Effect of sodium valproate on luteinizing hormone secretion in pre- 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 modulator is gamma-aminobutyric acid (GABA), but this has been little studied in humans. The aim of this study was to examine whether acute or chronic modulation of the GABA-ergic system with the drug sodium valproate (VPA) affects gonadotropin secretory frequency and/or amplitude in a steroid-dependent manner, and whether any such modulation might interact with endogenous opioids. Sixty postmenopausal women (age range 50-60 yr, group I), 50 postmenopausal women who had been on estrogen replacement therapy (group II), and 30 women in the luteal phase of their regular menstrual cycle (age range 25-40 yr, group III) were studied. VPA was administered acutely using doses of 300, 600, and 1200 mg orally. Samples for serum gonadotropins were taken at intervals over 24 h. Each dose of VPA caused significant LH suppression in group I. The maximum degree of suppressibility was the same with the three doses of VPA (14-20%). However, no dose had any effect on gonadotropin levels in group II. In group III, the single high dose of 1200 mg VPA significantly suppressed serum LH levels. The efficacy of chronic VPA administration in the three groups studied was assessed by measuring LH pulsatility (10-min samples) over 6 h, before and after 1 month's treatment with VPA. No change in either mean basal LH or in the LH pulsatility parameters 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 associated with a significant decrease in LH pulse frequency (P < 0.01). Naloxone infusion alone significantly increased mean serum LH and LH pulse frequency in group II patients (P < 0.01), and this elevation was antagonized by VPA pretreatment. Naloxone infusion alone significantly increased mean LH levels and LH pulse frequency in patients in group III, and this was also blocked by VPA pretreatment. These results suggest that an acute increase in GABA-ergic tone may inhibit gonadotropin secretion in the estrogen-deprived state, or when endogenous opioid inhibition is blocked in postmenopausal women on estrogens, as well as during 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.