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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-2525
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 7 4224-4231
Copyright © 2005 by The Endocrine Society

Sex-Related Differences in Stimulated Hypothalamic-Pituitary-Adrenal Axis during Induced Gonadal Suppression

Karen Putnam, George P. Chrousos, Lynnette K. Nieman and David R. Rubinow

Office of Special Populations (C.A.R.), National Institute of Mental Health, Rockville, Maryland 20857; Behavioral Endocrinology Branch (P.J.S.), Geriatric Psychiatry Branch (K.P.), and Behavioral Endocrinology Branch (D.R.R.), National Institute of Mental Health, Bethesda, Maryland 20892; Department of Military and Emergency Medicine (P.A.D.), Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814; Clinical Center Nursing Department (M.A.D.), National Institutes of Health, Bethesda, Maryland 20892; Department of Psychiatry (M.A.), Weill Medical College of Cornell University, New York, New York 10021; and Developmental Endocrinology Branch (G.P.C.), and Pediatric and Reproductive Endocrinology Branch (L.K.N.), National Institute of Child Health and Human Development, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: David R. Rubinow, National Institute of Mental Health, Building 10-CRC, Room 6-5340, 10 Center Drive MSC 1276, Bethesda, Maryland 20892-1276. E-mail: rubinowd{at}mail.nih.gov.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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 µg/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).


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IT IS AXIOMATIC that the capacity to adapt to stress influences the development of many subsequent pathophysiological and behavioral processes. Sex-related differences in the stress response have been noted in the literature for more than 40 yr (1, 2, 3) and may contribute to marked sex differences in the prevalence of disorders like depression (4). Both basal and stimulated hypothalamic-pituitary-adrenal (HPA) axis activity are increased in female compared with male rats (5, 6, 7); many, but not all (8), studies report increased stimulated ACTH in female rats, and most find increased stimulated cortisol (1, 5, 6). These differences have been presumed to represent an augmenting effect of estradiol or a suppressive effect of androgens on the HPA axis. Data supportive of both hypotheses exist, with estradiol shown to increase and dihydrotestosterone, the nonaromatizable form of testosterone, to decrease both ACTH and cortisol responses to stress (9, 10, 11).

In human studies, reported sex differences are inconsistent and appear age and paradigm dependent. In general, young men and old women demonstrate increased stimulated HPA activity compared with old men and young women. The increased activity in young men is seen more consistently with psychological (12, 13, 14, 15, 16) than with pharmacological or physiological stressors (12, 17, 18, 19, 20). Some of the variance across studies is a consequence of the multitude of psychological and pharmacological stimuli employed. Indeed, apart from the effects of age on HPA axis regulation, few studies have examined other modulatory variables, such as the effects of different stress paradigms, and none has examined how differences in reproductive steroids between men and women influence HPA axis regulation. Differences in circulating gonadal steroids are often used speculatively to explain differences between sexes or between young (increased gonadal steroid levels) and old (decreased gonadal steroid levels) same-sex subjects (e.g. the loss in menopausal women of the enhanced adrenal reactivity compared with men seen in young women) (19). Using a gonadal hormone suppression and replacement paradigm, we have previously demonstrated that gonadal steroids do regulate HPA axis activity in women (21).

It remains unclear whether HPA axis responses of men and women differ independently from the acute, activational effects of their respective gonadal steroids. In studies with gonadectomized or neonatally estrogenized rats, Patchev et al. (22, 23) and McCormick et al. (24) observed sex differences (e.g. increased HPA axis response to stress in females) independent of differences in circulating gonadal steroid levels, which suggests an innate or organized difference in the HPA axis response to stress. Such organizational effects describe the ability of gonadal steroids to program, early in development, subsequent central nervous system responses to gonadal steroids later in life (25, 26). Hence, observed sex differences in central nervous system function could reflect genomic differences, organizationally or developmentally programmed effects (caused by earlier differential gonadal steroid exposure), and/or acute, activational effects of recent gonadal steroid exposure. In the last instance, sex differences in HPA axis responses would be expected to disappear if gonadal steroids were removed (e.g. through castration), whereas sexual dimorphisms would persist if the responses were developmentally programmed and not dependent upon the concurrent gonadal steroids.

