Inhibin exists in 2 forms, each of which shares the same alpha subunit and, when covalently linked to 1 of 2 distinct subunits called beta-a and beta-b, inhibits pituitary FSH secretion. On the other hand, the dimers of 2 beta subunits, termed activins AA, AB and BB, are potent stimulators of FSH secretion and release in vitro.
NCBI Summary:
This gene encodes a member of the TGF-beta (transforming growth factor-beta) superfamily of proteins. The encoded preproprotein is proteolytically processed to generate a subunit of the dimeric activin and inhibin protein complexes. These complexes activate and inhibit, respectively, follicle stimulating hormone secretion from the pituitary gland. Polymorphisms near this gene are associated with pre-eclampsia in female human patients. [provided by RefSeq, Aug 2016]
General function
Ligand, Hormone, Growth factor
Comment
Cellular localization
Secreted
Comment
Ovarian function
Follicle development, Luteinization, Germ cell development
Comment
Inhibin-B secretion and FSH isoform distribution may play an integral part of follicular selection in the natural menstrual cycle. Yding Andersen C et al. (2016) The aim of the present paper is to expand the concept on how follicular selection takes place in the follicular phase of the natural menstrual cycle. It is suggested that inhibin-B exerts a more intimate role in this process than previously understood. Inhibin-B shows a peak in the circulation around cycle day 7, simultaneous with selection of the dominant follicle, whereas levels of estradiol and inhibin-A only start to increase a few days later suggesting that inhibin-B is mainly responsible for down-regulating pituitary FSH release. New data now demonstrate that the circulatory peak of inhibin-B is reflected by peak production of inhibin-B, in contrast to inhibin-A, in the selected follicle with a diameter of 10-12 mm, where concentrations are one thousand times higher than in the circulation.This high inhibin-B concentration also exerts paracrine effects, stimulating theca cell androgen production in concert with LH. New data now suggest that in the corresponding granulosa cells androgens up-regulate FSH receptor (FSHR) and LH receptor (LHR) mRNA expression, which in turn stimulate CYP19a mRNA expression providing the follicles which most effectively undertake these processes with the best chance of becoming selected.Inhibin-B production is stimulated by FSH and it appears that the acidic isoforms of FSH induce inhibin-B secretion most efficiently thereby, for the first time, placing the changing FSH isoform profile during the follicular phase in a physiological context.Collectively, it appears that inhibin-B is an integral part of follicular selection in the normal menstrual cycle, exerting both endocrine and paracrine effects and facilitating continued growth of the selected follicle.//////////////////
da Silva SJ, et al reported the expression of activin subunits and receptors in the developing human ovary: activin A promotes germ cell survival and proliferation before primordial follicle formation.
The formation of the essential functional unit of the ovary, the primordial follicle, occurs during fetal life in humans. Factors regulating oogonial proliferation and interaction with somatic cells before primordial follicle formation are largely unknown. We have investigated the expression, localisation and functional effects of activin and its receptors in the human fetal ovary at 14-21 weeks gestation. Expression of mRNA for the activin betaA and betaB subunits and the activin receptors ActRIIA and ActRIIB was demonstrated by RT-PCR. Expression of betaA mRNA increased 2-fold across the gestational range examined. Activin subunits and receptors were localised by immunohistochemistry. The betaA subunit was expressed by oogonia, and the betaB subunit and activin receptors were expressed by both oogonia and somatic cells. betaA expression was increased in larger oogonia at later gestations, but was low in oocytes within newly formed primordial follicles. Treatment of ovary fragments with activin A in vitro increased both the number of oogonia present and oogonial proliferation, as detected by bromodeoxyuridine (BrdU) incorporation. These data indicate that activin may be involved in the autocrine and paracrine regulation of germ cell proliferation in the human ovary during the crucial period of development leading up to primordial follicle formation.
Expression regulated by
LH
Comment
Gene expression decreased. Luteinization of porcine preovulatory follicles leads to systematic changes in follicular gene expression. Agca C et al. The LH surge initiates the luteinization of preovulatory follicles and causes hormonal and structural changes that ultimately lead to ovulation and the formation of corpora lutea. The objective of the study was to examine gene expression in ovarian follicles (n = 11) collected from pigs (Sus scrofa domestica) approaching estrus (estrogenic preovulatory follicle; n = 6 follicles from two sows) and in ovarian follicles collected from pigs on the second day of estrus (preovulatory follicles that were luteinized but had not ovulated; n = 5 follicles from two sows). The follicular status within each follicle was confirmed by follicular fluid analyses of estradiol and progesterone ratios. Microarrays were made from expressed sequence tags that were isolated from cDNA libraries of porcine ovary. Gene expression was measured by hybridization of fluorescently labeled cDNA (preovulatory estrogenic or -luteinized) to the microarray. Microarray analyses detected 107 and 43 genes whose expression was decreased or increased (respectively) during the transition from preovulatory estrogenic to -luteinized (P<0.01). Cells within preovulatory estrogenic follicles had a gene-expression profile of proliferative and metabolically active cells that were responding to oxidative stress. Cells within preovulatory luteinized follicles had a gene-expression profile of nonproliferative and migratory cells with angiogenic properties. Approximately, 40% of the discovered genes had unknown function.
