Activin-A stimulates hypothalamic gonadotropin-releasing hormone release by the explanted male rat hypothalamus: interaction with inhibin and androgens

Abstract

The presence of activins in those hypothalamic regions containing gonadotropin-releasing hormone (GnRH)-secreting neurons suggests that these peptides may regulate the reproductive function modulating not only pituitary FSH release and biosynthesis, but also hypothalamic GnRH release. The purpose of this study was to evaluate the effects of activin-A, a homodimer of inhibin A subunit, on hypothalamic GnRH release in vitro and, because of their well known antithetical effects, to evaluate its interaction with inhibin. In addition, since androgens modulate the release of GnRH from male rat hypothalami, we thought it of interest to study the possible interplay between these steroids and activin on GnRH release. To accomplish this, we employed a hypothalamic organ culture system which enabled us to evaluate GnRH release from individually incubated hemi-hypothalami explanted from male rats. Activin-A stimulated GnRH release in a biphasic manner. The maximal effect was reached at a concentration of 10 ng/ml which increased GnRH output by about 75%. Inhibin abolished the stimulatory effect of a maximally effective concentration of activin-A in a dose-dependent manner, whereas alone it had no effect on GnRH output. As previously shown, testosterone (1 nmol/l) and dihydrotestosterone (DHT, 0·1 nmol/l) suppressed basal GnRH release, but only testosterone was able to inhibit the release of GnRH stimulated by activin-A. Since DHT is a non-aromatizable androgen, we evaluated whether the inhibitory effect of testosterone was due to its in vitro conversion into 17 -estradiol. The addition of 4-hydroxyandrostenedione, a steroidal aromatase inhibitor, did not influence the suppressive effect of testosterone on GnRH release stimulated by activin-A.In conclusion, activin-A stimulated hypothalamic GnRH release in vitro and this effect was abolished by inhibin and was blunted by testosterone. These findings suggest that activins may participate in the regulation of the hypothalamic-pituitary-gonadal axis by modulating GnRH release. The ability of testosterone to suppress the release of GnRH stimulated by activin-A indicates that this steroid has a potent negative feedback influence on GnRH release.

Activin, Inhibin, and Follistatin in Zebrafish Ovary: Expression and Role in Oocyte Maturation1

“…In agreement with these findings, an earlier study on goldfish pituitary also found that both activin and inhibin stimulated gonadotropin-II release [54]. Interestingly, while most studies in mammals have shown that activin and inhibin have opposite functions and that inhibin is a functional antagonist of activin [16], Alak et al [46] reported that activin A and inhibin A both enhanced oocyte maturation in rhesus monkeys. Since activin A and inhibin A had additive effects on monkey oocyte maturation, it was suggested that they might act at different levels and/or by different mechanisms [46].…”

“…Within the reproductive system, activins and inhibins have been found to regulate the release of GnRH from the hypothalamus [16] and FSH from the pituitary [1][2][3][4][5]. In addition, activins and inhibins exert many regulatory effects on the testis and ovary, such as steroidogenesis, proliferation of spermatogonia, proliferation of granulosa cells, modulation of FSH receptors, follicle development, and maturation [4,5,17].…”

Activin A Regulation of Gonadotropin-Releasing Hormone Synthesis and Release in vitro

“…The present results are similar to those shown by Calogero et al [23]. Using hemihypothalamic fragments in culture, they reported a 75% increase in GnRH output in response to activin after 6 h. The observations made using intact hypothalamic tissue as an experimental model differ from those using the GT1-7 cells, in which an activin-induced stimulation of protein secretion was not seen until 24 h. The more rapid effect in the explants may be attributed to the preserved integrity of the tissue, to the heterogeneity (multiple cell types) of the hypothalamic explants relative to the more homogenous GT1-7 cell population, or to the absence of the normal milieu of central regulatory factors in the GT1-7 cell culture.…”

“…In addition, they showed that chronic intracerebroventricular (icv) infusion of activin A stimulates FSH secretion in the rat. Recently, Calogero et al [23]reported that activin treatment of hemihypothalami, explanted from male rats, stimulates GnRH release in a biphasic manner and that this stimulation could be abolished by the activin antagonist, inhibin. Thus histological and functional data support the hypothesis that activin may serve as a paracrine regulator of GnRH release in the hypothalamus.…”

Neuropeptide Y in the forebrain of the adult male cichlid fish Oreochromis mossambicus: Distribution, effects of castration and testosterone replacement

“…It may be recalled that, in addition to androgens, testes secrete proteinous substances, such as activin and inhibins, that are known to exert feedback actions on the brain and pituitary (Franchimont et al, 1989;Tilbrook and Clarke, 2001). Calogero et al (1998) suggested the combinatory participation of activin, inhibins, and testosterone in the regulation of hypothalamopituitarygonadal axis in rat by modulating hypothalamic GnRH release. Search for such testicular factors that may upregulate the NPY-containing system in the brain of tilapia may be rewarding.…”