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PubMed2001

Circulating follistatin concentrations are higher and activin concentrations are lower in polycystic ovarian syndrome.

Familial polycystic ovarian syndrome (PCOS) has been proposed to be linked to a site near the follistatin gene. We studied the concentrations of circulating follistatin, activin A and inhibin B in well-characterized subjects with PCOS (n = 108) and controls without PCOS (n = 20). Mean (+/- SEM) concentrations of follistatin were higher (P < 0.05) in PCOS (0.27 +/- 0.03 ng/ml) than controls (0.15 +/- 0.02 ng/ml) and activin A were lower (P < 0.05) in PCOS (0.20 +/- 0.01ng/ml) than controls (0.24 +/- 0.02 ng/ml). Inhibin B concentrations were not different between the two groups: PCOS (0.06 +/- 0.01ng/ml), and controls (0.06 +/- 0.01ng/ml). It is proposed that higher concentrations of follistatin with lower concentrations of activin A may relate to follicular development not proceeding beyond 8-10 mm and may be partly responsible for the lack of pre-ovular follicle development in PCOS.

Activins↗

PubMed2002

Inhibin and activin secretion during murine preantral follicle culture and following HCG stimulation.

BACKGROUND: Isolation and culture to antral stage of mouse preantral follicles provides an ideal system for investigating the endocrinology of follicular development to maturity. METHODS: The release of inhibin A, inhibin B, pro-alphaC and activin A was measured at specific time-points throughout an in-vitro culture period of 8 days. At the end of culture, follicles were induced to ovulate in vitro by the addition of HCG and the resulting hormone secretion studied both at 20 h and at 6 h intervals. RESULTS: During the preovulatory culture period, the concentrations of inhibin A, B, pro-alphaC and activin A increased significantly. Compared with control, there was a significant decline at 24 h in the concentrations of inhibin A [P < 0.001; 216 +/- 47 versus 823 +/- 110 arbitrary mouse units (amu)/ml], inhibin B (P < 0.01; 131 +/- 23 versus 361 +/- 45 amu/ml) and pro-alphaC (P < 0.001; 14 +/- 5 versus 1198 +/- 212 pg/ml). In contrast, there was a significant increase in the concentration of activin A (P < 0.001; 1.32 +/- 0.04 versus 0.34 +/- 0.03 ng/ml). CONCLUSIONS: These data provide clear evidence of a profound change in the relative secretion rates of inhibin and activin relative to ovulation and suggest that the principal role of activin A may be at time of ovulation rather than during follicular development.

Activins↗

PubMedDate not supplied

Linkage mapping of the ovine alpha-inhibin (INHA) beta(A)-inhibin/activin (INHBA) and beta(B)-inhibin/activin (INHBB) genes.

A full-sib mapping population was typed for Taql Southern blot RFLPs at the ovine alpha-inhibin (INHA), beta(A)-inhibin/activin (INHBA), and beta(B)-inhibin/activin (INHBB) loci. The most likely positions were found by genetic linkage analysis. INHA was placed on ovine chromosome 2q, between microsatellite markers BM6444 and INRA135, while INHBB was located 39 cM proximal to INHA between markers BMS1126 and BMS2626. The INHBA gene, a comparative mapping anchor locus, mapped to chromosome 4, between microsatellites OARCP26 and BMS719. These data confirm and refine previous chromosomal assignments by in situ hybridization, provide comparative mapping information, and identify microsatellite markers suitable for QTL association studies with inhibin/activin genes in ruminants.

Activins↗

PubMed2001

Age-dependent activin receptor expression pinpoints activin A as a physiological regulator of rat Sertoli cell proliferation.

It is currently believed that the fertility level of the adult mammalian testis is related to the total number of Sertoli cells, which is established in the early prepubertal life. We have previously reported that, in an in-vitro system, terminal Sertoli cell proliferation is sustained by activin A in concert with FSH. In this paper, we have addressed the question of whether this activin A effect correlates with activin receptor II (ActRII) expression pattern during early post-natal testis development. We first determined the precise developmental interval of activin proliferative effect on Sertoli cells in vitro and then analysed the expression of ActRII in purified testicular cell populations by Northern blot and in-situ hybridization. While the 3 kb ActRII isoform was widely expressed at different ages and in several testicular cells, including Sertoli cells, germ cells and myoid cells, the canonical 6 kb ActRII isoform was specifically and transiently expressed at a high rate in Sertoli cells at 7-9 days after birth, the time when these cells respond to activin A in vitro. In the light of these results, we conclude that activin A regulates terminal Sertoli cell proliferation in the rat testis and that this effect is mediated by the 6 kb isoform of ActRII.

