Pituitary Follicle-stimulating Hormone Secretion Research Articles

Transcriptome sequencing analysis of porcine granulosa cells treated with an anti-inhibin antibody

Inhibin can regulate granulosa cell proliferation and function via direct action on granulosa cells, or indirectly through stimulation of pituitary follicle-stimulating hormone secretion. Thus far, it has not been possible to unravel or formulate the chain of molecular events that lead to enhanced granulosa cell proliferation and function using conventional gene expression analysis. The aim of this study was to examine the biological effects of immuno-neutralization of inhibin bioactivity in porcine granulosa cells using transcriptome profiling by the RNA-seq technology.Treatment of granulosa cells with anti-inhibin α subunit antibodies increased both cell proliferation and estradiol secretion. Data revealed by RNA sequencing were subjected to bioinformatic analysis. The results showed that a total of 476 genes, including 27 novel genes, were differentially expressed in anti- inhibin antibody-treated granulosa cells compared to untreated granulosa cells. RNA sequencing data were validated by qRT-PCR which confirmed differential expression (upregulation and downregulation) of eighteen of twenty selected genes A total of 476 differentially expressed genes were enriched in processes such as matrix remodeling, chemokine activity, protein binding, and structural molecular activities, and which could be related to granulosa cell proliferation, estradiol synthesis, and ovarian follicle growth. In particular, the data emphasized the importance of extracellular matrix remodeling and the involvement of chemokines in enhanced granulosa cell function, which are important features of ovarian follicle growth, development, maturation, and ovulation. This study provided a new level of understanding of enhanced granulosa cell function and ovarian follicle development achieved through immuno-neutralization of endogenous inhibin bioactivity.

English

This study aimed to investigate the effect of zinc supplementation on testicular tissue as a feed-back mechanism of the pituitary secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) on cigarette smoker subjects. Total of twenty subjects participated in this study as per the national bioethics committee guidelines. Venous blood samples were collected for determination of serum level of LH and FSH before and after zinc supplementation. LH and FSH determination were done using enzyme-linked immunosorbent assay (ELISA). A t-test was used to compare the means of two groups, P value was considered significant if ≤ 0.05. Results showed that LH serum levels were elevated in smokers as compared to the control group (p 0.05). Similar observation was found in FSH levels (p>0.05). After one month of zinc supplementation, LH levels decreased in smokers group (after: 4.14 ± 2.38 mlU/ml, before: 7.43 ± 4.32 mlU/ml; p>0.05). FSH levels also decreased after zinc supplementation in smokers group (after: 1.50 ± 1.12 mlU/ml, before: 3.88 ± 1.57 mlU/ml; p>0.05). The improving effect of zinc supplementation on LH and FSH pituitary and testicular steroid secretions for smoker subjects is obviously observed. These findings can be implemented to contribute to the outcome of zinc treatment associated with smoking. Key words: Zinc, biometals, smoking, gonadotropins, luteinizing hormone (LH), follicle-stimulating hormone (FSH), trace elements.

Differentially Expressed miRNAs after GnRH Treatment and Their Potential Roles in FSH Regulation in Porcine Anterior Pituitary Cell

Hypothalamic gonadotropin-releasing hormone (GnRH) is a major regulator of follicle-stimulating hormone (FSH) secretion in gonadotrope cell in the anterior pituitary gland. microRNAs (miRNAs) are small RNA molecules that control gene expression by imperfect binding to the 3′-untranslated region (3′-UTR) of mRNA at the post-transcriptional level. It has been proven that miRNAs play an important role in hormone response and/or regulation. However, little is known about miRNAs in the regulation of FSH secretion. In this study, primary anterior pituitary cells were treated with 100 nM GnRH. The supernatant of pituitary cell was collected for FSH determination by enzyme-linked immunosorbent assay (ELISA) at 3 hours and 6 hours post GnRH treatment respectively. Results revealed that GnRH significantly promoted FSH secretion at 3 h and 6 h post-treatment by 1.40-fold and 1.80-fold, respectively. FSHβ mRNA at 6 h post GnRH treatment significantly increased by 1.60-fold. At 6 hours, cells were collected for miRNA expression profile analysis using MiRCURY LNA Array and quantitative PCR (qPCR). Consequently, 21 up-regulated and 10 down-regulated miRNAs were identified, and qPCR verification of 10 randomly selected miRNAs showed a strong correlation with microarray results. Chromosome location analysis indicated that 8 miRNAs were mapped to chromosome 12 and 4 miRNAs to chromosome X. Target and pathway analysis showed that some miRNAs may be associated with GnRH regulation pathways. In addition, In-depth analysis indicated that 10 up-regulated and 3 down-regulated miRNAs probably target FSHβ mRNA 3′-UTR directly, including miR-361-3p, a highly conserved X-linked miRNA. Most importantly, functional experimental results showed that miR-361-3p was involved in FSH secretion regulation, and up-regulated miR-361-3p expression inhibited FSH secretion, while down-regulated miR-361-3p expression promoted FSH secretion in pig pituitary cell model. These differentially expressed miRNAs resolved in this study provide the first guide for post-transcriptional regulation of pituitary gonadotrope FSH secretion in pig, as well as in other mammals.

