Pregnancy-associated plasma protein-A gene expression in human ovaries is restricted to healthy follicles and corpora lutea.

Recently, Pregnancy-Associated Plasma Protein-A (PAPP-A) in human follicular fluid was identified as an insulin-like growth factor binding protein-4 protease (IGFBP-4ase). The ability of IGFBP-4ase to inactivate the FSH antagonist, IGFBP-4, has suggested a possible role for PAPP-A in regulating FSH action. Despite growing interest in this protease, the question of whether the PAPP-A gene is expressed in ovaries of normal cycling women is unknown. To fill this basic gap in our knowledge, we have identified the cellular sites of PAPP-A gene expression in normal human ovaries by in situ hybridization. PAPP-A mRNA was low or undetectable in preantral follicles, small (1-2 mm) healthy and atretic antral follicles, larger atretic antral follicles, surface epithelium, tunica albuginea and connective tissue cells. In contrast, an intense PAPP-A hybridization signal was evident in the healthy antral follicles examined from 5 mm to the preovulatory stage. In these follicles, the signal was restricted to the granulosa cells (GC). An intense signal for PAPP-A mRNA was also present in healthy corpora lutea (CL), being localized to a subset of large luteal cells. Collectively, these results provide the first evidence that the gene encoding PAPP-A is expressed in ovaries of normal cycling women and show that the gene is expressed almost exclusively in healthy GC and CL cells. The restricted pattern of PAPP-A expression in normal human ovaries suggests that PAPP-A may be a functional marker of the dominant follicle and its product, the CL. Although the physiological function of ovarian PAPP-A remains to be identified, we hypothesize it might play a role in controlling survival, growth, and/or differentiation of the dominant follicle and CL by inactivating the gonadotropin antagonist, IGFBP-4.

Expression of activin and follistatin in the rat hypothalamus: anatomical association with gonadotropin-releasing hormone neurons and possible role of central activin in the regulation of luteinizing hormone release.

The central role of activin in the regulation of the reproductive axis remains largely unexplored. Evidence suggests that activin may play a role in control-linggonadotropin-releasing hormone (GnRH) release. We assessed potential neuroanatomical associations between activin- and GnRH-neuronal systems via examination of the distribution of activin betaA-subunit and activin binding protein (follistatin) protein and mRNA signals relative to GnRH neurons in the adult rat brain. Activin betaA-subunit-immunostained fibers were distributed throughout the hypothalamus and GnRH-positive perikarya, and fibers were in close association with betaA-subunit-immunoreactive fibers. Follistatin mRNA-expressing cells were also identified throughout the hypothalamus with GnRH fibers often observed juxtaposed to follistatin cell bodies. Colocalization of either the betaA-subunit or follistatin within GnRH neurons was not detected. The functional significance of central activin in the regulation of the reproductive axis was also demonstrated. The intracerebroventricular infusion of rh-activin A significantly increased luteinizing hormone, but not follicule-stimulating hormone, serum levels in adult male rats. Taken together, the present results support an interaction between activin and GnRH neuronal systems in the rat hypothalamus, and suggest activin may act within the brain to regulate the reproductive axis.