Activin Receptors, Type II↗

PubMed1989

Possible involvement of inhibin in altered follicle-stimulating hormone (FSH) secretion during dissociated luteinizing hormone (LH) and FSH release: unilateral castration and experimental cryptorchidism.

Male rats were either unilaterally or bilaterally castrated, or were rendered cryptorchid when they were either 15 or 45 days old. Subsequently, blood was sampled over the next several weeks and plasma luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), and immunoreactive inhibin-alpha (irI alpha) levels were measured by specific radioimmunoassays (RIAs). At the end of the experiment, gonadal expression of inhibin-alpha, inhibin-beta A, and inhibin-beta B subunits was measured by S1 nuclease analysis and in situ hybridization. In both age groups, bilateral castration (BC) produced the expected marked (p less than or equal to 0.01) increases in plasma LH and FSH levels, and concomitant decreases in T and irI alpha secretion within 1 - 2 days after surgery. In 15-day-old animals, unilateral castration (UC) significantly increased FSH and decreased circulating levels of irI alpha, but did not measurably alter LH or androgen production. At 7 days after surgery, the level of inhibin mRNA in the remaining testis was unchanged. In 45-day-old animals, UC caused a measurable increase in FSH, with little or no changes in the circulating levels of irI alpha. Plasma T levels were lowered (p less than or equal to 0.05) by UC; however, there were no statistical changes in LH levels in these UC rats. Finally, T administration markedly reversed UC-induced increase in FSH secretion in both age groups. Androgen therapy also interfered with inhibin release in 45-day-old, but not in 15-day-old rats. In rats 15 days old at the time of surgery, cryptorchidism produced a small but measurable increase (p less than or equal to 0.05) in LH release at Week 6 only, which was accompanied by a significant (p less than or equal to 0.01) decline in T secretion. Plasma FSH levels were elevated at all times in cryptorchid rats, and at 2, 4, and 6 wk, these levels were not statistically distinguishable (p greater than 0.05) from those of castrated animals. In this group of rats, cryptorchidism caused a transient increase (p less than or equal to 0.05) in irI alpha values 1 wk after surgery, but no changes at later times. Finally, measurement of testicular inhibin-alpha subunit messenger RNA (mRNA) levels showed an approximately 2-fold increase compared to total RNA levels in the testis. However, because of the significant decrease in total RNA levels per testis caused by cryptorchidism, the absolute change in inhibin-alpha subunit mRNA levels per testis corresponded to an approximately 3-fold decrease.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2001

Effect of activin A on in vitro development of rat preantral follicles and localization of activin A and activin receptor II.

Preantral follicles (140-160 microm) were isolated mechanically from the ovaries of 10-day-old rats and cultured in groups of four to six for 6 days in medium containing 0, 1, 10, or 100 ng/ml of activin A. Activin stimulated (P < 0.05) the growth of preantral follicles in a dose-dependent fashion and enhanced the proliferation of preantral, oocyte-free follicular cells. Furthermore, treatment with activin induced the majority of follicles to form an antrum-like structure and helped to maintain the ultrastructure of these follicles during culture. Activin A also induced further changes characteristic of follicle and oocyte maturation, such as the elongation of granulosa cells contacting the oocyte and migration of the cortical granules to the oocyte cortex. In addition, gene expression for activin and activin receptor type II (ActR II) was demonstrated in both the oocytes and the somatic cells using the reverse transcription-polymerase chain reaction, and immunohistochemical studies demonstrated the presence of activin and ActR II proteins in the somatic tissue and, especially, the oocytes of these follicles. It is concluded that, in vitro, activin A stimulates the growth of rat preantral follicles and promotes antrum formation. Furthermore, because activin A and ActR II are synthesized within preantral follicles, intrafollicular activin likely plays an important role in early follicular development.