Use of letrozole challenge test to adjust gonadotropin dose in non–down-regulated cycles

The use of a letrozole challenge test to predict ovarian response is described. The authors show that a ratio of cycle day 7 to cycle day 3 post-letrozole FSH level >1.5 is associated with poor ovarian response.

Congenital hypogonadotropic hypogonadism in females: Clinical spectrum, evaluation and genetics

Congenital hypogonadotropic hypogonadisms (CHH) are a well-known cause of pubertal development failure in women. In a majority of patients, the clinical spectrum results from an insufficient and concomitant secretion of both pituitary gonadotropins LH and FSH that impedes a normal endocrine and exocrine cyclical ovary functioning after the age of pubertal activation of gonadotropic axis. In exceptional but interesting cases, they can result from an elective deficit of one of the gonadotropins follicle-stimulating hormone (FSH) or luteinizing hormone (LH) by genetic anomaly of their specific ß sub-unit. CHH prevalence, estimated from teaching hospital series, is considered to be two to five fold less important in women compared to men bearing the disease. This frequency is probably under-estimated in reason of under-diagnosis of forms with partial pubertal development. Isolated or apparently isolated forms (i.e., Kallmann syndrome with anosmia or hyposmia not spontaneously expressed by the patients) of these diseases are most of the time discovered during adolescence or in adulthood in reason of lacking, incomplete or even apparently complete pubertal development, but with almost constant primary amenorrhea. In a minority of cases and mainly in familial forms, genetic autosomal causes have been found. These cases are related to mutations of genes impinging the functioning of the pituitary-hypothalamic pathways involved in the normal secretion of LH and FSH (mutations of GnRHR, GnRH1, KISS1R/GPR54, TAC3, TACR3), which are always associated to isolated non syndromic CHH without anosmia. Some cases of mutations of FGFR1, and more rarely of its ligand FGF8, or of PROKR2 or its ligand PROK2 have been shown in women suffering from Kallmann syndrome or its hyposmic or normosmic variant. In complex syndromic causes (mutations of CHD7, leptin and leptin receptor anomalies, Prader-Willi syndrome, etc.), diagnosis of the CHH cause is most often suspected or set down before the age of puberty in reason of the associated clinical signs, but some rare cases of paucisymptomatic syndromic causes can initially be revealed during adolescence, like isolated non syndromic CHH or Kallmann syndrome.

INHIBINS INHIBINS - QUALITIES, QUALITIES, SIGNIFICANCE SIGNIFICANCE AND HIS ROLE IN PREGNANCY PREGNANCY

<p>Inhibins are glycoprotein hormones of which there are two molecular forms, inhibin A and inhibin B. Classically, inhibin is known to have a negative feedback effect on pituitary follicle-stimulating hormone secretion. The fetoplacental unit produced inhibin throughout pregnancy. Inhibin Ais the predominant molecular form of inhibin in maternal circulation from 4 week of gestation. Although the precise biological function of inhibin Ain pregnancy is unclear, it is evident from recent studies that inhibin A could be a better marker of placental function than human chorionic gonadotropin because of its shorter half-life. The possible clinical application for the measurement of inhibin Ain early pregnancy could be in predicting miscarriage , Down's syndrome, preeclampsia and fetal growth restriction in the first and/or second trimester before the onset of yhe clinical symptoms. Inaddition, several evidences underline the potential role and the clinical usefulness of their measurements in the diagnosis, prevention,prognosis and follow-up of different gestational pathologies such as:threatened abortion, placental tumors, hypertensive disorders of pregnancy,intrautherine growth restriction,fetal hypoxia.The measurement of inhibin Aand activin Ainto the biological fluids of pregnancy will offer in the future further possibilities in early diagnosis,prediction and monitoring pregnancy diseases.</p>

