Effects of valproate-induced alteration of the GABAergic system on pulsatile luteinizing hormone secretion in ovariectomized women

Abstract

It is well established that valproate increases hypothalamic concentrations of gamma-aminobutyric acid (GABA). Although little research has been done on the role of GABA in the control of pulsatile luteinizing hormone (LH) secretion in humans, our group recently found that administration of valproate had no significant effect on pulsatile LH secretion in late follicular and mid-late luteal phase normal women. However, the results of several studies of rats suggest that GABAergic regulation of LH secretion may depend on steroid levels. The objective of this work was to determine whether regular administration of sodium valproate inhibits pulsatile LH secretion in ovariectomized women. Twelve women who had undergone ovariectomy for causes other than malignant tumors were each studied in two 8 h sessions, in each of which blood samples were taken every 5 min. The first session was the control; for the second. 400 mg of sodium valproate was administered every 8 h during the seven preceding days and at 08.00 h and 14.00 h on the day of the study session. Serum valproate was determined by repolarization fluorescence spectrophotometry, and LH, estradiol and progesterone by radioimmunoassay. The serum LH series were subjected to a deconvolution procedure to reconstruct the pattern of pituitary LH secretion. Luteinizing hormone pulses were identified by the authors' non-parametric method. Control and post-valproate results were compared with regard to number of pulses, pulse duration, the quantity of LH secreted in each pulse, interpulse interval and mean serum LH level. There was no statistically significant difference between control and post-valproate results for any of the variables considered. It is concluded that sustained serum valproate levels do not alter pulsatile secretion of LH in ovariectomized women. This implies that, in humans, GABA is probably not a decisive factor in the regulation of the GnRH pulse generator.

Early hormonal changes during valproate or carbamazepine treatment

“…5,6 In the current study, serum testosterone concentrations increased in half of the women during the first 3 months of VPA therapy, which is similar to the frequency to VPA-related hyperandrogenism observed in patients on long-term VPA treatment in previous studies. 16,17 In addition, it seems unlikely that VPA would directly affect gonadotropin secretion in patients with epilepsy because changes in serum gonadotropin levels were opposite in men and women in the early phase of VPA medication in the current study. This may imply that the women at high risk of developing hyperandrogenism and PCO on long-term VPA treatment may be identified already in an early stage of treatment by measuring serum testosterone concentrations.…”

L‐hydroxytryptophan amplifies pulsatile secretion of LH in the follicular phase of normal women

“…This pulsatility is due to control of LH secretion by the hypothalamic GnRH 'pulse generator' (Wilson et al, 1984), which in turn is influenced by steroid hormone status (Kesner et al, 1987) and, it is assumed, by other cerebral stimuli whose transmission to the hypothalamus involve various neuronal pathways and neurotransmitters. Of the latter, the effects of catecholamines (Veldhuis et al, 1983;Kaufman & Vermeulen, 1989), opioids (Yen et al, 1985) and GABA (Lado-Abeal et al, 1994, 1996 on pulsatile LH secretion in humans have been studied extensively.…”

L‐5‐hydroxytryptophan does not stimulate LH secretion directly from the pituitary in patients with gonadotrophin releasing hormone deficiency

“…Unlike many other neurotransmitters, including catecholamines (Veldhuis et al ., 1983; Kaufman & Vermeulen, 1989), opioids (Yen et al ., 1985) and GABA (Lado Abeal et al ., 1996), serotonin has been the subject of relatively little research (Urban & Veldhuis, 1990; Pijl et al ., 1993; Ulrich et al ., 1994) in connection with the regulation of LH secretion in humans, although its involvement in LH regulation in rats is supported by considerable histological (Parent et al ., 1981; Steinbusch, 1984; Kiss & Halász, 1985) and physiological (Vitale & Chiocchio, 1993) evidence. However, we recently found (Lado‐Abeal et al ., 1997) that pulsatile administration of L ‐5‐hydroxytryptophan (5‐HTP, the immediate precursor of serotonin) amplifies LH secretion in women in the follicular phase so long as they have an active GnRH pulse generator.…”