Activin Receptors, Type II↗

PubMed2001

Interactions between follicle-stimulating hormone and growth factors in modulating secretion of steroids and inhibin-related peptides by nonluteinized bovine granulosa cells.

The aim was to investigate potential interactions between FSH and intraovarian growth factors in modulating secretion of inhibin A (inh A), activin A (act A), follistatin (FS), estradiol (E2), and progesterone (P4) by bovine granulosa cells cultured under conditions in which a nonluteinized FSH-responsive phenotype is maintained. Cells from 4- to 6-mm follicles were cultured in serum-free medium containing insulin (10 ng/ml) and androstenedione (10(-7) M), and effects of ovine FSH (0.037-3 ng/ml) were tested alone and in combination with insulin-like growth factors (IGF) (LR3 IGF-I analogue; 2-50 ng/ml) and epidermal growth factor (EGF; 0.1-10 ng/ml). Medium was changed every 48 h and cultures ended after 144 h, when cell number was determined. Between 48-96 h and 96-144 h, FSH promoted (P < 0.0001) increases in output of inh A (6-fold), act A (15-fold), FS (6-fold), and E2 (18-fold), with maximal responses (in parentheses) elicited by 0.33 ng/ml FSH during the final period. Higher FSH doses (1 and 3 ng/ml) gave reduced responses for each of the above hormones, whereas P(4) output was maximal (3-fold) at these doses. FSH promoted a slight increase in cell number ( approximately 1.7-fold; P < 0.001). LR3 IGF-I alone markedly increased (P < 0.0001) output of inh A (8-fold), act A (41-fold), FS (12-fold), and E2 (18-fold); this was accompanied by modest increases (P < 0.01) in P4 output ( approximately 2.5-fold) and cell number ( approximately 2-fold). Whereas FSH enhanced inh A, act A, FS, and E2 secretion evoked by lower doses of LR3 IGF-I, it suppressed (P < 0.001) the response to the highest dose. EGF alone promoted a 1.7-fold increase in cell number (P < 0.001) without affecting hormone release; however, it abolished (P < 0.001) FSH-induced secretion of inh A, act A, FS, and E2. Both FSH alone and LR3 IGF-I alone dose-dependently increased the act A:FS ratio ( approximately 3-fold; P < 0.005) and act A:inh A ratio (3-fold to 6-fold; P < 0.001), suggesting that both factors selectively raise activin "tone" and that this could be a key requirement for FSH and IGF-induction of follicular E2 production. This hypothesis was reinforced by the finding that addition of FS, to reduce the act A:FS ratio and sequester secreted activin, markedly suppressed (P < 0.001) FSH (3-fold)-, and LR3 IGF-I (2-fold)-induced E2 output.

Activins↗

PubMed1997

Focal brain injury increases activin betaA mRNA expression in hippocampal neurons.

The role of activin in the mammalian brain is of increasing interest as evidence accumulates to suggest a number of different neural functions. Here, we report that activin betaA mRNA is transiently induced in dentate gyrus neurons after unilateral mechanical brain injury by saline injection. Expression is dependent on NMDA receptor activation since pretreatment with MK801 (5 mg/kg, i.p.) largely attenuates the signal. Induction also requires de novo protein synthesis, as cycloheximide (10 mg/kg, i.p.) pretreatment abolishes the expression of activin betaA mRNA 1 h after injury. These results show that activin betaA mRNA expression is regulated by excitatory activity induced by focal brain injury and suggests a possible neuroplastic role in the recovery from such injury.

Animals↗

PubMed1998

Activin is an essential early mesenchymal signal in tooth development that is required for patterning of the murine dentition.