ESTROGEN RESPONSE ELEMENT DEPENDENT AND INDEPENDENT ESTROGEN RECEPTOR ALPHA SIGNALING PATHWAYS DIFFERENTIALLY REGULATE PITUITARY GONADOTROPIN TRANSCRIPTION AND SECRETION IN THE FEMALE MOUSE

Pituitary gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH) are both secreted by pituitary gonadotropes in response to gonadotropin-releasing hormone (GnRH). However, these gonadotropins are independently regulated throughout the estrous cycle to coordinate the timing of follicle development and ovulation. GnRH release is suppressed by estrogen negative feedback until, on the afternoon of proestrous, when estrogen positive feedback actions result in a GnRH and LH surge and the induction of ovulation. Subsequently, a FSH surge occurs to stimulate the development of a new cohort of follicles until when inhibin, produced by follicles, feeds back to the pituitary to suppress further FSH production and release. In ovariectomized females, estrogen treatment is capable of suppressing LH and FSH. While known to require the estrogen receptor alpha (ERalpha), the molecular mechanisms of this suppression remain unclear. Classical ERalpha signaling occurs through binding to an estrogen response element (ERE) in DNA, whereas in nonclassical signaling, ERalpha participates in protein-protein interactions to alter the activity of transcription factors at non-ERE sites (i.e. NF-kB, AP-1, or Sp1). Previously, our lab generated a Nonclassical Estrogen Receptor Knock In (NERKI) mouse model using a mutant ERalpha that is unable to bind to ERE but retains EREindependent activity. Breeding the NERKI mouse with the ERalpha knock out model (ERKO), we are able to selectively restore only EREindependent signaling to the ERalpha null background (NERKI/ERKO) and genetically dissociate in vivo roles for the ERE-dependent and independent ERalpha signaling pathways. Using this model, we have recently shown the ERE-independent ERalpha signaling pathway as capable of mediating partial estrogen negative feedback of serum LH. In this study, the ERE-dependent and independent estrogen effects on serum FSH and pituitary gonadotropin LHbeta and FSHbeta subunit transcription are examined following ovariectomy. We find that estrogen mediated suppression of pituitary LHbeta mRNA and serum FSH require the EREdependent ERalpha pathway. In contrast, the ERE-independent ERalpha signaling pathway is capable of mediating partial estrogen suppression of FSHbeta mRNA transcription and serum LH. These results support a model where, in the absence of other ovarian factors, estrogen acting through the ERE-dependent ERalpha pathway suppresses both LH and FSH transcription and secretion, whereas estrogen acting through the ERE-independent pathway partially suppresses LH secretion and FSHbeta transcription but is permissive to LHbeta transcription and FSH secretion. These data suggest that the balance of ERE-dependent and independent ERalpha signaling pathways may enable estrogen to dynamically regulate the transcription and secretion of both pituitary gonadotropins LH and FSH across the estrous cycle. Supported by NIH/NICHD grant PO1 HD21921, CMBD Training Grant T32 GM008061, UVA Ligand Core- NICHD (SCCPRR) Grant U54-HD28934 (platform)

Serum inhibin B and follicle-stimulating hormone levels as markers in the evaluation of azoospermic men: a comparison

Inhibin B is a glycoprotein hormone produced mainly by Sertoli cells of the testes in the adult male. It selectively suppresses the secretion of pituitary follicle-stimulating hormone (FSH) and has local paracrine actions in the testes. Its measurement is useful for investigating the role of inhibin B in male gonadal dysfunction. The objective of this study was to investigate the efficacy of serum inhibin B in men with nonobstructive azoospermia in comparison with FSH. Serum concentration of FSH was measured using microparticle enzyme immunoassay, inhibin B by specific solid phase sandwich enzyme-linked immunosorbent assay in men with nonobstructive azoospermia (n = 46) and control fertile men (n = 5). Mean inhibin B and FSH level was 104.6 pg ml(-1) and 4.0 mIU ml(-1) in control men whereas the value for nonobstructive azoospermic men was 17.06 pg ml(-1) and 31.1 mIU ml(-1) respectively. Inhibin B and FSH levels were significantly different in azoospermia than controls (P < 0.0001). There were six cases of nonobstructive azoospermia with normal inhibin B. Testicular histology did not find any evidence of spermatogenesis in three cases with normal inhibin B. This demonstrated that inhibin B was not a superior predictor for testicular function in our study.