We attempted to address the role of sex, independent of differences in sex steroids, on HPA axis function in humans by comparing the response to stressors in males and females under conditions of leuprolide acetate-induced hypogonadism. Furthermore, to evaluate whether the observed response was stress paradigm dependent, we employed both pharmacological and physiological stressors: ovine-CRH (o-CRH) stimulation and graded exercise stimulation.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The data in this study were obtained during the hypogonadal condition of a larger study investigating the effects of leuprolide acetate-induced hypogonadism and hormonal replacement (estradiol and progesterone in women, testosterone in men) on behavioral and physiological stimuli (21, 27).

Subject selection

Subjects were recruited through advertisements in local newspapers. All participants were between the ages of 18 and 45, were without current medical illness (as assessed by medical history, physical examination, laboratory tests, chest x-ray, and electrocardiogram), were without a history of psychiatric illness or substance abuse (as assessed by the Structured Clinical Interview for DSM III-R or IV) (28, 29), and were taking no medications. Male and female volunteers completed 2 months of daily mood ratings, and females additionally recorded the days of menses. Women participating in this study demonstrated no evidence of premenstrual mood symptoms and had regular menstrual cycles ranging between 27 and 31 d before entering the leuprolide study. Pregnancy tests were performed on all women before study entry, and participants were required to use barrier forms of contraception throughout the course of the study. Protocols were reviewed and approved by the National Institute of Mental Health and the Uniformed Services University of the Health Sciences Institutional Review Boards. All subjects gave both written and verbal consent to study participation and were paid for their participation according to the schedule of payment issued by the National Institutes of Health Normal Volunteer Office.

Study design: leuprolide study

Women. Women participating in the larger study received five monthly injections of the GnRH agonist leuprolide acetate (Lupron; 3.75 mg) after the 2-month screening period and the maximal exercise test (see below). During the hypogonadal condition (the focus of this study), women received 2 months of leuprolide acetate alone. After the hypogonadal period in the larger study, women were randomly assigned to receive 5 wk of either estradiol or progesterone (21). The exercise and CRH procedures were performed between wk 5 and 8 of the hypogonadal condition. In subjects participating in both procedures (n = 3), the exercise procedure was performed first, with 4–10 d separating the procedures.

Men. Men participating in the larger study received three monthly injections of leuprolide acetate (7.5 mg) after the 2-month screening period and the maximal exercise test. After the first month of leuprolide acetate, men were randomly assigned to receive either 200 mg testosterone enanthate or placebo (sesame oil) injections (the hypogonadal condition) every 2 wk for the first month of add-back and then received the other injections (testosterone or placebo) after crossover. The exercise and CRH procedures were performed between wk 3 and 4 of the placebo (hypogonadal) condition. In subjects participating in both procedures (n = 8), the exercise procedure was performed first, with 3–10 d separating the procedures.

Because the purpose of this study was to assess sex differences under roughly similar hormonal conditions, comparisons were made between men and women during procedures performed during the hypogonadal portion of the leuprolide studies. Data comparing hypogonadal to hormone-replaced conditions during exercise in women and during CRH in men have been published previously (21, 30).

Exercise procedure

Subjects were instructed not to eat the morning of the exercise tests and to abstain from caffeine and alcohol consumption and from running or other strenuous activity during the 24 h before testing. All exercise sessions were initiated between 0700 and 0800 h. The maximal exercise treadmill test (see below) was performed before initiating leuprolide, and the submaximal test was performed during the second month on leuprolide. As described below, the physiological stress delivered in this paradigm is individualized as a percentage of the subject’s maximum aerobic capacity, thus assuring comparability across subjects.

Maximal test. After screening, volunteers participated in a maximal treadmill exercise test to determine their maximal oxygen uptake (VO2max). This was determined by a progressive treadmill exercise protocol conducted to volitional exhaustion. Oxygen consumption and carbon dioxide production during the maximal exercise test and during the subsequent exercise test sessions were measured with a Metabolic Measurement Cart 2900c (SensorMedics Inc., Yorba Linda, CA), and electrocardiogram and heart rate were monitored continuously.

Submaximal test. On arrival, an iv catheter was inserted in an antecubital vein, and subjects drank 5 ml/kg body weight of water to ensure uniform hydration. The exercise test began 60 min after the subject finished drinking.