Development of the mammalian tooth has been intensively studied as a model system for epithelial/mesenchymal interactions during organogenesis, and progress has been made in identifying key molecules involved in this signaling. We show that activin betaA is expressed in presumptive tooth-germ mesenchyme and is thus a candidate for a signaling molecule in tooth development. Analysis of tooth development in activin betaA mutant embryos shows that incisor and mandibular molar teeth fail to develop beyond the bud stage. Activin betaA is thus an essential component of tooth development. Development of maxillary molars, however, is unaffected in the mutants. Using tissue recombination experiments we show that activin is required in the mesenchyme prior to bud formation and that although activin signaling from mesenchyme to epithelium takes place, mutant epithelium retains its ability to support tooth development. Implantation of beads soaked in activin A, into developing mandibles, is able to completely rescue tooth development from E11.5, but not E12.5 or E13.5, confirming that activin is an early, essential mesenchyme signal required before tooth bud formation. Normal development of maxillary molars in the absence of activin shows a position specific role for this pathway in development of dentition. Functional redundancy with activin B or other TGFbeta family members that bind to activin receptors cannot explain development of maxillary molars in the mutants since the activin-signaling pathway appears not to be active in these tooth germs. The early requirement for activin signaling in the mesenchyme in incisor and mandibular molar tooth germs must be carried-out in maxillary molar mesenchyme by other independent signaling pathways.

Activins↗

PubMed2001

Resveratrol inhibits intestinal tumorigenesis and modulates host-defense-related gene expression in an animal model of human familial adenomatous polyposis.

We studied the effect of oral administration of resveratrol, a natural constituent of grapes, on tumorigenesis in Min mice. Min mice are congenic mice genetically predisposed to develop intestinal tumors as a result of a mutation of the Apc gene. Resveratrol (0.01% in the drinking water containing 0.4% ethanol) was administered for seven weeks to Min mice starting at five weeks of age. The control group was fed the same diet and received water containing 0.4% ethanol. Resveratrol prevented the formation of colon tumors and reduced the formation of small intestinal tumors by 70%. Comparison of the expression of 588 genes in the small intestinal mucosa showed that resveratrol downregulated genes that are directly involved in cell cycle progression or cell proliferation (cyclins D1 and D2, DP-1 transcription factor, and Y-box binding protein). In addition, resveratrol upregulated several genes that are involved in the recruitment and activation of immune cells (cytotoxic T lymphocyte Ag-4, leukemia inhibitory factor receptor, and monocyte chemotactic protein 3) and in the inhibition of the carcinogenic process and tumor expansion (tumor susceptibility protein TSG101, transforming growth factor-beta, inhibin-beta A subunit, and desmocollin 2). Our data highlight the complexity of the events associated with intestinal tumorigenesis and the multiplicity of the molecular targets of resveratrol. The high potency and efficacy of resveratrol support its use as a chemopreventive agent in the management of intestinal carcinogenesis.

Adenomatous Polyposis Coli↗

PubMed2002

Epidermal growth factor and TGFalpha promote zebrafish oocyte maturation in vitro: potential role of the ovarian activin regulatory system.

Epidermal growth factor (EGF) and TGFalpha are well known for their activities in the ovary. Both factors initiate signal transduction by binding to the common EGF receptor that has been demonstrated in the ovary across vertebrates from fish to humans. Using zebrafish as the model, we demonstrated in the present study that recombinant human EGF and TGFalpha significantly enhanced final maturation of the fully grown, follicle-enclosed oocytes (0.58-0.65 mm) in vitro in a clear time- and dose-dependent manner. The effect of EGF/TGFalpha was additive to that of hCG at low concentrations, but the additivity diminished when the concentration increased. Both actinomycin D and cycloheximide completely blocked the effect of EGF/TGFalpha, indicating that the promotion of oocyte maturation by EGF/TGFalpha requires de novo mRNA transcription and protein synthesis. Interestingly, the effect of EGF/TGFalpha could be blocked by cotreatment with follistatin, a potent binding protein for activin, an ovarian growth factor belonging to the TGFbeta superfamily. Semiquantitative RT-PCR assays showed that both EGF and TGFalpha significantly stimulated the expression of activin betaA and activin type II receptor in the cultured zebrafish ovarian follicle cells in a clear time- and dose-dependent manner. This together with our previous report that activin had a potent stimulatory effect on zebrafish oocyte maturation strongly suggests that the intrinsic ovarian activin system is probably a downstream mediator of EGF/TGFalpha actions in the zebrafish ovary.