Ethanol-induced alterations in Rab proteins: possible implications for pituitary dysfunction

Chronic exposure of pubertal male rats to ethanol results in a decline in serum testosterone, increased gonadotropins, pituitary luteinizing hormone (LH) and follicle stimulating hormone (FSH) content, and decreased or inappropriately normal serum LH and FSH levels, suggesting impaired secretory release of gonadotropins. The molecular mechanisms behind this disorder are undefined, but a disruption of vesicle-mediated secretory processes is possible because intracellular protein trafficking pathways are involved in secretion of glycoproteins such as FSH and LH. Because small GTP-binding proteins of Rab family have been implicated as key regulators of membrane and protein trafficking in mammalian cells, this study was designed to test if ethanol-impaired pituitary FSH and LH secretion is associated with changes in Rab proteins, particularly Rab1B, Rab3B, Rab6, and Rab11. Male Sprague–Dawley rats 35 days old were pair-fed a Lieber–DeCarli diet with ethanol or without ethanol for 5 to 60 days. After ethanol exposure, serum testosterone levels decreased while LH and FSH were inappropriately unchanged. Immunohistochemical staining showed decreased Rab1B, Rab3B, and Rab11 protein levels in ethanol-treated pituitaries. Immunoblotting showed that ethanol induced a transient reduction in Rab6 after 5 days of ethanol exposure, whereas Rab3B decreased after 20 days, Rab11 after 30 days, and Rab1B after 60 days. Despite these changes in Rab proteins, mRNA levels were unaffected by ethanol exposure. We concluded that reductions in key Rab proteins may lead to altered vesicle trafficking and may play a role in disruption of pituitary FSH and LH secretion caused by ethanol.

Animal models of inhibin action.

The physiology of inhibin has been investigated using rodent and ruminant animal models in both in vitro and in vivo studies. Inhibin was originally defined as a substance that causes selective suppression of follicle-stimulating hormone (FSH) secretion by pituitary gonadotropes. Although this definition is still valid, it fails to encompass the breadth of inhibin's actions. In addition to its endocrine action on pituitary FSH secretion, inhibin has a local paracrine action in its target tissues. The inhibin alpha subunit appears to play an important role in determining whether inhibin or activin is produced in cells. More recently, transgenic and knockout mouse models have highlighted the importance of inhibin for fertility and the inhibin alpha subunit for tumor suppression. Whether inhibin exerts its effects by a direct action on the gonad or by regulating FSH secretion, it is clear that inhibin is essential for normal reproductive function. In this article, we review the rodent and ruminant models employed to investigate inhibin physiology and examine the potential of inhibin-based vaccines to enhance gonadal function.

Role of inhibin in normal and high-risk pregnancy.

Inhibins are glycoprotein hormones of which there are two molecular forms, inhibin A and inhibin B. Classically, inhibin is known to have a negative feedback effect on pituitary follicle-stimulating hormone secretion. The fetoplacental unit produces inhibin throughout pregnancy. Inhibin A is the predominant molecular form of inhibin in maternal circulation from 4 weeks of gestation. Although the precise biological function of inhibin A in pregnancy is unclear, it is evident from recent studies that inhibin A could be a better marker of placental function than human chorionic gonadotropin because of its shorter half-life. The possible clinical applications for the measurement of inhibin A in early pregnancy could be in predicting miscarriage, Down's syndrome, preeclampsia, and fetal growth restriction in the first and/or second trimester before the onset of the clinical symptoms. The source of inhibins, factors controlling inhibin production, the possible functions of inhibin, and the use of inhibin measurement in normal and high-risk pregnancy are reviewed.

