Evidence for Increased Dopaminergic and Opioid Activity in Patients with Hypothalamic Hypogonadotropic Amenorrhea*

Abstract

To gain insight into the psychoneuroendocrine basis for the reduced gonadotropin secretion in the hypothalamic hypogonadotropic amenorrhea syndrome, the roles of endogenous opioids and dopamine (DA) on gonadotropin and PRL release were evaluated. Responses of LH, FSH, and PRL to a DA receptor antagonist [metoclopramide (MCP); 10 mg, iv] and to an opioid receptor antagonist (naloxone infusion; 1.6 mg/h for 4 h) were analyzed in eight patients and compared with identical studies carried out in nine normal women during the low estrogen phase of the cycle. Neither MCP administration nor the naloxone infusion induced any changes in serum gonadotropinlevels in normal women. In contrast, four of eight patients responded to both receptor antagonistswith a significant increase in LH levels. The LH increment elicited by naloxone exhibited an amplification of the pulsatile pattern of release, suggesting hypothalamic LRF mediation. The other four patients with prepubertal levels of basal LH and lower concentrations of PRL and estradiol failed to show LH increments in response to either receptor antagonist. There were no significant FSH changes under these experimental conditions. Mean basal PRL concentrations were lower (P < 001) and the acute rise in PRL levels induced by MCP were smaller (P < 0.05) in all eight patients compared to those seen in normalsubjects. While the four LH responders and the normal womenexhibited no change in PRL levels during the naloxone infusion, a remarkable 100% rise in PRL was observed in the four LH nonresponders. These data suggest that at least two distinguishableforms of hypothalamic dysfunction exist in these patients; one exhibited LH increments after both opioid and DA antagonists but no PRL change in response to naloxone, and the other showed no LH increment after either receptor antagonist but did exhibit an unequivocal increase in PRL in response to naloxone. The former group may reflect an alteration of the opiate-DA system, while the latter may represent either a more severe form of the same syndrome or a distinct neuroendocrine aberration of gonadotropin and PRL secretion.