the control of transcription of the βA and βB genes but suggest that the constitutive transcription of the alpha subunit is less dependent on FSH. In contrast, in LH receptor knockout (LuRKO) female mice inhibin βA subunit mRNA levels were similar to those measured in normal/heterozygous females but levels of inhibin α and βB subunit mRNAs were significantly higher than in the normal group. This was reflected in significantly higher inhibin B protein levels in ovaries and serum. An inability to respond to LH combined with high circulating levels of FSH leads to a high proportion of antral follicles in LuRKO females, with granulosa cells constituting the major cell type within the ovary. The high percentage of antral granulosa cells is likely to account for the significantly higher levels of inhibin B production in these ovaries.

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