The insulin hypoglycemia-induced inhibition of gonadotropin-releasing hormone pulse generator activity in the rhesus monkey: roles of vasopressin and corticotropin-releasing factor.

Abstract

Insulin-induced hypoglycemia (IIH) profoundly inhibits the activity of the hypothalamic GnRH pulse generator. The aim of this study was to determine the role of vasopressin and CRF in this response. Ovariectomized rhesus monkeys with chronically implanted recording electrodes in the mediobasal hypothalamus and with intracerebroventricular (icv) cannulas in the lateral ventricle were placed in primate chairs, and blood samples were taken every 10 min. Pulse generator activity was monitored electrophysiologically by detecting characteristic increases in hypothalamic multi-unit activity (MUA volleys) and by attendant LH pulses measured in peripheral blood. Arginine vasopressin (AVP) infused via the i.c.v. cannula (50 micrograms/60 microliters.h) in eight monkeys failed to decrease pulse generator activity, as measured by the frequency of MUA volleys, but decreased mean serum LH concentrations (P < 0.001) while increasing serum cortisol levels (P < 0.02). Central administration of an AVP antagonist ([deamino-Pen1, O-Me-Tyr2-Arg8] vasopressin) in four monkeys at a rate (180 micrograms/60 microliters.h) that had previously been found to block the aforementioned effects of coadministered AVP failed to prevent the IIH-induced inhibition of GnRH pulse generator activity and LH secretion in the same animals. On the other hand, a CRF antagonist, [D-Phe12,Nle21,38,C alpha MeLeu37] rat CRF-(12-41), infused i.c.v. at a rate of 500 micrograms/60 microliters.h in four monkeys, delayed the inhibition of pulse generator frequency in response to IIH. These results suggest that AVP does not mediate the hypoglycemia-induced inhibition of GnRH pulse generator frequency in the rhesus monkey, but that CRF may be involved in this response.

Androgen Receptor Antagonism and an Insulin Sensitizer Block the Advancement of Vaginal Opening by High-Fat Diet in Mice1

“…In this regard, acute treatment with insulin can inhibit pulsatile LH release by producing hypoglycemia and an accompanying stress response [66,67]. This is a different role for insulin than that proposed by the present work, in which increased insulin in the circulation is produced in likely a more gradual manner by dietary manipulation and is proposed to serve at least in part as a driver of androgen synthesis.…”

On the Role of Gonadotropin-Releasing Hormone (GnRH) in the Operation of the GnRH Pulse Generator in the Rhesus Monkey

“…In either case, it is highly unlikely that their diffusion from the CSF could have bypassed the arcuate region of the hypothalamus, the primary structure un derlying pulsatile GnRH secretion [27][28][29], which is di rectly adjacent to the infundibular recess of the third ven tricle. Furthermore, the same ICV infusion system has been used for the administration of arginine vasopressin with an immediate action on GnRH pulse generator activity that was prevented by the co-infusion of an inhib itory analog [22] supporting a direct effect on hypotha lamic structures. Therefore, the lack of an effect of antide or of GnRH administered centrally suggests that, in this species, GnRH is probably not involved in the operation of this hypothalamic oscillator either as an integrator or as a neuromodulator.…”

“…The animals were fitted with bilateral recording electrode arrays implanted in the mediobasal hypothalamus [21], with cannulae in one of the lateral cerebral ventricles [22] and with chronic indwelling cardiac catheters terminating in subcutaneously-implanted access ports [21].…”

Normal Suppression of the Reproductive Axis Following Stress in Corticotropin-Releasing Hormone-Deficient Mice*

“…Furthermore, 5 h of restraint, which activates the hypothalamic-pituitary-adrenocortical (HPA) axis and CRH gene expression (13), completely inhibits the proestrus LH surge and ovulation in intact cycling rats (14). Other stressors (undernutrition, hypoglycemia, or electric foot-shock) also inhibit LH secretion and pulsatility (15)(16)(17) as well as GnRH gene expression in the mPOA (18), and these effects are reversed following administration of a CRH antagonist in gonadectomized rats (17,19) and monkeys (20). These results further suggest that CRH inhibits GnRH activity through CRH receptors.…”