Patients with Premenstrual Syndrome Have a Different Sensitivity to a Neuroactive Steroid during the Menstrual Cycle Compared to Control Subjects

Abstract

We have evaluated the functional sensitivity to a neuroactive steroid in 12 women with and 12 women without premenstrual syndrome (PMS) at two stages of the menstrual cycle, by comparing the effects of three increasing doses of intravenous pregnanolone (3α-hydroxy-5β-pregnan-20-one) on saccadic eye velocity (SEV) and self-rated sedation. Control subjects in the follicular and luteal phase showed a significant reduction in SEV after pregnanolone injections compared to vehicle. In PMS patients, pregnanolone injections induced a significant dose-related decrease in SEV compared to vehicle only in the follicular phase, not in the luteal phase. After pregnanolone injections, sedation scores increased significantly from vehicle among control subjects in the luteal phase but not among PMS patients in either cycle phase. High-severity PMS patients responded with less decrease in SEV and less increase in sedation scores following pregnanolone injections compared to low-severity patients. Control subjects increased their SEV response to pregnanolone in the luteal phase compared to the follicular phase, whereas PMS patients did not. These findings are compatible with a decreased GABA_A-receptor sensitivity in brain areas controlling saccadic eye movements among PMS patients in the late luteal phase.

Progesterone selectively increases amygdala reactivity in women

“…This suggestion is supported by studies showing that the response of healthy women to a pregnanolone dose is larger in the luteal than the follicular phase. 54 Furthermore, women with PMS experience more severe symptoms during cycles with high luteal phase progesterone and estradiol levels, 55 and higher estrogen doses increase negative mood symptoms during the progestin phase of hormonal replacement therapy. 56 The mechanism by which allopregnanolone could increase amygdala activity is not well understood.…”

“…Whereas the administration of progesterone or estradiol after gonadal hormone suppression does not produce mood changes in healthy women, it produces negative mood symptoms in women with PMS. 9 Furthermore, PMS patients have a different sensitivity to pregnanolone during the high progesterone luteal phase, 54 suggesting that allopregnanolone could affect amygdala activity differently in patients with PMDD/PMS. Because the amygdala is pathologically activated in certain anxiety 39 and mood disorders, 40 we speculate that allopregnanolone might increase amygdala activity to a larger extent in women with PMDD/PMS than in healthy women as observed in this study, which could explain part of the negative mood symptoms in PMDD/PMS and possibly other gonadal hormonerelated mood disorders.…”

Neurosteroids in the context of stress: Implications for depressive disorders

“…benzodiazepines (Sundstrom et al, 1997a(Sundstrom et al, , 1997b. The clinical significance of these results comes from their findings that when PMDD women are divided into lower versus higher symptom severity groups, the more severe PMDD symptom groups respond with less of a reduction in SEV (Sundstrom et al, 1997b(Sundstrom et al, , 1998 and with lower sedation ratings (Sundstrom et al, 1998) in response to benzodiazepines. Since there is no evidence that PMDD women differ in the density or affinity of peripheral benzodiazepine receptors, at least as measured on lymphocytes (Daly et al, 2001), the findings of Sundstrom and colleagues indicate diminished functional sensitivity of GABA A receptors in PMDD.…”

“…Since benzodiazepines, acting via the GABA A receptor, are known to reduce SEV in a dose-dependent fashion (Hommer et al, 1986), SEV is believed to be a sensitive measure of benzodiazepine/GABA A receptor sensitivity in humans. Using placebo-controlled designs, Sundstrom and colleagues have shown in a series of studies that PMDD women show less of a reduction in SEV to intravenous diazepam (Sundstrom et al, 1997a), midazolam (Sundstrom et al, 1997b), and pregnanolone (Sundstrom et al, 1998) than non-PMDD controls. Behaviorally, PMDD women also generally report less sedation in response to the i.v.…”

Effective open‐label treatment of premenstrual dysphoric disorder with venlafaxine

“…[12][13][14] But other neurotransmitters and neuromodulators, in particular the gammaaminobutyric acid (GABA), adrenergic, and opioid systems, have also been implicated in the pathophysiology of PMS and PMDD. [15][16][17] Venlafaxine is a novel bicyclic antidepressant that inhibits neuronal re-uptake of serotonin and norepinephrine. It has become an effective first-line agent in the treatment of depressive disorder and generalized anxiety disorder.…”