Comparison of Inhibin A Immunoassays: Recommendation for Adoption of Standardized Reporting

Serum inhibin A measurements have become increasingly common in clinical use, and their inclusion in prenatal screening for Down syndrome has been recently advocated. Two methods are commercially available for the specific measurement of dimeric inhibin A in human serum or plasma (1). Given the absence of a gold standard and the evolving clinical utility of inhibin A, a detailed comparison of the two inhibin A ELISAs is warranted. In the studies reported here, we undertook the evaluation of these methods and a direct comparison of their performance. The results obtained support the use of both methods and provide a basis for comparing values across these methods. Furthermore, we recommend that laboratories adopt a reporting unit of IU/mL based on the recombinant human Inhibin A International Reference Preparation (IRP) distributed by the National Institute for Biological Standards and Control on behalf of the WHO (91/624). Inhibin A is a dimeric glycoprotein hormone belonging to the transforming growth factor-β superfamily of cytokines. In addition to its numerous local, tissue-specific regulatory or “cytokine-type” actions (2)(3)(4), ovary-produced inhibin A is an important negative feedback hormone that suppresses pituitary secretion of follicle-stimulating hormone during the late follicular and luteal phases of the menstrual cycle (5)(6). Furthermore, circulating concentrations of inhibin A appear to reflect tumor mass for certain forms of ovarian cancer (7), particularly granulosa cell adenocarcinomas, and measurement of inhibin A also may be useful in assessment of gestational trophoblastic disease (8)(9). In addition, the measurement of serum inhibin A has recently been demonstrated as useful in the clinical setting as part of the “quadruple” antenatal screen for Down syndrome (10)(11)(12). The only analytical methods developed to date for measuring the picomolar concentrations of inhibin A found in peripheral blood …

G769A variation of inhibin alpha-gene in korean women with premature ovarian failure.

Premature ovarian failure (POF) is menopause before the age of 40 years. The frequency of POF is about 1% of all women. Recently inhibin alpha gene (INHalpha) has been indicated as candidate in POF pathogenesis. Inhibin, a glycoprotein, is a gonadal hormone, which can inhibit the synthesis and secretion of pituitary follicle-stimulating hormone (FSH), which has an important role in the recruitment and development of ovarian follicles during the folliculogenesis. G769A variation of INHalpha, alanine, is highly conserved across species, and has an important role of its receptor binding. We screened a G769A transition in the INHalpha from the total population of the patients of 84 women with POF and 100 normal fertile women. We found no variation between the normal subjects and the POF patients. G769A variation of INHalpha is rare in Korea women with POF.

Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54.

Hypogonadotropic hypogonadism is defined as a deficiency of the pituitary secretion of follicle-stimulating hormone and luteinizing hormone, which results in the impairment of pubertal maturation and of reproductive function. In the absence of pituitary or hypothalamic anatomical lesions and of anosmia (Kallmann syndrome), hypogonadotropic hypogonadism is referred to as isolated hypogonadotropic hypogonadism (IHH). A limited number of IHH cases are due to loss-of-function mutations of the gonadotropin-releasing hormone receptor. To identify additional gene defects leading to IHH, a large consanguineous family with five affected siblings and with a normal gonadotropin-releasing hormone receptor coding sequence was studied. Homozygosity whole-genome mapping allowed the localization of a new locus within the short arm of chromosome 19 (19p13). Sequencing of several genes localized within this region showed that all affected siblings of the family carried a homozygous deletion of 155 nucleotides in the GPR54 gene. This deletion encompassed the splicing acceptor site of intron 4-exon 5 junction and part of exon 5. The deletion was absent or present on only one allele in unaffected family members. GPR54 has been initially identified as an orphan G protein-coupled receptor with 40% homology to galanin receptors. Recently, a 54-aa peptide derived from the KiSS1 protein was identified as a ligand of GPR54. The present study shows that loss of function of GPR54 is a cause of IHH, and it identifies GPR54 and possibly KiSS1 protein-derived peptide as playing a major and previously unsuspected role in the physiology of the gonadotropic axis.

Expression of calretinin and the alpha-subunit of inhibin in granular cell tumors.

Granular cell tumors (GCTs) typically express S-100 protein, which has been used as a marker in differential diagnosis. Calretinin, a calcium-binding protein related structurally to S-100, and inhibin, a polypeptide hormone secreted primarily by ovarian granulosa cells and testicular Sertoli cells and functioning as an inhibitor for pituitary follicle-stimulating hormone secretion, are potentially useful but not well-evaluated markers for GCTs. We studied 43 cases of GCT with antibodies to calretinin, the inhibin alpha-subunit, and S-100 protein. All tumors were positive for inhibin alpha-subunit and S-100 protein, with 50% or more cells showing moderate to strong staining. Forty tumors (93%) were positive for calretinin, ranging from focal weak to diffuse strong staining. Enhanced staining for calretinin in the tumor cells adjacent to hyperplastic squamous epithelium was observed in 9 of 13 cases showing pseudoepitheliomatous hyperplasia. Calretinin and the inhibin alpha-subunit are useful markers for GCTs. The expression of calretinin, a primarily neuronal protein, in GCTs further supports its neural differentiation or derivation. The elevated calretinin expression in the tumor cells adjacent to the hyperplastic squamous epithelium suggests a role for calretinin in the tumor cells-squamous epithelium interaction.