Activin Receptors, Type II↗

PubMed2002

Inhibin suppresses and activin stimulates osteoblastogenesis and osteoclastogenesis in murine bone marrow cultures.

Using primary murine bone marrow cell cultures, we demonstrate that inhibin suppresses osteoblastogenesis and osteoclastogenesis. In contrast, activin supports osteoblast formation (by alkaline phosphatase-positive and mineralized colony formation); and activin also stimulates osteoclast formation (as measured by staining tartrate-resistant acid phosphatase-positive multinucleated cells). Inhibin, the activin antagonist follistatin, and the bone morphogenetic protein antagonist noggin can all suppress endogenous activin accumulation in bone marrow cultures. Associated with this decrease in activin is the loss of mineralized osteoblastic colony formation (colony forming unit-osteoblast; CFU-OB). However, exogenous activin administration, even in the presence of noggin, permits both alkaline phosphatase-positive and CFU-OB colony formation in vitro. In contrast, the stimulatory effects of locally produced activin on osteoblast and osteoclast development are not likely to be dominant over the suppressive effects of gonadally derived inhibin. The suppressive effect of inhibin is maintained in the presence of either activin or bone morphogenetic protein, suggesting the presence of a distinct inhibin-specific receptor. Taken together, the direct regulation of osteoblastogenesis and osteoclastogenesis by inhibin and activin in vitro suggest that changes in the inhibin/activin ratio detected by bone marrow cells, during the perimenopausal transition, contribute to altered cell differentiation and may be associated with the increased bone resorption observed at this time.

Activins↗

PubMed2000

Localization of activin beta(A)-, beta(B)-, and beta(C)-subunits in humanprostate and evidence for formation of new activin heterodimers of beta(C)-subunit.

Activin ligands are formed by dimerization of activin ss(A)- and/or ss(B)-subunits to produce activins A, AB, or B. These ligands are members of the transforming growth factor-ss superfamily and act as growth and differentiation factors in many cells and tissues. New additions to this family include activin ss(C)-, ss(D)-, and ss(E)-subunits. The aim of this investigation was to examine the localization of and dimerization among activin subunits; the results demonstrate that activin ss(C) can form dimers with activin ss(A) and ss(B) in vitro, but not with the inhibin alpha-subunit. Using a specific antibody, activin ss(C) protein was localized to human liver and prostate and colocalized with ss(A)- and ss(B)-subunits to specific cell types in benign and malignant prostate tissues. Activin C did not alter DNA synthesis of the prostate tumor cell line, LNCaP, or the liver tumor cell line, HepG2, in vitro when added alone or with activin A. Therefore, the capacity to form novel activin heterodimers (but not inhibin C) resides in the human liver and prostate. Activin A, AB, and B have diverse actions in many tissues, including liver and prostate, but there is no known biological activity for activin C. Thus, the evidence of formation of activin AC or BC heterodimers may have significant implications in the regulation of levels and/or biological activity of other activins in these tissues.

Activins↗

PubMed1996

Characterization and determination of the biological activities of noncleavable high molecular weight forms of inhibin A and activin A.

Recombinant expression of human alpha- and beta A-inhibin subunit cDNAs in mammalian 293 cells results in the secretion of 20-53K free alpha-subunit-derived products, 30-105K alpha beta A-inhibin dimers, and 24-110K beta A-activin dimers. The present study verifies that the wide variation in the size of these products is due to incomplete cleavage of the proteolytic processing sites and the differential glycosylation of the N-linked glycosylation site at amino acid number 302 in the alpha C-subunit. The identity of each of these products was established by mutagenesis of proteolytic processing sites and N-linked glycosylation sites, combined with the analysis of transfection products by immunoprecipitation and one- and two-dimensional SDS-PAGE (SDS/SDS-beta-ME). Transient expression of processing site mutants of the alpha- and beta A-subunits in 293 cells was used to generate microgram quantities of noncleavable 55K and 65K inhibin dimers, and noncleavable 110K activin A dimers. The 55K and 65K inhibin A forms were purified and found to be fully biologically active in a rat pituitary cell bioassay. The 110K high molecular weight (HMW) form of human activin A failed to show any FSH-releasing activity in the pituitary assay. Since radioactively labeled 55K and 65K inhibin A and 110K activin A remained intact after incubation with rat pituitary cells for 72 h, there appears to be no conversion of these dimers to lower molecular weight forms by proteolytic cleavage at additional sites. These results show for the first time that 55K and 65K inhibit A are intrinsically biologically active and do not require cleavage to the 32K form for activation. In contrast, cleavage of the 110K activin A precursor to the 24K form would appear to be necessary for activity.

