Sex-related differences in stimulated hypothalamic-pituitary-adrenal axis during induced gonadal suppression.

CONTEXT: Sex-related differences in the stress response are well described in the animal literature but in humans are inconsistent and appear to reflect both the method used to stimulate the hypothalamic-pituitary-adrenal (HPA) axis and the age of the subjects. Sex-related differences in reproductive steroid levels further confound efforts to define the specific role of the sex of the individual in stress axis responsivity. OBJECTIVE: The aim of this study was to address this role independent of differences in reproductive steroid levels. We compared HPA axis response to pharmacological (CRH) and physiological (exercise) stressors in two groups of young to middle-aged (18-45 yr) men (n = 10 and 8) and women (n = 12 and 13) undergoing gonadal suppression with leuprolide acetate (monthly im injection of 7.5 mg in men and 3.75 mg in women). DESIGN: Exercise and CRH stimulation tests were performed during induced hypogonadal conditions. SETTING: The study was conducted at a National Institutes of Health Clinical Center Outpatient Clinic. PATIENT OR OTHER PARTICIPANTS: Male and female normal volunteers participated in the study. MAIN OUTCOME MEASURES: The main outcome measures were stimulated ACTH and cortisol levels. RESULTS: Both CRH (1 microg/kg) stimulation and graded treadmill exercise stimulation occurred in the month after the second leuprolide injection to ensure gonadal suppression. Despite the absence of sex differences in estradiol or testosterone at the time of testing, men showed increased stimulated ACTH (repeated-measures ANOVA for CRH, P < 0.005) and cortisol (repeated-measures ANOVA for exercise, P < 0.05) compared with women. Among the summary measures, area under the curve (AUC) for cortisol was significantly greater in men than women after exercise. Although the AUC for ACTH was not significantly different across sexes, the initial AUC (0-30 min) was significantly greater in men for both procedures. No significant sex differences were found in a measure of adrenal responsivity, the cortisol to ACTH ratio, for either procedure. Cortisol-binding globulin levels did not differ between men and women and were not correlated with stimulated HPA axis measures. These data confirm earlier reports of sex differences in stimulated HPA axis activity and demonstrate that these differences exist even under induced hypogonadal conditions (i.e. in the absence of characteristic differences in reproductive steroids).

Testosterone suppression of CRH-stimulated cortisol in men.

Despite observations of age-dependent sexual dimorphisms in hypothalamic-pituitary-adrenal (HPA) axis activity, the role of androgens in the regulation of HPA axis activity in men has not been examined. We assessed this role by performing CRH stimulation tests in 10 men (ages 18-45 years) during gonadal suppression with leuprolide acetate and during testosterone addition to leuprolide. CRH-stimulated cortisol levels as well as peak cortisol and greatest cortisol excursion were significantly lower (p<0.05, 0.005, and 0.01, respectively) during testosterone replacement compared with the induced hypogonadal condition (leuprolide plus placebo); cortisol area under the curve was lower at a trend level (p<0.1). Paradoxically, CRH-stimulated corticotropin (ACTH) was increased significantly during testosterone replacement (p<0.05). The cortisol : ACTH ratio, a measure of adrenal sensitivity, was lower during testosterone replacement (p<0.1). A mixed effects regression model showed that testosterone but not estradiol or CBG significantly contributed to the variance of cortisol. These data demonstrate that testosterone regulates CRH-stimulated HPA axis activity in men, with the divergent effects on ACTH and cortisol suggesting a peripheral (adrenal) locus for the suppressive effects on cortisol. Our results further demonstrate that the enhanced stimulated HPA axis activity previously described in young men compared with young women cannot be ascribed to an activational upregulation of the axis by testosterone.

Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression.

CONTEXT: Alternative and over-the-counter medicines have become increasingly popular choices for many patients who prefer not to take traditional antidepressants. The adrenal androgen and neurosteroid dehydroepiandrosterone (DHEA) is available as over-the-counter hormonal therapy and previously has been reported to have antidepressant-like effects. OBJECTIVE: To evaluate the efficacy of DHEA as a monotherapy treatment for midlife-onset depression. DESIGN: A double-blind, randomized, placebo-controlled, crossover treatment study was performed from January 4, 1996, through August 31, 2002. Settings The National Institute of Mental Health Midlife Outpatient Clinic in the National Institutes of Health Clinical Center, Bethesda, Md. Patients Men (n = 23) and women (n = 23) aged 45 to 65 years with midlife-onset major or minor depression participated in this study. None of the subjects received concurrent antidepressant medications. Intervention Six weeks of DHEA therapy, 90 mg/d for 3 weeks and 450 mg/d for 3 weeks, and 6 weeks of placebo. MAIN OUTCOME MEASURES: The 17-Item Hamilton Depression Rating Scale and Center for Epidemiologic Studies Depression Scale. Additional measures included the Derogatis Interview for Sexual Functioning. Results were analyzed by means of repeated-measures analysis of variance and post hoc Bonferroni t tests. RESULTS: Six weeks of DHEA administration was associated with a significant improvement in the 17-Item Hamilton Depression Rating Scale and the Center for Epidemiologic Studies Depression Scale ratings compared with both baseline (P<.01) and 6 weeks of placebo treatment (P<.01). A 50% or greater reduction in baseline Hamilton Depression Rating Scale scores was observed in 23 subjects after DHEA and in 13 subjects after placebo treatments. Six weeks of DHEA treatment also was associated with significant improvements in Derogatis Interview for Sexual Functioning scores relative to baseline and placebo conditions. CONCLUSION: We find DHEA to be an effective treatment for midlife-onset major and minor depression.

