Inhibin and activin modulate the release of gonadotropin-releasing hormone, human chorionic gonadotropin, and progesterone from cultured human placental cells.

Abstract

Although it is clear that human chorionic gonadotropin (hCG) and progesterone play fundamental roles in pregnancy, the regulation of placental production of these hormones remains to be defined. Recent evidence suggests that the human placenta expresses proteins related to inhibin (afi subunits) or activin (8P subunits). Inhibin and activin (folliclestimulating hormone-releasing protein) possess opposing activities in several biological systems including pituitary folliclestimulating hormone (follitropin) secretion, erythroid differentiation, and gonadal sex-steroid production. The actions of purified inhibin and activin on hormonogenesis by primary cultures of human placental cells were studied. The addition of activin increased gonadotropin-releasing hormone (GnRH) and progesterone production and potentiated the GnRHinduced release of hCG. Inhibin by itself did not modify placental immunoreactive GnRH, hCG, and progesterone secretion but reversed the activin-induced changes. Neither inhibin nor activin influenced the release of human placental lactogen. Furthermore, transforming growth factor (3, structurally related to inhibin/activin, did not signifcantly influence hormone release from cultured placental cells. These results support the hypothesis that inhibin and activin may play a role in regulating the release of GnRH, hCG, and progesterone from placenta and implicate inhibin-related proteins in the endocrine physiology of human pregnancy.Inhibins are heterodimeric proteins, consisting of an a subunit and one of two ,8 subunits (13A or PB), that were originally identified based upon their abilities to selectively suppress follicle-stimulating hormone (FSH) secretion (1-6). FSHreleasing proteins or activins were subsequently isolated and characterized as dimers comprised of inhibin (3 subunits APA or AJB) (7,8). Although inhibin and activin were first isolated from the gonads, various tissues including the placenta contain inhibin subunit mRNAs (9-12). Whereas the gonads contain a large excess of a-over (B-chain mRNAs, the placenta has an excess of p-subunit mRNAs; such observations raise the possibility that the placenta might have a preponderance of,,8 dimers (12). However, there is not yet conclusive evidence that intact activin is synthesized by human placenta.Placental inhibin a-subunit immunoreactivity is localized in the cytotrophoblast layer of the villi (11), a region shown earlier to contain other regulatory peptides including gonadotropin-releasing hormone (GnRH;, somatostatin (21), and corticotropin-releasing factor (22). The evidence that the placenta produces these hypophysiotropic peptides, which modulate the secretion of various hormones related to those in the pituitary [human chorionic gonadotropin (hCG), human placental lactogen (hPL), and corticotropin], supports the hypothesis that placental hormonogenesis may be regulated in part by locally produced peptides (13)(14)(15)(16)(17)(18)(19)(20)(21)(22).A recent report (11) showed that the addition of inhibin antiserum increased hC...

Activin A and activin receptors in gestational tissue from preeclamptic pregnancies

“…Activin binds to ActRII or ActRIIB and the ligand receptor complex interacts with type I receptors Alk4 and possibly Alk2 leading to signal transduction (Attisano et al 1996). In situ studies have localised activin receptor ActRII and ActRIIB mRNA to the syncytium and amniotic epithelium (Petraglia et al 1994), consistent with the proposed roles for activin in both the regulation of placental secretion of various hormones, such as gonadotrophin hormone-releasing hormone, progesterone, human chorionic gonadotrophin (Petraglia et al 1989, Song et al 1996 and oestradiol (Ni et al 2000), and in the onset of parturition, as suggested by inducing prostaglandin release by the fetal membranes (Petraglia et al 1993b). However, we found only weak, sporadic receptor ActRIIB (also receptor Alk2 and ActRII) staining by immunohistochemistry in the trophoblast and amniotic epithelium which does not fully support a role for activin A in placental hormonogenesis or parturition in vivo in either healthy or preeclamptic women.…”

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

“…Keelan et al Activin has been reported to exert a stimulatory effect on gonadotrophin-releasing hormone and hCG secretion from the placenta (37). Similarly, recent studies by Song et al (38) have shown that treatment of villous trophoblast cultures with activin A has a stimulatory effect on hCG production.…”

Concentrations of activin A, inhibin A and follistatin in human amnion, choriodecidual and placental tissues at term and preterm

“…Although we have been unable to reproduce this finding, we have recently demonstrated an effect of activin A on prostaglandin E 2 production by amnion explants (Keelan et al 1999). Effects of activin on placental hormone production have been documented which may impact on the mechanism or timing of labour (Petraglia et al 1989, Florio et al 1995, Song et al 1996. Activin may also play hitherto unrecognised roles in the mechanism of parturition including local effects on cytokine function , Keelan et al 1999.…”