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Phytoestrogens and Gonadotropin-Releasing Hormone Pulse Generator Activity and Pituitary Luteinizing Hormone Release in the Rat¹

Division of Anatomy, Cell and Human Biology, Division of Physiology (S.R.M.), GKT School of Biomedical Sciences, King’s College London, Guy’s Campus, London, United Kingdom SE1 1UL; Medical Research Council Human Reproductive Sciences Unit (I.A.S.), Edinburgh, United Kingdom EH3 9ET; and AstraZeneca, Central Toxicology Laboratory (A.N.B.), Alderley Park Macclesfield, Cheshire, United Kingdom SK10 4TJ

Address all correspondence and requests for reprints to: Dr. Kevin T. O’Byrne, Division of Anatomy, Cell and Human Biology, Endocrine and Reproductive Research Group, GKT School of Biomedical Sciences, 2.36D, New Hunts House, King’s College London, Guy’s Campus, London, United Kingdom SE1 1UL. E-mail: kevin.o'byrne{at}kcl.ac.uk

Phytoestrogens can produce inhibitory effects on gonadotropin secretion in both animals and humans. The aims of this study were 2-fold: 1) to determine in vivo whether genistein and coumestrol act on the GnRH pulse generator to suppress hypothalamic multiunit electrical activity volleys and associated LH pulses and/or on the pituitary to suppress the LH response to GnRH; and 2) to examine the effect of these phytoestrogens on GnRH-induced pituitary LH release in vitro and to determine whether estrogen receptors are involved. Wistar rats were ovariectomized and chronically implanted with recording 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 bolus followed by 2.4 mg/h for 8.5 h) resulted in a profound inhibition of pulsatile LH secretion, a 50% reduction in the frequency of hypothalamic multiunit electrical activity volleys, and a complete suppression of the LH response to exogenous GnRH. In contrast, both genistein (1.6-mg bolus followed by 2.4 mg/h for 8.5 h) and vehicle were without effect on pulsatile LH secretion. Coumestrol (10^-5 M; over 2 or 4 h) suppressed GnRH-induced pituitary LH release in vitro, an effect blocked by the antiestrogen ICI 182,780. It is concluded that coumestrol acts centrally to reduce the frequency of the hypothalamic GnRH pulse generator. In addition, the inhibitory effects of coumestrol on LH pulses occur at the level of the pituitary by reducing responsiveness to GnRH via an estrogen receptor-mediated process.