The effects of pharmacologically induced hypogonadism on mood in healthy men.

BACKGROUND: The effects of declining androgen secretion on mood regulation and the potential psychotropic efficacy of androgen replacement in men are largely undetermined. OBJECTIVE: To examine the effects on mood of the acute suppression of testosterone secretion. DESIGN: A double-blind, placebo-controlled, crossover (self-as-own-control) study. SETTING: An ambulatory care clinic in a research hospital. PARTICIPANTS: Thirty-one healthy adult men with no history of psychiatric illness or substance or anabolic steroid abuse. INTERVENTIONS: Men received depot leuprolide acetate (Lupron, 7.5 mg intramuscularly) every 4 weeks for 3 months. After the first month of Lupron alone, all men received (in addition to Lupron) testosterone enanthate (200 mg intramuscular) or placebo (sesame oil as color-matched vehicle) every 2 weeks for 1 month each in a crossover design. The order of administration of testosterone and placebo was randomly assigned and counterbalanced. MAIN OUTCOME MEASURES: Mood and behavior rating scores (self-report and rater administered). RESULTS: With the exceptions of hot flushes, libido, and the feeling of being emotionally charged, none of the symptoms measured showed a significant difference across eugonadal, Lupron plus placebo, and Lupron plus testosterone conditions. Despite the absence of a uniform effect of Lupron plus placebo on mood, 3 men experienced clinically relevant mood symptoms during this induced hypogonadal condition. High baseline levels of sexual functioning predicted the greatest decline in sexual function during Lupron plus placebo. CONCLUSIONS: These data, the first to describe the effects on mood of induced hypogonadism in healthy young men, suggest that short-term hypogonadism is sufficient to precipitate depressive symptoms in only a small minority of younger men. The predictors of this susceptibility remain to be determined.

Concordant restoration of ovarian function and mood in perimenopausal depression.

OBJECTIVE: Despite reports of estradiol's therapeutic efficacy in perimenopausal depression, the relationship between ovarian function and mood in perimenopausal depression remains unclear. The purpose of this study was to examine changes in mood and pituitary-ovarian axis function in women exhibiting perimenopausal depression. METHOD: Depression ratings (from the Center for Epidemiologic Studies-Depression Scale [CES-D Scale]) and follicle-stimulating hormone (FSH) plasma levels of depressed perimenopausal women (N=110) attending a menopause clinic were obtained at baseline and after a 6-week screening period. RESULTS: Eighteen women experienced an improvement in depression (50% decline in CES-D Scale scores) at week 6, which was associated with a significant decrease in FSH plasma levels (baseline: mean=73.3 IU/liter [SD=42.0]; week 6: mean=42.2 IU/liter [SD=28.6]). Similarly, those subjects experiencing a 50% drop in FSH plasma levels had significant decreases in CES-D Scale scores (baseline: mean=23.3 [SD=6.8]; week 6: mean=18.1 [SD=10.9]). However, between women with CES-D Scale scores > or = 15 and those with CES-D Scale scores <15, no significant differences in FSH levels were observed either at baseline (mean=65.5 IU/liter [SD=35.7] and 60.9 IU/liter [SD=34.9], respectively) or at week 6 (mean=56.2 IU/liter [SD=36.6] and 51.5 IU/liter [SD=34.2]). CONCLUSIONS: Mood variability in women with perimenopausal depression may reflect episodic alterations in ovarian function that are best detected by longitudinal study designs.

Differential menstrual cycle regulation of hypothalamic-pituitary-adrenal axis in women with premenstrual syndrome and controls.

Previous studies in animals indicate that reproductive steroids are potent modulators of the hypothalamic-pituitary-adrenal (HPA) axis, a physiologic system that is typically dysregulated in affective disorders, such as major depression. Determination of the role of reproductive steroids in HPA axis regulation in humans is of importance when attempting to understand the pathophysiology of premenstrual syndrome (PMS), a disorder characterized by affective symptoms during the luteal phase of the menstrual cycle. We performed two studies using treadmill exercise stress testing to determine the effect of menstrual cycle phase and diagnosis on the HPA axis in women with PMS and controls and the role of gonadal steroids in HPA axis modulation in control women. The results of these studies indicate that women with PMS fail to show the normal increased HPA axis response to exercise during the luteal phase and that progesterone, not estradiol, produces increased HPA axis response to treadmill stress testing in control women. These data demonstrate that women with PMS, when symptomatic, appear to have an abnormal response to progesterone and, furthermore, do not display the HPA axis abnormalities characteristic of major depression.

Effects of metergoline on symptoms in women with premenstrual dysphoric disorder.

OBJECTIVE: The authors investigated the role of acute serotonergic modulation in the efficacy of selective serotonin reuptake inhibitors (SSRIs) in women with premenstrual dysphoric disorder. METHOD: Patients with premenstrual dysphoric disorder (whose symptoms had remitted during treatment with fluoxetine) and a group of unmedicated healthy comparison women received the serotonin receptor antagonist metergoline as part of a double-blind, placebo-controlled crossover study. RESULTS: The patients with premenstrual dysphoric disorder experienced a return of symptoms 24 hours after treatment with metergoline but not diphenhydramine (active placebo). The comparison women experienced no changes in mood. CONCLUSIONS: These data support the role of altered serotonergic transmission in the efficacy of SSRI treatment for premenstrual dysphoric disorder.