Inhibition of gonadotropin-releasing hormone release as the basis of pituitary-gonadal dysfunction during treatment with 4-aminopyrazolo-(3,4-d)-pyrimidine.
The inhibitor of hepatic lipoprotein release, 4-aminopyrazolo-(3,4-d)-pyrimidine (4-APP), has been shown to reduce testosterone production via impairment of pituitary gonadotropin secretion rather than through decreased cholesterol availability. It was previously shown that serum LH 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 were maintained. Also, there was a reduction in pituitary GnRH receptors which was consistent with hypothalamic GnRH deficiency. The present studies were undertaken to examine the mechanism by which 4-APP inhibits GnRH synthesis and/or release. Intact, adult male or 2-week 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. However, naloxone stimulation of GnRH secretion into portal blood was absent in rats treated with 4-APP. In vitro, the potassium-induced release of GnRH from perifused medial hypothalami was reduced by 60% in 4-APP-treated male rats while hypothalamic GnRH content remained unchanged. These data indicate that 4-APP has an inhibitory effect on the mechanism of GnRH release, and that analysis of its actions should clarify the processes involved in neurohormone secretion.
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002369:Castration; D005260:Female; D006066:Gonads / Q000187:drug effects*; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D010902:Pituitary Gland / Q000187:drug effects*; D010906:Pituitary Hormone-Releasing Hormones / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D010906:Pituitary Hormone-Releasing Hormones; C004420:4-aminopyrazolo(3,4-d)pyrimidine; D009270:Naloxone; D007986:Luteinizing Hormone; D000225:Adenine