Activins↗

PubMed2001

Effect of cytokines and growth factors on the secretion of inhibin A, activin A and follistatin by term placental villous trophoblasts in culture.

OBJECTIVE: Maternal serum inhibin A and activin A are higher in pre-eclampsia than in normal pregnancy. The placenta is a source of these proteins in pregnancy. The aim of this study was to investigate the effect of growth factors and proinflammatory cytokines that are raised in pre-eclampsia on the secretion of dimeric inhibin A, activin A and follistatin by villous cytotrophoblasts in culture. DESIGN AND METHODS: Villous cytotrophoblasts were prepared from term placentae and cultured in serum-free media. Cells were treated with increasing concentrations of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, transforming growth factor (TGF)-beta1, granulocyte and monocyte colony-stimulating factor (GMCSF), inhibin A, activin A and follistatin for 2 days. Culture supernatants were assayed for human chorionic gonadotrophin (hCG), inhibin A, activin A and follistatin as appropriate. Experiments were repeated at least three times with each cytokine or growth factor and the data pooled. RESULTS: Cytotrophoblasts syncytialise and spontaneously secrete hCG, inhibin A and activin A in culture. Follistatin levels were <20 pg/ml in most experiments. Activin A secretion was increased in culture in a dose-dependent manner by IL-1beta (approximately 150%, P<0.05), TNF-alpha (approximately 35%, P=0.02) and GMCSF (approximately 100%, P<0.01). hCG secretion was inhibited in a dose-dependent manner by TNF-alpha (50%, P<0.05). Inhibin A was stimulated by IL-1beta ( approximately 30%, P=0.05). Inhibin A, activin A, follistatin or TGF-beta1 did not have a significant effect on any measured parameters. CONCLUSIONS: These data show that inflammatory cytokines increase the secretion of activin A by trophoblasts in culture. The presence of very low levels, or no follistatin (<20 pg/ml) in the culture media suggests 'free' activin A could have autocrine/paracrine effects on cytotrophoblasts. Inhibin A secretion was stimulated by IL-1beta. However, absence of an effect by the other cytokines investigated on inhibin A in this study suggests that the mechanism(s) involved in increasing maternal circulating levels of inhibin A and activin A in pre-eclampsia are controlled differentially.

Activins↗

PubMed2001

[Expression of inhibin alpha and inhibin/activin beta A subunits in the developing follicles of the duck].

The very sensitive quantitative competitive reverse transcription-polymerase chain reaction (RT-PCR) was used to investigate the expression of mRNA for the inhibin alpha and inhibin/activin beta A subunit in the developing ovarian follicles of the duck. The results indicated all follicles showed the expression of mRNA for the inhibin alpha and inhibin/activin beta A. The inhibin alpha subunit mRNA is expressed more abundantly than the beta A subunit in the large preovulatory follicles. Competitive RT-PCR revealed that the expression of inhibin alpha subunit is the highest in small yellow follicles (SYF), the mean relative content for the F1, F2, F3, F4/5 and LWF (large white follicle) was 0.26 +/- 0.05, 0.28 +/- 0.07, 0.57 +/- 0.12, 0.98 +/- 0.09 and 0.026 +/- 0.006, respectively, compared to a mean relative content of 1.00 for the SYF. The highest level of inhibin/activin beta A mRNA was found in the F1 follicle, the mean relative content for the F2, F3, F4/5, SYF and LWF was 0.218 +/- 0.09, 0.111 +/- 0.03, 0.058 +/- 0.011, 0.053 +/- 0.013 and 0.005 +/- 0.002, respectively, compared to a mean relative content of 1.00 for the F1 follicle. Our data suggest that the expression of the alpha subunit is reduced with follicular development whereas beta A subunit expression is dramatically enhanced, which indicates the expression of inhibin alpha and inhibin/activin beta A subunit is differentially regulated during follicular development. In addition, the highest level of beta A mRNA in F1 follicle indicates the production of dimeric inhibin and/or activin primarily occurred in the largest F1 follicle.

