Inhibition of Gonadotropin-Releasing Hormone Release as the Basis of Pituitary-Gonadal Dysfunction during Treatment with 4-Aminopyrazolo-(3,4-d)-Pyrimidine*

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Abstract
The inhibitor of hepatic lipoprotein release, 4-aminopyrazolo(3,4-d)pyrimidine (4-APP), was shown to reduce testosterone production via impairment of pituitary gonadotropin secretion rather than through decreased cholesterol availability. Apparently, serum LH [luteinizing hormone] levels were reduced by more than 75% in male rats treated with 4-APP, but pituitary stores of LH and the gonadotropin response to exogenous GnRH [gonadotropin-releasing hormone] were maintained. Also, there was a reduction in pituitary GnRH receptors which was consistent with hypothalamic GnRH deficiency. The mechanism by which 4-APP inhibits GnRH synthesis and/or release was examined. Intact, adult male or 2 wk ovariectomized female rats were treated daily with 25 mg/kg 4-APP for 3 days. Both sexes showed lowered basal serum levels of LH and absence of the elevations in serum LH normally elicited by the opiate antagonist, naloxone. In pituitary portal plasma collected from normal male rats, GnRH was significantly elevated by naloxone treatment, confirming that naloxone acted at the level of hypothalamic GnRH release. Naloxone stimulation of GnRH secretion into portal blood was absent in rats treated with 4-APP. In vitro, the K-induced release of GnRH from perifused medial hypothalami was reduced by 60% in 4-APP-treated male rats while hypothalamic GnRH content remained unchanged. Apparently, 4-APP has an inhibitory effect on the mechanism of GnRH release; analysis of the actions should clarify the processes involved in neurohormone secretion.