Neuroendocrine control of follicle-stimulating hormone (FSH) secretion: II. Is follistatin-induced suppression of FSH secretion mediated via changes in activin availability and does it involve changes in gonadotropin-releasing hormone secretion?

The objective of the present study was to determine to what extent activin participates in setting the level of FSH secretion and if this regulation includes mediation via changes in GnRH secretion. We administered follistatin, the high-affinity binding protein for activin, to five ovariectomized sheep; we reasoned that the resultant binding of follistatin to activin should lower activin bioavailability and FSH secretion. Hypophyseal portal and peripheral blood samples were collected simultaneously at 10-min intervals for 18 h to measure GnRH, LH, FSH, and both activin-free and total follistatin. Six hours into collection, each ewe received 150 microg/kg i.v. of recombinant human follistatin-288. A week later, the same ewes were subjected to a second series of blood collections of similar length (time control). The FSH levels in pituitary portal blood were approximately 8-fold higher than those in the peripheral circulation. The FSH secretory patterns changed minimally during the time-control period. In contrast, follistatin had profound suppressive effects on FSH secretion. Maximal FSH suppression after FS-288 administration occurred at 5-6 h in the pituitary portal (65% suppression) and 9-10 h in the peripheral (48% suppression) circulation. Follistatin had no effect on GnRH or LH secretory patterns. Disappearance of total follistatin (i.e., free follistatin plus activin-bound follistatin) from the circulation was slower (P < 0.05) than that of free follistatin alone, suggesting that some of the follistatin was complexed with circulating activin, thus reducing the bioavailability of activin. The slower clearance of total follistatin and the lack of follistatin effects on GnRH secretion suggest that changes in activin bioavailability dictate the level of pituitary FSH secretion and that this is a pituitary-specific effect.

Effect of nutrition on the balance of production of ovarian and pituitary hormones in ewes.

Nutrition-induced changes in liveweight can induce changes in ovarian function and ovulation rate. This study was designed to test the hypothesis that heavy ewes are able to maintain similar concentrations of follicle-stimulating hormone (FSH) to light ewes through a loss of responsiveness to ovarian negative feedback. This hypothesis leads to the prediction that administration of ovarian hormones on the basis of metabolic body weight would result in the same gonadotrophin (FSH) concentrations in-light and heavy ovariectomised ewes. We therefore examined the ovarian content of oestradiol and inhibin, and the FSH response to administration of these ovarian hormones in acutely ovariectomised heavy and light Merino ewes produced by differential feeding. At ovariectomy, follicular fluid was aspirated from the 6 largest follicles in each ewe and assayed for oestradiol and inhibin. Six days later, blood was sampled every 6 h for 2 days. Ewes were then given two subcutaneous progesterone implants and injected subcutaneously every 6 h for 5 days with oestradiol (37.4 ng kg-0.75) and charcoal-stripped bovine follicular fluid (0.04 ml kg-0.75). Blood was sampled before each injection and the plasma was assayed for FSH and inhibin. Oestradiol and its receptors were assayed in uterine tissue. Nutrition-induced increases in liveweight led to increases in the number of oestrogenic, potentially ovulatory ovarian follicles and the total ovarian content of oestradiol and inhibin. In the uterus, more oestradiol receptors and a higher oestradiol uptake were observed in light than in heavy ewes. After ovariectomy, FSH concentrations were inversely related to liveweight. However, when the ewes were treated with doses of ovarian hormones that were proportional to liveweight, the slope of the decline in FSH concentrations was independent of liveweight. We conclude that nutrition alters the balance between pituitary FSH secretion and gonadal feedback by changing the responsiveness to the inhibitory effects of oestradiol and inhibin.