The submaximal treadmill exercise test consisted of 5 min of exercise at 50% of VO2max, 5 min at 70%, a 2-min break for blood drawing, another 5 min at 70%, and 5 min at 90% of VO2max. Exercise intensities of 50, 70, and 90% of VO2max were enforced by adjusting the grade and speed of the treadmill. The exercise was followed by a cool-down period of 5 min at a minimal workload, then 35 min of rest in a semirecumbent position. Blood for baseline plasma levels of estradiol, testosterone, and cortisol-binding globulin (CBG) was drawn at baseline along with cortisol and ACTH. Blood for subsequent measurements of cortisol and ACTH was drawn at 10 min (70% VO2max), 20 min (90% VO2max), and 30, 40, 50, and 60 min (during recovery from exercise).

o-CRH test

Subjects presented to the clinic between 0700 and 0800 h, after an overnight fast. All participants were weighed, placed in a semirecumbent position, and then had an iv inserted in an antecubital vein. Approximately 40 min after the insertion of the iv, baseline blood for cortisol, ACTH, testosterone, estradiol, and CBG was obtained. Subjects then received 1 µg/kg o-CRH by iv push. Blood for cortisol and ACTH was obtained at 5, 15, 30, 60, 90, 120, 150, and 180 min after administration of the o-CRH. A 24-h urine collection was obtained for measurement of cortisol, but because of inadequate collections, they were not considered appropriate for analysis.

Assays

Blood samples were drawn in prechilled tubes and stored at –70 C until assayed. All assays were performed by Endocrine Sciences (Calabasas Hills, CA). Individual subjects had samples from all of their tests run in the same assay.

Baseline measures. CBG was measured directly by RIA; the intra- and interassay coefficients of variation (CV) were 7.8 and 11%, respectively. Estradiol was measured by RIA after extraction (hexane:ethyl acetate) and LH20 column chromatography in a modification of the procedure by Wu and Lundy (31). Extraction recovery was 80%, and the assay sensitivity was 0.5 ng/dl (18.4 pmol/liter). The intraassay CV was 3.2%, and the interassay CV was 9.2%. Testosterone was measured by RIA after extraction (hexane:ethyl acetate) and alumina column chromatography. Extraction recovery was 90%, sensitivity 3 ng/dl (0.1 nmol/liter), intraassay CV 7%, and interassay CV 9%.

Serial measures. Cortisol was measured directly by RIA with intra- and interassay CV of 3.9 and 8.3%, respectively. Sensitivity of the assay was 1 ng/dl (27.6 nmol/liter). The ACTH immunoradiometric assay uses paired monoclonal and polyclonal antibodies, reactive, respectively, with the N-terminal and the C-terminal regions of ACTH (32). The intraassay CV was 6.2%, the interassay CV 11%, and the sensitivity 5 pg/ml (1.1 pmol/liter).

Behavioral measures. Although all subjects were euthymic at baseline, depression (Beck Depression Inventory) (33) ratings were obtained before the CRH and exercise tests to make certain that HPA axis responses did not reflect differences in mood during leuprolide administration.

Statistics

Sample size for this repeated-measures design was calculated in a power analysis performed with NCSS PASS (Kaysville, UT). Based on the difference in sample means obtained in an earlier study (21), a sample size of nine per group had an 80% power to detect the predicted differences as significant at an {alpha} of 0.05.

To ensure the effectiveness of leuprolide in creating a relatively hormone-deficient or hypogonadal condition, baseline levels of testosterone and estradiol were obtained. The levels of testosterone and estradiol during leuprolide administration in men were compared with those in women by Student’s t tests. Baseline measures of HPA axis function (cortisol, ACTH, and CBG) as well as the ages of subjects and baseline depression ratings also were compared between sexes with Student’s t tests.

Differences between men and women in CRH-stimulated and exercise-stimulated ACTH and cortisol levels were assessed with repeated-measures ANOVA (ANOVA-R) (Systat 9; SPSS Inc., Chicago, IL), with sex as the between-subjects variable and time as the within-subjects variable. Time had nine levels for the CRH procedure and seven levels for the exercise procedure (the two baseline points before the procedures were averaged). When the results of the ANOVA-R were significant, Bonferroni corrected post hoc comparisons were performed to maintain an overall type I error of 0.05. ANOVA-R was used as the primary statistical comparison because it takes maximal advantage of all of the data collected, unlike summary measures, e.g. area under the curve (AUC), which may not discriminate between differences in the shape of the response curve. The cortisol to ACTH ratio was used as a repeated measure to assess adrenal responsivity, and differences between men and women were assessed with ANOVA-R. To normalize the distribution of the data, data were log transformed before ANOVA. Additional ANOVAs were performed comparing stimulated ACTH and cortisol in men who received leuprolide for 3 vs. 7 wk before the procedures.

