The mechanism of action of alcohol to suppress gonadotropin secretion

Alcohol suppresses reproduction in humans, monkeys and small rodents by suppressing release of luteinizing hormone (LH). The major action is on the hypothalamus to decrease release of LH-releasing hormone (LHRH). The release of LHRH is controlled by nitric oxide (NO). The hypothesized pathway is via norepinephrine-induced release of NO from NOergic neurons which activates LHRH release, We have evaluated details of this process in male rats by incubating medial basal hypothalamic (MBH) explants in vitro and examining the release of NO and metabolites generated by NO which control LHRH release. Norepinephrine increased release of NO as measured by determining the content of the enzyme at the end of the experiment (30 min) by adding [C-14]arginine to the homogenate and measuring its conversion to [C-14]citrulline since this is formed in equimolar quantities with NO by nitric oxide synthase (NOS). Since this increase in content presumably caused by activation of the enzyme by norepinephrine was blocked by the alpha(1) receptor blocker prazosin, it appears that alpha(1) receptors activate NOS by increasing intracellular free calcium in the NOergic neuron which combines with calmodulin to activate nitric oxide synthase. The release of LHRH induced by nitroprusside (NP), a donor of NO, results in an increase in cyclic (c)GMP in the medium supporting the activation of guanylate cyclase by nitroprusside. This activation is important in releasing LHRH since addition of 8-monobutyryl cGMP also released the peptide. Ethanol had no effect on the content of NO or the increase in content induced by norepinephrine indicating that it did not act on NOS. Earlier experiments indicated that prostaglandin E-2 (PGE(2)) was important in releasing LHRH. PGE(2) is produced by activation of cyclooxygenase by NO since this could occur following addition of the NO donor nitroprusside. Not only does NP increase PGE(2) release, but also the conversion of [C-14]arachidonic acid to its metabolites, particularly PGE(2). Ethanol acts at this step since it completely blocks the release of LHRH induced by NP and the increase in PGE(2) induced by NP, Therefore, the results support the theory that norepinephrine acts to stimulate NO release from NOergic neurons. This NO diffuses to the LHRH terminals, where it activates guanylate cyclase, leading to an increase in cGMP. At the same time, it also activates cyclooxygenase. The increase in cGMP increases intracellular free calcium, required for activation of phospholipase A(2). Phospholipase A(2) converts membrane phospholipids into arachidonic acid, the substrate for conversion by the activated cyclooxygenase to PGE, which then activates the release of LHRH. Since alcohol inhibits conversion of labeled arachidonic acid to PGE(2), it must act either directly to inhibit cyclooxygenase or by some other mechanism which, in turn, inhibits the enzyme.