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.
Brain catecholamines have been implicated in the regulation of gonadotrophin release. It has been recently reported that noradrenaline (NA), applied within the hypothalamic paraventricular nucleus, suppresses the pulsatile release of LH in the rat through a corticotrophin-releasing hormone (CRH)-dependent mechanism. Prolactin (PRL) is also able to suppress hypothalamic GnRH release following activation of the CRH-releasing neurone. Given that PRL stimulates the release of NA from hypothalamic explants and that NA stimulates the release of hypothalamic CRH, we hypothesized that this neurotransmitter may be involved in the intrahypothalamic neuroendocrine circuit mediating the inhibitory effects of PRL on GnRH release. To test this hypothesis, we evaluated the effects of PRL on GnRH release in the presence of alpha- or beta-adrenergic receptor antagonists using a static hypothalamic organ culture system which enabled us to evaluate immunoreactive GnRH (iGnRH) release from individually incubated, longitudinally halved hypothalami. As previously shown, PRL at a concentration of 100 nM inhibited basal iGnRH release by about 35%. Phentolamine, a non-selective alpha-adrenergic receptor antagonist, prazosin, an alpha 1-receptor antagonist, and yohimbine, an alpha 2-receptor antagonist, overcame the inhibitory effect of PRL on iGnRH release in a concentration-dependent fashion. In contrast, propranolol, a non-selective beta-adrenergic receptor antagonist, atenolol, a beta 1-receptor antagonist, and ICI-118,551, a beta 2-receptor antagonist, had no effect. None of these compounds had any effect on basal iGnRH release. These findings suggested that an alpha-adrenergic mechanism is involved in the suppressive effects of PRL on GnRH release. Since the activation of alpha-adrenergic receptors increases hypothalamic CRH release, we evaluated whether PRL stimulates CRH release via an alpha-adrenergic mechanism. PRL stimulated basal CRH release by about twofold and this effect was inhibited by phentolamine in a concentration-dependent fashion. In conclusion, alpha-, but not beta-, adrenergic receptors mediate the inhibitory effects of PRL on GnRH release in vitro. We speculate that, at least under these experimental conditions, PRL inhibits GnRH release through an alpha-adrenergic mechanism which activates the CRH-secreting neurone.
Endothelin (ET)-1 and ET-3, two peptides with a potent vasoconstrictive property, produce a variety of biological effects in different tissues by acting through two different receptors, the ET-1 selective ET A receptor and the nonselective ET B receptor. An increasing body of literature suggests that ET-1 acts as a paracrine/autocrine regulator of ovarian function. Indeed, ET B receptors have been identified in rat granulosa cells and ET-1 is a potent inhibitor of progesterone production. In contrast, inconsistent data have been reported about the role of ET-1 on estrogen production and the effects of ET-3 are not known. Therefore, the present study was undertaken to evaluate the effects of ET-1 and ET-3 on estrogen and cAMP production, and the receptor type involved. Given that prostanoids modulate ovarian steroidogenesis and that many actions of ETs are mediated by these compounds, we also evaluated whether the effects of ETs on estrogen and cAMP production might be prostanoid-mediated. ET-1, ET-3, and safarotoxin-S6c (SFX-S6c), a selective ET B receptor agonist, inhibited basal estrogen production by granulosa cells obtained from immature, estrogen-primed female rats, in a concentration-dependent manner. All three peptides were also capable of inhibiting the production of estrogen stimulated by a half-maximal (1 mIU/ml) and a maximally stimulatory (3 mIU/ml) concentration of FSH. ET-1 and ET-3 dose-dependently suppressed basal and FSH (1 mIU/ml)-stimulated cAMP production. ET-3 and SFX-S6c were significantly more potent than ET-1 in suppressing estrogen production, suggesting that this effect was not mediated by the ET A receptor. Indeed, BQ-123, a selective ET A receptor antagonist, did not influence the inhibitory effects of ET-1 and ET-3 on basal and FSH-stimulated estrogen release. To determine a possible involvement of prostanoids, we evaluated the effects of maximally effective concentrations of ET-1 and ET-3 on estrogen and cAMP production in the presence of indomethacin, a prostanoid synthesis inhibitor. This compound did not have any effect on the suppressive effects of ETs on basal or FSH (1 mIU/ml)-stimulated estrogen or cAMP production.In conclusion, ET-1 and ET-3 were able to inhibit estrogen and cAMP production by rat granulosa cells, indicating that the inhibitory effects of ETs on ovarian steroidogenesis are not limited to progesterone biosynthesis. This effect does not appear to be mediated by prostanoids or by the classical ET A and ET B receptors, at least under these experimental conditions.
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