Three additional summary measures of CRH- and exercise-stimulated HPA axis function were compared across sexes with Student’s t tests: AUC, stimulated peak value (MAX), and difference between peak value and baseline (mean of the two preprocedure values) ({delta} MAX). AUC was calculated by a baseline-corrected trapezoidal integration method. Comparisons of these three measures across sexes were performed for both ACTH and cortisol. The {alpha} (level of significance) was set at 0.017 (0.05/3) to adjust for type 1 errors associated with multiple comparisons. Additionally, a measure of the robustness of the early response to stimulation, the incremental AUC (0–30) (34), was calculated for both procedures.

Pearson product moment correlation coefficients were used to evaluate the relationship between baseline values of testosterone, estradiol, and CBG, and the AUC, MAX, and {delta} MAX for ACTH and cortisol.

Pearson product moment correlation coefficients also were calculated to determine whether levels of testosterone, estradiol, testosterone to estradiol ratio, or CBG during leuprolide or changes in levels of these factors from prestudy baseline to leuprolide were associated with changes in stimulated measures of ACTH and cortisol (AUC, MAX, and {delta} MAX).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Twelve women and 10 men received CRH, and 13 women and eight men performed the exercise procedure. The mean ages (± SD) of subjects participating in this study were similar and as follows: CRH men (31.4 ± 7.5 yr), CRH women (33.0 ± 8.0 yr), exercise men (29.5 ± 7.7 yr), and exercise women (31.5 ± 6.2 yr). Leuprolide significantly reduced gonadal steroid levels in both men and women; at the time of the procedures, mean estradiol and testosterone levels were in the hypogonadal range in both women and men (Table 1Go). The mean reduction in testosterone levels in men from prestudy to leuprolide was 424 ± 104 ng/dl (14.75 ± 3.6 nmol/liter) before CRH, and the mean reduction in estradiol levels in women was 48.8 ± 2.7 pg/ml (179.1 ± 9.9 pmol/liter) compared with early follicular values prestudy. Similar reductions were observed before exercise during leuprolide. No significant differences were seen in testosterone or estradiol between men and women before CRH or exercise; the nonsignificantly higher mean testosterone values in men before the exercise procedure primarily reflect the influence of two subjects, because all but two subjects had testosterone levels less than 60 ng/dl (2.08 nmol/liter) (Table 1Go). No sex differences were seen in basal levels of ACTH, cortisol, or CBG. Baseline levels of both ACTH and cortisol were substantially higher before exercise compared with the CRH procedure in both men and women (Table 1Go). Depression (Beck Depression Inventory) ratings were similar in men (1.0 ± 1.6) and women (1.5 ± 2.1) before the CRH infusion and were slightly but not significantly higher in women (4.7 ± 5.7) compared with men (0.9 ± 1.1) before exercise (t18 = 1.9; P < 0.1).


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  		TABLE 1. Mean (±SD) baseline and stimulated (a) hormonal values for CRH- and exercise-stimulated procedures

 
ACTH

A significant sex by time effect was seen for CRH-stimulated ACTH (F8,152 = 2.95; P < 0.005), reflecting increased stimulated ACTH in men vs. women. Post hoc Bonferroni comparisons at each time point showed significant increases in men vs. women at 15, 30, and 60 min after administration of CRH (Fig. 1Go). A trend for greater exercise-stimulated ACTH also was seen in men (F1,18 = 3.91; P < 0.1) (see Fig. 2Go). CRH-stimulated ACTH AUC, MAX, and {delta} MAX were all greater in men at a trend level of significance (t19 = 1.86–2.01; P < 0.1). Although sex differences in exercise-stimulated ACTH AUC were not statistically significant, the incremental AUC (0–30), the initial response to stimulation, was significantly greater in men than women for both CRH and exercise paradigms (t19 = 2.6, P < 0.05; t19 = 2.71, P < 0.05, respectively).



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  		FIG. 1. Significant sex x time effect (F8,152 = 2.95; P < 0.005) reflecting increased CRH-stimulated ACTH in men compared with women. *, Significant difference between men and women (P < 0.01); #, P < 0.10. No significant sex differences were observed in stimulated cortisol. Data are means ± SE.

