Influence of sodium valproate on late follicular phase pulsatile LH secretion in normal women

Lado-Abeal, Joaquín; Agricola, J. Cabezas; Carreira, J.; Cabezas-Cerrato, J

doi:10.1111/j.1365-2265.1991.tb00931.x

Cited by 19 publications

(4 citation statements)

References 41 publications

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“…The inhibition of pubertal development by GABA agonists in our patient is consistent with the inhibition of LH secretion by valproate seen in peripubertal subjects (17). In adult women, however, such an inhibition could not be observed (34,35), in agreement with our finding that the GABA agonist muscimol and the antagonist bicuculline did not affect pulsatile GnRH secretion in the postpubertal rat hypothalamus at 50 days of age (14). These late developmental changes in GABA receptormediated effects may be related to sex steroids, because acute inhibition of pulsatile LH secretion by valproate was found in postmenopausal women (19).…”

Section: Discussionsupporting

confidence: 90%

Amino Acid Neurotransmission and Initiation of Puberty: Evidence from Nonketotic Hyperglycinemia in a Female Infant and Gonadotropin-Releasing Hormone Secretion by Rat Hypothalamic Explants

Bourguignon¹

1997

Journal of Clinical Endocrinology & Metabolism

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The pulse frequency of hypothalamic GnRH secretion increases at the onset of puberty. In rodents and primates, this process involves facilitatory and inhibitory effects mediated through hypothalamic N-methyl-D-aspartic acid (NMDA) and gamma-aminobutyric acid (GABA) receptors, respectively. Precocious puberty was observed in an 11-month-old girl with nonketotic hyperglycinemia. This was thought to result from the effect of high concentrations of glycine (112 micromol/L in cerebrospinal fluid; normal, 3-12) acting on NMDA receptors as a coagonist of glutamate. Regression of pubertal development during anticonvulsive treatment with GABA agonists (loreclezole and vigabatrin) suggested that the stimulatory effects of glycine could be overcome by GABA receptor-mediated inhibition. These two hypotheses were tested in the in vitro model of the explanted hypothalamus from infantile (15-day-old) male rats. Glycine concentrations of 1-10 micromol/L increased the pulse frequency of GnRH secretion. This acceleration was prevented by 7-chlorokynurenic acid, a glycine antagonist at the NMDA receptor complex, and by the GABA agonist loreclezole. In addition, loreclezole and vigabatrin suppressed the developmental increase in the frequency of pulsatile GnRH secretion. The observation of precocious puberty in an infant with hyperglycinemia followed by pubertal regression during GABA agonist therapy and the in vitro findings in hypothalamic explants suggest that stimulatory inputs mediated through NMDA receptors and inhibitory inputs through GABA receptors are involved in the initiation of puberty.

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Section: Discussionsupporting

confidence: 90%

Amino Acid Neurotransmission and Initiation of Puberty: Evidence from Nonketotic Hyperglycinemia in a Female Infant and Gonadotropin-Releasing Hormone Secretion by Rat Hypothalamic Explants

Bourguignon¹

1997

Journal of Clinical Endocrinology & Metabolism

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“…In particular, hardly any work has been done on the possible relationship ofthe GABAergic system to the pulsatility of LH secretion (22,23,42). This low level of research activity has been due partly to blood samples, and partly to the lack of a broad group of safe, specific drugs allowing external control of this interaction.…”

Section: Discussionmentioning

confidence: 98%

“…This low level of research activity has been due partly to blood samples, and partly to the lack of a broad group of safe, specific drugs allowing external control of this interaction. We have reported previously that VPA-induced alteration of the GABAergic system has no significant effect on pulsatile LH secretion by normal women during the late follicular phase (22) and mid-late luteal phase (23) (and therefore no effect on mean serum LH concentrations during these periods), a finding in keeping with the results of other researchers (41)(42)(43). The results on ovariectomized women now reported appear to confirm that, in this respect as in others, the neurotransmitter-mediated mechanisms controlling the hypothalamo-pituitary axis in humans differ from those operating in rats.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, valproate administration causes a rapid rise in GABA levels in presynaptic terminals (19) and an increased release of GABA into the synaptic cleft (20,21). We reported recently that alteration of the GABAergic system by sodium valproate had no significant effect on pulsatile LH secretion by normal women during the late follicular phase (22) and mid-late luteal phase (23). However, the findings in rats that the rise in serum LH concentration following ovariectomy is associated with a fall in hypothalamic GABA levels, and that the fall in serum LH concentration following administration of estradiol is associated with an increase in hypothalamic GABA levels (7,24), suggest that GABAergic regulation of LH secretion may depend on steroid levels (25,26).…”

mentioning

confidence: 98%

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

Lado-Abeal¹,

Liz²,

Rey

et al. 1996

European Journal of Endocrinology

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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.

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The effect of sodium valproate on luteinizing hormone secretion in women with polycystic ovary disease

Popović

Spremovic

1995

J Endocrinol Invest

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The aim of this study was to examine whether modulation of the GABA-ergic system (with sodium valproate) affects gonadotropin secretory frequency and amplitude in women with polycystic ovarian syndrome (PCOS). Six women aged 25 +/- 2 years with diagnosed PCOS and six healthy women aged 26 +/- 2 years at day 7-11 of menstrual cycle were included in the study. Sodium valproate 1200 mg p.o./day (600 mg t.i.d.) was administered for five days in both groups. Efficacy of treatment was assessed in women with PCOS by measuring six hour LH pulsatility (every .10 min), and by GnRH tests before and after treatment. Basal serum steroids were assessed as well. Hormones were determined by radioimmunoassay and pulse detection was carried out by the program PULSAR. The administration of valproate did not change basal serum LH concentration (9.1 +/- 0.6 vs 9.0 +/- 0.8 IU/L p > 0.05) nor LH pulse frequency (7.3 +/- 0.5 vs 6.3 +/- 0.5 p > 0.05) or the LH pulse amplitude (3.0 +/- 0.5 vs 3.5 +/- 0.4 p > 0.05). LH response to GnRH (mean peak 43.6 +/- 5.2 vs 44.1 +/- 6.0 IU/L p > 0.05) did not change either. Valproate did not affect the LH secretory activity in women with PCOS. There was no change in FSH, and prolactin secretion. In five patients with PCOS valproate caused further increase in serum testosterone level but this did not reach significance in the group as a whole (5.6 +/- 1.0 vs 9.1 +/- 2.0 nmol/L p > 0.05).

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Influence of sodium valproate on late follicular phase pulsatile LH secretion in normal women

Abstract: Activation of the GABAergic system with sodium valproate had no biologically significant effect on the late follicular phase pulsatile LH secretion of these normal women.

Cited by 19 publications

References 41 publications

Amino Acid Neurotransmission and Initiation of Puberty: Evidence from Nonketotic Hyperglycinemia in a Female Infant and Gonadotropin-Releasing Hormone Secretion by Rat Hypothalamic Explants

Amino Acid Neurotransmission and Initiation of Puberty: Evidence from Nonketotic Hyperglycinemia in a Female Infant and Gonadotropin-Releasing Hormone Secretion by Rat Hypothalamic Explants

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

The effect of sodium valproate on luteinizing hormone secretion in women with polycystic ovary disease

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