[Acute and chronic treatment with sodium valproate on gonadotropin hormone levels before menopause and during menopause].
BACKGROUND
Gamma-aminobutyric acid receptors are found in neurons secreting gonadotropin-releasing hormone and in pituitary gonadotrophs.


OBJECTIVE
the examination of 1. acute and chronic effects of sodium-valproate (agonist of gamma-aminobutyric acid) on gonadotropin secretion in women; 2. the role of valproate in negative feed back effects of oestradiol; 3. if the effects of Valproate are hypothalamic or hypophyseal.


METHODS
Three groups of patients are examined (50 patients in each group): 1. group of menopausal women; 2. group of substituted menopausal women (Estroderm TTS 200 g); 3. group of women in luteal phase. The same tests were performed in each group: a) examination of one dose acute effects of Valproate and dose dependent effects (doses of 300, 600, 1200 mg, given to three subgroups; there were ten women in each subgroup); b) examination of one dose acute effects of Valproate on pulsatile secretion of luteinizing hormone (from ten women of each group blood samples for determination of luteinizing hormone pulsatility were taken in 10-min-intervals over the period of 6 h, except in luteal phase, and over the period of 8 h; c) examination of chronic effects of Valproate (10 women of each group used 1200 mg of sodium valproate for one month, except women in luteal phase who were given Valproate for 10 days).


RESULTS
Menopausal women. The maximal fall of luteinizing hormone was similar in all three doses: 14-20%; effects were dose dependent in this group of patients-the higher dose, the longer duration of effect. Substituted menopausal women. There was no effect on gonadotropin secretion. Women in luteal phase. The similar fall in luteinizing hormone and follicle stimulating hormone was recorded with 300 mg and 600 mg of Valproate. The maximal fall in luteinizing hormone was about 80% and of follicle stimulating hormone about 50%; effects were not dose dependent. In all three groups we found that (1) with suppression of the concentration of luteinizing hormone, the frequency of pulses of luteinizing hormone was changed; (2) chronic effects of Valproate on gonadotropin secretion were not significant; (3) prolactin values were not significantly affected by Valproate.


CONCLUSIONS
The three groups have different values of reproductive hormones. It is not possible to determine endogenous gamma-aminobutyric level by using gamma-aminobutyric acid antagonists because of their convulsive actions. In a steroid deprived state (such as menopause women), Valproate causes the statistically significant fall in luteinizing hormone level (20% fall). This fall is present with every dose used in this study, and is dose dependent. The influence of Valproate on gonadotropin secretion is the most evident in luteal phase. This can be explained by permissive effects of progesterone on gamma-aminobutyric acid neurotransmission. According to these results, the effects of Valproate are dependent on ovarian steroid hormone levels. The change in luteinizing hormone pulse frequency after Valproate points to a hypothalamic site of action of Valproate. These results suggest that an acute increase in tone of gamma-aminobutyric acid may inhibit gonadotropin secretion in the oestrogen-deprived state, as well as during the luteal phase of the menstrual cycle. It is possible that neuron pathways using gamma-aminobutyric acid as a neurotransmitter interact with opioids in the inhibitory modulation of gonadotropins in human females.
Spremović-Radjenović
S
S
Institute of Gynaecology and Obstetric, Belgrade.
Popović
V
V
Matijasević
S
S
Erić-Marinković
J
J
D015914:Estrogen Replacement Therapy; D005260:Female; D018682:GABA Agents / Q000494:pharmacology*; D006801:Humans; D008183:Luteal Phase / Q000378:metabolism; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism*; D008593:Menopause / Q000097:blood*; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology*
D018682:GABA Agents; D014635:Valproic Acid; D007986:Luteinizing Hormone
Akutno i hronicno lejstvo natrijum-valproata na nivo gonadotropnih hormona pre menopauze i u menopauzi.