Popovic V, Spremovic-Radjenovic S, Eric-Marinkovic J, Grossman A
Institute of Endocrinology, University, Clinical Center, Belgrade, Yugoslavia.
J Clin Endocrinol Metab. 1996 Jul;81(7):2520-4. doi: 10.1210/jcem.81.7.8675571.
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.
促性腺激素释放激素（GnRH）神经元的同步活动可通过兴奋性和抑制性回路进行调节：一种这样的抑制性调节因子是γ-氨基丁酸（GABA），但这在人类中研究较少。本研究的目的是检查用丙戊酸钠（VPA）药物对GABA能系统进行急性或慢性调节是否以类固醇依赖的方式影响促性腺激素的分泌频率和/或幅度，以及任何这种调节是否可能与内源性阿片类物质相互作用。研究了60名绝经后妇女（年龄范围50 - 60岁，第一组）、50名接受雌激素替代疗法的绝经后妇女（第二组）和30名处于正常月经周期黄体期的妇女（年龄范围25 - 40岁，第三组）。通过口服300、600和1200 mg剂量急性给予VPA。在24小时内间隔采集血清促性腺激素样本。每组VPA的每个剂量均导致第一组促黄体生成素（LH）显著抑制。三种VPA剂量的最大抑制程度相同（14 - 20%）。然而，没有剂量对第二组的促性腺激素水平有任何影响。在第三组中，单次高剂量1200 mg VPA显著抑制血清LH水平。通过在VPA治疗1个月前后测量6小时内的LH脉冲性（10分钟样本）来评估三组中慢性给予VPA的效果。未发现平均基础LH或LH脉冲性参数有变化。第一组中静脉输注纳洛酮（1.6 mg/h，持续6小时）对LH脉冲性没有影响。当在静脉输注纳洛酮前给予1200 mg VPA时，LH抑制水平为18%，且与LH脉冲频率显著降低相关（P < 0.01）。单独静脉输注纳洛酮显著增加第二组患者的平均血清LH和LH脉冲频率（P < 0.01），而这种升高被VPA预处理所拮抗。单独静脉输注纳洛酮显著增加第三组患者的平均LH水平和LH脉冲频率，这也被VPA预处理所阻断。这些结果表明，GABA能张力的急性增加可能在雌激素缺乏状态下抑制促性腺激素分泌，或者在接受雌激素治疗的绝经后妇女中内源性阿片类物质抑制被阻断时，以及在月经周期的黄体期抑制促性腺激素分泌。在人类女性中，GABA能通路可能在促性腺激素的抑制性调节中与阿片类物质相互作用。