 


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  		FIG. 2. Significant effect of sex on exercise-stimulated cortisol (F1,18 = 4.84; P < 0.05) and trend for effect on ACTH (F1,18 = 3.91; P < 0.1), both increased in men compared with women. Data are means ± SE.

 
Cortisol

Sex differences in CRH-stimulated cortisol were not significant (F1,19 = 2.58; P < 0.1), but stimulated values after exercise were significantly greater in men than women (F1,18 = 4.84; P < 0.05) (Figs. 1Go and 2Go). Similarly, whereas exercise-stimulated cortisol AUC and MAX were significantly greater in men than in women (t18 = 2.13, 2.18; P < 0.05), no significant differences were observed after CRH.

Significant effects of time were observed for both cortisol and ACTH as expected. Comparison of stimulated ACTH and cortisol values in men who participated in the procedures after 3 vs. 7 wk of leuprolide (depending on whether their placebo month was proximate to the month of leuprolide alone) revealed no significant differences with exercise- or with CRH-stimulated ACTH or exercise-stimulated cortisol; CRH-stimulated cortisol, however, was significantly greater in the men with the shorter latency after leuprolide administration (F1,8 = 12.2; P < 0.01). No significant differences were found in the cortisol to ACTH ratio, a measure of adrenal responsivity, after either procedure. However, if the analysis was restricted to the first 90 min after CRH administration, a significant sex by time effect (F5,95 = 3.35; P = 0.008) was seen, largely attributable to the increased ratio for women compared with men (Fig. 3Go). Finally, after Bonferroni correction, no significant correlations were observed between baseline estradiol, testosterone, testosterone to estradiol ratio, or CBG and AUC, MAX, and {delta} MAX values for ACTH and cortisol after either the CRH or exercise procedures in either the men or women. Similarly, no significant correlations were observed when the change in gonadal steroid (or CBG) levels from prestudy to leuprolide was examined.



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  		FIG. 3. Absence of significant differences in CRH- and exercise-stimulated cortisol to ACTH ratios in men and women. Data are means ± SE.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Multiple investigations have shown inconsistent effects of sex on the HPA axis response to stressors. Nonetheless, a recurrent observation is that sex, age, and stimulation paradigm interact in determining the response to a stressor. Disentangling these effects has proved to be very difficult. One of the obvious confounds for sex differences in HPA axis response is the difference in endogenous gonadal steroid levels. Indeed, some of the age-dependent sex differences (e.g. increased cortisol and ACTH response to psychological stress in young men and to pharmacological or physiological stimuli in older women) are presumed to reflect age-related changes in reproductive steroids. Additionally, differences observed between sexes may represent acute, activational products of disparate levels of reproductive steroids (estradiol and testosterone), or they may represent organizational (or developmental) effects programmed earlier in life and independent of adult steroid levels. By comparing the HPA axis responses of young men and women during leuprolide-induced hypogonadism, we were able to minimize the confounding impact of differences in gonadal steroid levels by creating similar reproductive steroid conditions. (In these studies, testosterone and estradiol levels did not significantly differ in men and women, although relatively elevated testosterone levels were present in men before exercise.) We also were able to separate the effects of aging from those of reproductive decline, because gonadal suppression was performed in young men and women. Finally, we hoped to partially control for paradigm-dependent effects by employing two dissimilar stressors, one pharmacological (CRH) stressor acting at the pituitary, and the other a maximal physiological (exercise) HPA axis stimulus.

With both pharmacological and physiological stressors, we observed greater HPA axis response in young to middle-aged men compared with women. CRH-stimulated ACTH (sex by time effect) and exercise-stimulated cortisol were both significantly greater in men than women. Exercise-stimulated ACTH was also higher in men, albeit at a trend level of significance. AUC for ACTH, ACTH MAX, and ACTH {delta} MAX were greater at a trend level in men after CRH (but not after exercise), and cortisol AUC and cortisol MAX were significantly greater in men than women after exercise but not after CRH stimulation. Furthermore, men appeared to respond more rapidly to both CRH and exercise, because the ACTH AUC at 30 min was significantly greater in men for both procedures. Although considerable individual variability (as noted elsewhere) (35) prevented some of these measures from reaching statistical significance, the overall pattern is clearly one of increased HPA reactivity in men at both pituitary and adrenal levels.

