Interaction of estradiol and LHRH on LH release in rhesus females: evidence for a neural site of action.

The effects on LH release of infusing luteinizing hormone-releasing hormone (LHRH 80 mug/20 min) into the third ventricle, the pituitary, and the peripheral circulation were compared in spayed rhesus monkeys. Within 30 min after iv administration, serum LH concentrations increased to twice to preinfusion levels, and by 120 min declined to original values. Intraventricular or intrapituitary infusions of LHRH resulted in similar LH increments, but the peaks occurred somewhat later (70 to 90 min) and the elevations persisted beyond 200 min. Estradiol-17beta (E2) administered by a sc silastic capsule caused a 5-fold increase in serum E2 within 1 h and reduced serum LH levels by 65% within 4 h. The LH release caused by intrapituitary LHRH was significantly suppressed by maintaining for 72 h E2 concentrations near 100 pg/ml, a level inadequate for stimulating an LH surge. A comparable E2 treatment before intraventricular infusion of LHRH, however, did not inhibit LH release. This difference between the effects of intrapituitary and intraventricular LHRH was demonstrable only in E2-treated monkeys. Moreover, the release of LH after intraventricular infusion of LHRH in E2-treated females was blocked (P less than 0.001) by a single iv injection (90 min before LHRH) of haloperidol (1 mg/kg BW) or phentolamine (5 mg/kg), but was not altered by phenoxybenzamine (3 mg/kg) or propranolol (5 mg/kg). Without E2 pretreatment, LH release after intraventricular LHRH was enhanced by each drug. Phentolamine, injected into both E2- and non-E2-treated monkeys 90 min before an intrapituitary infusion of LHRH had no demonstrable effects on the patterns of serum LH. Our interpretation of these data is that E2 at a concentration below the level that triggers an LH surge has a dual action on LHRH-induced LH release in monkeys: an inhibitory effect exerted directly on the pituitary and a stimulatory effect on the brain. Furthermore, the paradoxical effects of the drugs with and without E2 are due to the involvement of two distinct neuronal systems. The postulated neural effects of both E2 and these drugs can be explained either by an increase in the quantity of injected or secreted LHRH which ultimately binds to LH-secreting cells or by the release of additional endogenous LH-stimulating agents together with ventricular LHRH.