Journal of Clinical Endocrinology & Metabolism, Vol 80, 818-823, Copyright © 1995 by Endocrine Society

ARTICLES

The effect of alprazolam on serum cortisol and luteinizing hormone pulsatility in normal women and in women with stress-related anovulation

SJ Judd, J Wong, S Saloniklis, M Maiden, B Yeap, S Filmer and L Michailov
Department of Medicine, Flinders Medical Center, Australia.

Alprazolam, a benzodiazepine derivative, stimulates specific gamma- aminobutyric acidA receptors and has been found to inhibit CRH activity in the brain. This study examined the effect of alprazolam on serum cortisol and LH pulsatility in six women in the early follicular phase (EFP), six women in the midluteal phase (MLP), and six women with stress-related anovulation (SRA) of normal weight, but with a previous history of anorexia nervosa. Subjects were given alprazolam (2 mg, orally) or an identical placebo capsule at 0900 h, and blood samples were collected through an indwelling venous catheter every 10 min for 8 h in the SRA women and 10 h in EFP and MLP women. Women with SRA were also given clomiphene (100 mg/day) for 5 days before a further 8-h blood sampling session. As expected, there was a diurnal decline in serum levels of cortisol, which was significantly less in women with SRA (55 +/- 4%) than those in both EFP (76 +/- 4%) and MLP women (75 +/- 3%; P < 0.005). The food-related rise of cortisol that follows lunch in normal women was absent in women with SRA. Alprazolam accentuated the decline in serum cortisol, and in all three groups, the mean serum cortisol level after alprazolam treatment was significantly less (P < 0.05) than that after placebo. In SRA women, alprazolam restored visible LH pulses in all women and increased the mean LH pulse frequency (P < 0.02) and pulse amplitude (P < 0.05). This was associated with an increase in mean serum LH from 1.3 +/- 0.3 to 3.0 +/- 0.06 IU/L (P < 0.02). In EFP women, alprazolam reduced the frequency of LH pulsatility from a mean of 5.8 +/- 0.7 to 3.2 +/- 0.5 pulses/10 h (P < 0.02) and increased the mean pulse amplitude from 2.4 +/- 0.5 to 5.0 +/- 1.1 IU/L (P < 0.0005). Alprazolam had no significant effect on LH pulsatility or amplitude in MLP women. To explain this variation in response to alprazolam, we propose that alprazolam accelerates the GnRH pacemaker in SRA women by inhibiting excessive CRH activity, which blocks the GnRH pacemaker in these women. In normal women, we hypothesize that tonic inhibition of the GnRH pacemaker by CRH is minimal, and the reduced pulsatility of LH after alprazolam treatment in EFP women results from inhibition of stimulatory noradrenergic neurons. In MLP women, we propose that preexisting opioid inhibition of noradrenergic neurons by progesterone blocks this effect of alprazolam.

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