Roles of Inhibins, Activins, and Follistatin in the Female Reproductive System

Some 10 years have elapsed since inhibins were first isolated from ovarian follicular fluid and characterized as disulphide-linked dimeric glycoproteins capable of selectively suppressing the synthesis and secretion of follicle-stimulating hormone (FSH) by pituitary gonadotropes. There have been numerous surprises subsequent to this breakthrough, including the discovery and molecular characterization of activins and follistatins, proteins which share with inhibin an ability to modulate pituitary FSH secretion. It has also emerged that (i) inhibins and activins are members of the diverse but structurally related transforming growth factor β (TGFβ) peptide family; (ii) follistatin, although structurally unrelated to the TGFβ family, modulates activin bioactivity by acting as a specific high-affinity binding protein; (iii) inhibins, activins, and follistatin function as intragonadal autocrine/paracrine regulators of follicle cell differentiation and steroidogenesis; (iv) inhibins, activins, and follistatin are expressed and subserve local regulatory roles in numerous extragonadal tissues, including brain, adrenal, bone marrow, and placenta but perhaps most notably in anterior pituitary—the classical target tissue for inhibin; (v) the activin–follistatin system may play a key role in early embryogenesis. This article focuses on these developments of the past decade with particular reference to the distribution and functional roles of inhibins, activin, and follistatin in tissues related to the female reproductive system, including hypothalamus, anterior pituitary, ovary, and placenta.

Serum concentrations of follicle stimulating hormone and luteinizing hormone in normal girls and boys during prepuberty and at early puberty.

Serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) morning levels were determined in 327 normal prepubertal and early pubertal children of both sexes, utilizing a highly sensitive and specific microparticle enzyme immunoassay. Female (F) and male (M) prepubertal (Tanner's stage I) subjects were divided into 4 age groups: less than 3 months (F1, M1), 3 to 12 months (F2, M2) 12 to 24 months (F3, M3) and older than 24 months (F4 and M4). F pubertal subjects were classified in Tanner's stage breast II (F5) and III F6), while M pubertal subjects belonged to Tanner's stage genitalia II (M5). Serum LH levels were relatively low in prepubertal girls and showed a significant increment in group F6. By contrast, serum LH levels were relatively high in M1 and M2, decreased to levels similar to F in M3 and M4, and increased again at puberty in M5. Serum FSH levels were relatively high in girls of all prepubertal groups, even though they decrease significantly in M4. An increase was detected in pubertal group M6. All M prepubertal groups had significantly lower FSH levels than F prepubertal groups. The high serum LH of boys during the first year of life is probably a consequence of an activation of the hypothalamic GnRH pulse generator that is not apparent in girls. On the other hand, the high serum FSH of prepubertal girls is probably a consequence of a weak restraint influence of the prepubertal ovary on pituitary FSH secretion. This sexual dimorphism in gonadotropin secretion regulates, in a sex-specific fashion, prepubertal gonadal function in the two sexes.

Implication of inhibin and related proteins in fetal development.

Initial studies on inhibin, activin and follistatin focussed on their role as regulators of adult gonadal function via feedback regulation of anterior pituitary hormones and via intragonadal control of steroid hormones. The discovery of isoforms of follistatin which are either secreted or retained on the cell surface and which bind activin and, to a lesser extent, inhibin adds a further dimension to the regulation of these peptides. More recently, the cloning of inhibin and activin, and the observation of their close homology to the transforming growth factor-beta family of peptides, has led to an interest in their possible role as growth and differentiation factors. Activin, inhibin and follistatin are expressed in embryonic and fetal tissues, as well as in the placenta. However, although activin is a potent regulator of growth and differentiation in a number of cell types, their role in embryonic and fetal development has yet to be established. High concentrations of inhibin have been observed in the fetal gonads, particularly the testes, and in the fetal adrenals of a number of species and a sex difference in fetal plasma concentrations has also been observed. Although the stimulus for high concentrations of inhibin in the fetus is not know, they are associated with decreased testicular testosterone and a decrease in the concentration of circulating follicle-stimulating hormone (FSH); this suggests that, as in the adult, inhibin may be involved in the regulation of fetal testicular androgen and pituitary FSH secretion during late gestation. The recent reports of elevated concentrations of inhibin and, particularly, activin in amniotic fluid during late gestation and its ability to stimulate the production of prostaglandin E2 by fetal membranes provides yet another potential role for this hormone in the regulation of events leading to parturition.