Phytoestrogens and gonadotropin-releasing hormone pulse generator activityand pituitary luteinizing hormone release in the rat

Phytoestrogens can produce inhibitory effects on gonadotropin secretion in both animals and humans. The aims of this study were 2-fold: 1) to determin e in vivo whether genistein and coumestrol act on the GnRH pulse generator to suppress hypothalamic multiunit electrical activity volleys and associat ed LH pulses and/or on the pituitary to suppress the LH response to GnRH, a nd 2) to examine the effect of these phytoestrogens on GnRH-induced pituita ry LH release ill vitro and to determine whether estrogen receptors are inv olved. Wistar rats were ovariectomized and chronically implanted with recor ding electrodes and/or indwelling cardiac catheters, and blood samples were taken every 5 min for 7-11 h. Intravenous infusion of coumestrol (1.6-mg b olus followed by 2.4 mg/h for 8.5 h) resulted in a profound inhibition of p ulsatile LH secretion, a 50% reduction in the frequency of hypothalamic mul tiunit electrical activity volleys, and a complete suppression of the LH re sponse to exogenous GnRH. In contrast, both genistein (1.6-mg bolus followe d by 2.4 mg/h for 8.5 h) and vehicle were without effect on pulsatile LH se cretion. Coumestrol (10(-5) M; over 2 or 4 h) suppressed GnRH-induced pitui tary LH release in vitro, an effect blocked by the antiestrogen ICI 182,780 . It is con eluded that coumestrol acts centrally to reduce the frequency o f the hypothalamic GnRH pulse generator. In addition, the inhibitory effect s of coumestrol on LH pulses occur at the level of the pituitary by reducin g responsiveness to GnRH via an estrogen receptor-mediated process.