Ovarian localization
Primordial Germ Cell, Cumulus, Granulosa
Comment
The literature on inibibin, activins, and ovarian function has been summarized by Mather et al. (1997) , Woodruff et al. (1995) and Hillier et al. (1993). Hsueh et al. (1987) tested the intragonadal paracrine actions of heterodimers and homodimers of inhibin subunits. In cultured ovarian theca-interstitial cells and theca explants, the alpha beta heterodimer of inhibin enhances androgen biosynthesis stimulated by LH, whereas the activin beta beta homodimer suppresses androgen production. These data indicate that the inhibin-related gene products synthesized by granulosa cells may form heterodimers or homodimers to serve as intragonadal paracrine signals in the modulation of LH-stimulated androgen biosynthesis.
Changes in mouse granulosa cell gene expression during early luteinization. McRae RS et al. Changes in gene expression during granulosa cell luteinization have been measured using serial analysis of gene expression (SAGE). Immature normal mice were treated with pregnant mare serum gonadotropin (PMSG) or PMSG followed, 48 h later, by human chorionic gonadotropin (hCG). Granulosa cells were collected from preovulatory follicles after PMSG injection or PMSG/hCG injection and SAGE libraries generated from the isolated mRNA. The combined libraries contained 105,224 tags representing 40,248 unique transcripts. Overall, 715 transcripts showed a significant difference in abundance between the two libraries of which 216 were significantly down-regulated by hCG and 499 were significantly up-regulated. Among transcripts differentially regulated, there were clear and expected changes in genes involved in steroidogenesis as well as clusters of genes involved in modeling of the extracellular matrix, regulation of the cytoskeleton and intra and intercellular signaling. The SAGE libraries described here provide a base for functional investigation of the regulation of granulosa cell luteinization.
Follicle stages
Primary, Secondary, Antral, Preovulatory
Comment
Findlay JK, et al reviewed studies on the production and actions of inhibin and activin during folliculogenesis
in the rat.
Evidence to enhance the premise that inhibin and activin are local regulators of
ovarian folliculogenesis is presented in this review. Granulosa cells (GC) have been
identified as the source of inhibin/activin in the ovary on the basis of mRNA and
protein localisation and the measurement of the inhibin forms in GC conditioned
media. Expression of the subunit mRNAs changed with follicular development, being
maximal in the ovaries of 8-day-old rats, where secondary follicles predominate. The
expression of beta subunit mRNAs by GC isolated from diethylstilboestrol
(DES)-treated immature rats, was reduced in the absence of any change in alpha
subunit mRNA expression. Dimeric inhibin-A, -B and free alpha subunit were
produced by ovarian cell cultures prepared from 4- to 12-day-old rats. Inhibin-A
production by these cultures was responsive to FSH and TGF-beta, with preantral
follicles of day 8 ovaries exerting effects so profound that the inhibin A/alpha subunit
ratio increased, most likely due to a stimulation of beta(A) subunit production. In
contrast, inhibin-B was not stimulated by TGF-beta until day 8 and FSH until day 12.
Fractionation of GC conditioned media revealed a prominence of free alpha subunit
and inhibin-A, but little inhibin-B, suggesting that inhibin-B production declines with
follicular development. Activin receptor types I and II, Smads 1-8 and betaglycan
(beta-glycan) mRNAs were present in the rat ovary and showed distinct patterns of
expression between postnatal days 4 and 12. Oocytes and GC localised activin
receptor, Smad and beta-glycan proteins, with beta-glycan also present in theca cells
(TC). These data indicate that activin/TGF-beta signalling machinery and factors
which influence these pathways, are present in the postnatal rat ovary. Inhibin and activin play important and changing autocrine/paracrine roles in the
growth and differentiation of follicles, including the oocyte, has been supported by
these studies.
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: embryonic lethal Comment:Matzuk et al. (1995) generated mice with mutations either in activin beta-A or in both activin beta-A and activin
beta-B. Activin beta-A-deficient mice developed to term but died within 24 hours of birth. They lacked whiskers and
lower incisors and had defects in their secondary palates, including cleft palate, demonstrating that activin beta-A must
have a role during craniofacial development. Mice lacking both activin subunits showed the defects in both individual
mutants but no additional defects, indicating that there is no functional redundancy between these proteins during
embryogenesis.