Animals↗

PubMedDate not supplied

[Inhibin B immunocytochemistry for the prognosis assessment of undescended testis damage in children].

Inhibin B immunocytochemistry of both the alpha- and beta-subunits was studied in testicular biopsies from 18 prepubertal and postpubertal patients, with unilateral or bilateral cryptorchism. The present investigation was carried out to seek any prognostic significance for the expected fertility of such subjects in adulthood. All samples were also evaluated by histological and morphometric assessments, according a 1-6 grading sy-stem. In this way, the individual testicular changes were scored by quantitating tubular and germ cell hypoplasia, Sertoli cell hyperplasia, and peritubular fibrosis, where present. The results showed that in bilateral maldescended testes an unexpected expression often occurred of inhibin B beta-subunit in Sertoli cells, while inhibin B alpha-subunit there did not, denoting an early developmental arrest of the testis. It co-related with the high grade testicular damages, as a poor predictor of spermatogenesis. Unlike, unilateral retained testes mainly expressed inhibin B alpha-subunit, irrespective of tubular changes. In the latter instance, different pathogenetic factors of imbalanced testicular regulation can be perspected, other than the Inhibin-Activin system.

Adolescent↗

PubMed2001

Response of human fetal pituitary cells to activin, inhibin, hypophysiotropic and neuroregulatory factors in vitro.

Activin has been previously demonstrated to directly stimulate the synthesis of GnRH receptors and to increase FSH secretion in non-human pituitary cell cultures (PCC). Several results in Macaque monkeys failed to support an unequivocal role for Inhibin in FSH suppression. Whereas the bioactivity of Inhibin and Activin has been demonstrated in rat PCC, no data exist on human pituitary response to these peptides. We studied, therefore, the secretion of FSH and LH by dispersed human fetal PCC from > 140 midtrimester abortions in response to recombinant human (rh-) Activin-A, Inhibin, and other secretagogues. After mechanical and enzymatic dispersion, using collagenase and deoxyribonuclease, the human fetal pituitary cells were cullured on extracellular matrix (ECM) like material coaled 24 well plate (Primaria, Falcon) in fetal calf serum-containing medium. After 3 days incubation in serum-containing medium, the PCC were washed and preincubated for 90 mins in serum-free medium and incubated with rh-ActivinA, Inhibin, TGF-p, Follistatin, sex steroids, and GnRH in quadruplicate wells. The EC50 of rh-Activin-A for FSH secretion was ~ 10 ng/mL. rh- Activin-A was a more potent secretagogue for FSH secretion than GnRH. On the contrary, GnRH (20 ng/mL) was more potent than rh-Activin A for LH secretion. Nevertheless, a significant increase in LH secretion into the medium was brought about by rh-Activin-A. Inhibin decreased FSH secretion but LH response to Inhibin was inconsistent. GnRH opposed the inhibitory effect of Inhibin on both gonadotropins. In dynamic, short term, repetitive exposure of fetal pituitary fragments to rh-Activin-A (superfusionl we could not receive -a similar increase in LH & FSH as in static incubations, as opposed to a short GnRH exposure. Melatonin did not inhibit LH secretion in human PCC as opposed to rodents. In addition to their endocrine, paracrine, and sutocrine effects and to their role as possible markers, the TGF-b superfamily members may atiect embryogenesis and possibly immunomodulation of the fetus. In contrast to others, who could detect Inhibin-B only in male but not in female fetuses sera, we have measured Inhibin-B in both male and female midtrimester fetal sera, challenging the previous assumption that the fetal origin is only Sertoli cells. Human fetal PCC express the previously reported physiologic responses to Activin and Inhibin generated in non-human experiments on gonadotropin secretion in-vitro, and may serve as a physiologic model for studying human gonadotrope responses to the TGF-b family of peptides. Our preliminary data may provide the first unequivocal evidence for the validity of the Activin/Inhibin hypothesis in human.

Activins↗