Allopregnanolone levels and reactivity to mental stress in premenstrual dysphoric disorder.

BACKGROUND: This study was designed to examine basal and stress-induced levels of the neuroactive progesterone metabolite, allopregnanolone, in women with premenstrual dysphoric disorder (PMDD) and healthy control subjects. Also, because evidence suggests that allopregnanolone negatively modulates the hypothalamic-pituitary-adrenal axis, plasma cortisol levels were examined. An additional goal was to investigate the relationship between premenstrual symptom severity and luteal phase allopregnanolone levels. METHODS: Twenty-four women meeting prospective criteria for PMDD were compared with 12 controls during both the follicular and luteal phases of confirmed ovulatory cycles, counterbalancing phase at first testing. Plasma allopregnanolone and cortisol were sampled after an extended baseline period and again 17 min following the onset of mental stress. Owing to low follicular phase allopregnanolone levels, only luteal phase allopregnanolone and cortisol were analyzed. RESULTS: During the luteal phase, PMDD women had significantly greater allopregnanolone levels, coupled with significantly lower cortisol levels, during both baseline and mental stress. Moreover, significantly more controls (83%) showed the expected stress-induced increases in allopregnanolone compared with PMDD women (42%). Premenstrual dysphoric disorder women also exhibited a significantly greater allopregnanolone/progesterone ratio than control subjects, suggesting alterations in the metabolic pathways involved in the conversion of progesterone to allopregnanolone. Finally, PMDD women with greater levels of premenstrual anxiety and irritability had significantly reduced allopregnanolone levels in the luteal phase relative to less symptomatic PMDD women. No relationship between symptom severity and allopregnanolone was observed in controls. CONCLUSIONS: These results suggest dysregulation of allopregnanolone mechanisms in PMDD and that continued investigations into a potential pathophysiologic role of allopregnanolone in PMDD are warranted.

Effect of low-dose estrogen on hemodynamic response to stress.

OBJECTIVE: To determine the effect of low-dose esterified estrogen on hemodynamic responses at rest and during stress in postmenopausal women, and to compare the changes with those seen with conjugated equine estrogen. DESIGN: Open-label study of esterified estrogen compared with a double-blind, placebo-controlled investigation of conjugated equine estrogen. SETTING: Healthy volunteers in an academic research environment. PATIENT(S): Postmenopausal women with normal endometrium, not currently using hormones. INTERVENTION(S): Cardiovascular parameters at rest and in response to stressors were assessed in 11 postmenopausal women before and 6 months after receiving 0.3 mg esterified estrogen. Responses were compared with 42 postmenopausal women randomized to 0.625 mg conjugated equine estrogen or placebo. MAIN OUTCOME MEASURE(S): Changes in mean arterial pressure (MAP) and vascular resistance index from before to after treatment. RESULT(S): At rest, MAP increased 3.3 +/- 1.5 mm Hg (+/-SD) in the placebo group, while declining 2.3 +/- 1.5 mm Hg and 4.8 +/- 1.4 mm Hg, respectively, in the esterified estrogen and conjugated equine estrogen groups after treatment. During mental stressors, MAP dropped significantly in both treatment groups. At rest and during mental stressors, vascular resistance index decreased with estrogen treatment. CONCLUSION(S): Low-dose esterified estrogen improved hemodynamic patterns similar to standard doses of conjugated equine estrogen in postmenopausal women.

Smoking, oral contraceptives, and cardiovascular reactivity to stress.

OBJECTIVE: To investigate the effects of smoking and oral contraceptive (OC) formulation on hemodynamic responses to stress in women. METHODS: Twenty-three smokers and 23 nonsmokers taking different OC formulations (ie, containing higher or lower androgenic progesterones) were tested for cardiovascular reactivity during mathematic, speech preparation, speech, and cold pressor stress. RESULTS: During mental stress, smokers, regardless of OC formulation, had lower systolic blood pressure (BP) (eg, 10.2 versus 15.1 mmHg, P < .05), heart rate (eg, 7.5 versus 15.0 beats per minute, P < .01), and cardiac index reactivity (eg, 0.08 versus 0.48 L/minute/M2, P < .01) but greater vascular resistance index responses (eg, 115.6 versus -51.9 dyne-sec x cm(-5) x M2, P < .05). Women who took higher androgen OCs, regardless of smoking status, showed greater vascular resistance index increases during speech stress than those who took lower androgen OCs (215.8 versus 9.4 dyne-sec x cm(-5) x M2, P < .05). Smokers who took more androgenic OCs had greater systolic BP responses to speech preparation compared with nonsmokers who took the same OCs (12.1 versus 6.1 mmHg, P < .05), and smokers who took lower androgen OCs (12.1 versus 4.4 mmHg, P < .05). Least-squares means examination found that smokers who took higher androgen OCs had greater vascular resistance index increases to all mental stressors than nonsmokers who took lower androgen OCs. CONCLUSION: Higher androgen OCs might be linked to greater vascular and BP increases during stress, especially in smokers. Given that increased vascular resistance and BP contribute to cardiovascular mortality, those results suggest that androgenic profiles of synthetic progesterones might be an important consideration in OC choice.

Dysregulation of cardiovascular and neuroendocrine responses to stress in premenstrual dysphoric disorder.

Twelve women with prospectively confirmed premenstrual dysphoric disorder (PMDD or PDD) were compared with 12 healthy control subjects for cardiovascular and neuroendocrine responses to speech and mental arithmetic (Paced Auditory Serial Addition Task) stressors during both the follicular and luteal phases of the menstrual cycle. Structured clinical interview was used to assess psychiatric and abuse histories, and standardized questionnaires were administered to assess current life stress. Results revealed that PMDD women had significantly lower stroke volume, cardiac output and cortisol levels but significantly elevated norepinephrine and total peripheral resistance at rest and also during mental stressors compared with control subjects. These effects were evident in both cycle phases. Significantly more women with PMDD had histories of sexual abuse, and they also reported greater current life stress than control subjects. Consistent with a history of trauma, the PMDD women exhibited significantly greater ratios of norepinephrine to cortisol at rest and during stress. These results are interpreted as reflecting dysregulation of the stress response and may be related to histories of severe and/or chronic exposure to stress for a subgroup of PMDD women.

Menstrual cycle, blood pressure and ischemic pain sensitivity in women: a preliminary investigation.

Eleven women were tested twice for ischemic pain sensitivity; once during their follicular phase (Days 4-9) and once during their mid-late luteal phase (5-10 days after ovulation) of a confirmed ovulatory cycle. Additionally, in order to examine blood pressure-related hypoalgesic effects, each had 3-4 clinic blood pressures determined during an initial screening interview and each also completed a daily symptom calendar for one complete menstrual cycle prior to testing in order to investigate relationships between 'real life' symptomatology and laboratory-induced pain sensitivity. Results revealed significantly shorter pain tolerance times and marginally shorter pain threshold times in the luteal vs. follicular phase, while verbal descriptors of pain intensity (sensory) and pain unpleasantness (affective) did not vary with cycle phase. Clinic blood pressures were positively correlated with pain threshold and tolerance times assessed during both cycle phases. Real-life physical symptom ratings were predictive of laboratory pain intensity ratings during the follicular phase and tended to predict unpleasantness ratings during both phases. These results not only confirm recent reports of greater sensitivity to ischemic pain in women during the luteal phase of their cycle, but extend the literature by demonstrating pressure-related hypoalgesic effects in women during both cycle phases.