Our demonstration of increased CRH-stimulated ACTH, but not cortisol, in men replicates findings by Kirschbaum and colleagues (12, 13, 15, 16), who used psychological stressors, and Rubin et al. (36), who used a pharmacological cholinergic stimulus, physostigmine. These findings raise two related questions: why is CRH-stimulated ACTH higher in men, and why is stimulated cortisol not correspondingly higher? Although differences in feedback sensitivity or pituitary sensitivity to CRH cannot be ruled out as an explanation, data from both animal and human studies suggest that sex differences in arginine vasopressin (AVP) may underlie the increased stimulated ACTH that we observed in men. Rubin et al. (36) observed significantly greater physostigmine-stimulated AVP and ACTH in men compared with women; moreover, stimulated AVP and ACTH levels were significantly correlated in men but not in women. These findings suggested that endogenous AVP influenced HPA axis function to a greater extent in men than in women. In animal studies as well, Viau et al. (37) have identified markedly divergent dependence on CRH and AVP in response to stress by pubertal female and male rats, which suggests that different stress transduction systems may be employed by the sexes. These data then contradict the view that stress is processed identically in males and females.

Our findings with CRH stimulation are consistent with other studies not only in showing greater ACTH responses in men than women but also in failing to find higher cortisol levels. These observations led to the suggestion that adrenal sensitivity/responsivity was lower in men compared with women (15, 19, 38, 39). We did not find significant sex-related differences in the cortisol to ACTH ratio, a measure of adrenal responsivity, for either procedure, which is consistent with the absence of sex differences in adrenal responsivity reported in age-related hypogonadism (19). Cortisol to ACTH ratios after CRH administration were, however, significantly higher in women if the ANOVA was restricted to the first 90 min after infusion; this may reflect the greater ACTH secretion in men during this time period. Nonetheless, in the presence of either a maximal stressor (exercise) or significant anticipatory stress or both, no evidence of sex-related differences in adrenal sensitivity could be found. Thus, in the presence of sufficiently elevated ACTH levels with exercise, adrenal responsivity appears similar in hypogonadal men and women.

The possible relevance of AVP in the sex differences that we observed is further supported by the prominent role of AVP in the response to exercise. Smoak et al. (40) suggested that enhanced recruitment of AVP during exercise may explain the greater ACTH-stimulating capacity of exercise compared with CRH. Indeed, the presumed release of AVP by exercise in our subjects resulted in substantially greater increases in peak ACTH in both men and women, which diminished (to a trend) the sex-related difference in ACTH response, a difference that, in contrast, achieved significance in the CRH stimulation paradigm. Although sex differences in exercise-stimulated ACTH did not reach statistical significance in our subjects, exercise-stimulated cortisol was significantly greater in men. Notable as well were the relatively low levels of stimulated cortisol in the women despite marked elevations in stimulated ACTH. Thus, the major physiological stress provided by exercise, in addition to augmenting AVP secretion, may recruit changes at the adrenal that restrain adrenal responses [e.g. serotonin-mediated circadian inhibition (41) or reduced adrenal blood flow (42)], which, if sexually dimorphic, could produce sex-related differences in cortisol secretion.

The differential activation of the HPA axis in male and female rodents is primarily a consequence of differential exposure to testosterone and estradiol (37). Indeed, an abundant literature demonstrates activation of the HPA axis in rodents by estradiol and inhibition of the axis by testosterone. This latter effect may be mediated either through suppressive effects of testosterone on AVP or through activation by testosterone metabolites of estrogen receptor-ß (9, 10, 43, 44). The striking nature of these effects has led understandably to the speculation that sex-related differences in HPA axis function in humans must similarly reflect differential exposure to reproductive steroids, although the suppressive effects of testosterone in rats are difficult to translate into enhanced HPA axis response in men compared with women. Our detection of sex-related differences in stimulated HPA axis activity despite similar testosterone and estradiol levels demonstrates, for the first time, that acute exposure to reproductive steroids does not independently explain these differences in humans. Thus, the differences observed might be organized by earlier exposure to reproductive steroids, as suggested in rats (25, 26). We cannot rule out the possibility, however, that the effects of exposure to reproductive steroids might endure significantly beyond the interval of steroid suppression in this study. Nonetheless, we can conclude that sex-related differences in HPA axis activity in humans do not solely reflect acute, activational effects of reproductive steroids.

