EFFECT OF SODIUM VALPROATE ON LUTEINIZING-HORMONE SECRETION IN PREMENOPAUSAL AND POSTMENOPAUSAL WOMEN AND ITS MODULATION BY NALOXONE INFUSION

The synchronized activity of the GnRH neurons can be modulated through both excitatory and inhibitory circuits: one such inhibitory modulato r is gamma-aminobutyric acid (GABA), but this has been little studied in humans. The aim of this study was to examine whether acute or chron ic modulation of the GABA-ergic system with the drug sodium valproate (VPA) affects gonadotropin secretory frequency and/or amplitude in a s teroid-dependent manner, and whether any such modulation might interac t with endogenous opioids. Sixty postmenopausal women (age range 50-60 yr, group I), 50 postmenopausal women who had been on estrogen replac ement therapy (group II), and 30 women in the luteal phase of their re gular menstrual cycle (age range 25-40 yr, group III) were studied. VP A was administered acutely using doses of 300, 600, and 1200 mg orally . Samples for serum gonadotropins were taken at intervals over 24 h. E ach dose of VPA caused significant LH suppression in group I. The maxi mum degree of suppressibility was the same with the three doses of VPA (14-20%). However, no dose had any effect on gonadotropin levels in g roup II. In group III, the single high dose of 1200 mg VPA significant ly suppressed serum LH levels. The efficacy of chronic VPA administrat ion in the three groups studied was assessed by measuring LH pulsatili ty (10-min samples) over 6 h, before and after 1 month's treatment wit h VPA. No change in either mean basal LH or in the LH pulsatility para meters was found. Naloxone infusion(1.6 mg/h for 6 h)had no effect on LH pulsatility in group I. When 1200 mg of VPA was administered before naloxone infusion, the level of LH suppression was 18% and was associ ated with a significant decrease in LH pulse frequency (P < 0.01). Nal oxone infusion alone significantly increased mean serum LH and LH puls e frequency in group II patients (P < 0.01), and this elevation was an tagonized by VPA pretreatment. Naloxone infusion alone significantly i ncreased mean LH levels and LH pulse frequency in patients in group II I, and this was also blocked by VPA pretreatment. These results sugges t that an acute increase in GABA-ergic tone may inhibit gonadotropin s ecretion in the estrogen-deprived state, or when endogenous opioid inh ibition is blocked in postmenopausal women on estrogens, as well as du ring the luteal phase of the menstrual cycle. It is possible that GABA -ergic pathways interact with opioids in the inhibitory modulation of gonadotropins in the human female.