A multitude of factors may influence HPA activity and potentially account for differences between samples. Patients with a past history of depression, for example, may continue to show abnormal responses to HPA axis stimulation even when they are asymptomatic (42). Because all subjects participating in this study were screened to rule out a past history of depression, this confound can be ruled out. Furthermore, even though depression ratings at the time of the exercise procedure were higher in women, the difference between the men and women was neither statistically nor clinically significant and certainly could not explain their lower stimulated cortisol levels (because depression is accompanied by increased cortisol secretion). Increased CBG levels would decrease free cortisol levels, but CBG levels in our samples, as detected by RIA, were similar in men and women and were not significantly correlated with stimulated cortisol levels after adjustment for multiple comparisons. We cannot, however, rule out sex differences in CBG binding capacity that might influence free cortisol levels (see Ref. 45) or cortisol metabolism. Although we were unable to measure free cortisol in this study because of blood volume limitations, it is of note that in at least one previous study (16), differences in free cortisol in older subjects were accompanied by sex differences in CBG levels. Differences in ACTH bioactivity could account for sex-related differences in exercise-stimulated cortisol secretion, but the highly similar cortisol to ACTH ratios in men and women after exercise would argue against a less bioactive ACTH moiety in women. Although differences in the impact of a stressor across individuals would affect stimulated ACTH and cortisol levels, the relative intensity of the exercise stressor was standardized across subjects by indexing the stressor to each subject’s VO2max. Finally, recent studies (46, 47) suggest that dietary fats and carbohydrates can decrease the ACTH and cortisol responses to stress. Consequently, the sex differences that we observed could be epiphenomenal to differences in dietary composition. However, subjects had not had a meal for at least 4 h before the stimulation tests.

Several caveats deserve mention. First, not surprisingly, although our data are consistent with some studies employing psychological (12, 13, 14, 15, 16) or pharmacological (36) stimuli in younger men and women, they are discordant with others. For example, some reports describe greater exercise- or CRH-stimulated ACTH in young women compared with men (17, 19, 48, 49, 50), and the absence of sexual dimorphisms also has been reported (20). Differences in methodology (e.g. dose of CRH) or sample characteristics (age of subjects) may account for the conflicting results, but sex-related differences in reproductive steroids in all previous studies represent a major distinguishing characteristic from our study. Second, the unavailability of adequate integrated measures of cortisol secretion prevents us from assessing the effect of sex on basal (unstimulated) HPA axis activity. Third, the higher CRH-stimulated cortisol in men who received testosterone first (and hence had a shorter antecedent period of gonadal suppression) raises the possibility that CRH-stimulated cortisol levels would have been similar in men and women if all men had undergone a longer period of testosterone suppression. In fact, however, CRH-stimulated cortisol levels were not significantly different in men and women in this study. Furthermore, we have demonstrated previously that testosterone replacement in men in this paradigm decreases CRH-stimulated cortisol compared with findings during leuprolide-induced hypogonadism (30). Hence, higher testosterone levels in the men with a shorter duration of hypogonadism would not explain the higher CRH-stimulated cortisol seen in this group. Furthermore, the order of testosterone administration did not influence exercise-stimulated cortisol levels, which were significantly increased in men, or ACTH levels after either procedure. Nonetheless, we cannot rule out other factors that might change with duration of hypogonadism and regulate stimulated adrenal function. Similarly, because the duration of hypogonadism at the time of testing was longer in the women than the men, we cannot rule out a contribution of this differential latency to the sex differences observed. Fourth, although studies demonstrate that the results of both exercise (51) and CRH (52) testing are similar in morning and evening, it is possible that the differences we observed might be subject to circadian influences. Finally, the variability in the response across individuals was such that the differences observed often reached only a marginal level of significance. The relatively small size of our samples also dramatically decreases the power of our study to detect type II errors; consequently, it is possible that other sex differences or possible correlative effects of gonadal steroid levels on HPA axis function might have been detected with larger sample sizes.

These caveats notwithstanding, our findings augment those in the literature in several ways. First, we demonstrated that the increased HPA axis response reported in young men after psychological stressors is also apparent after pharmacological and physiological stressors. Furthermore, increased HPA axis activity in males occurs at the adrenal (with exercise) as well as at the pituitary. Second, our findings with the exercise procedure complement those observed with other stress paradigms and extend them by controlling for interindividual differences that may affect the results of other procedures. An advantage of the exercise stimulation paradigm, then, is that the parameters are indexed to the individual’s level of fitness to ensure a highly quantitative and equivalent degree of stress across individuals. Third, we have shown that the sex-related differences observed are not caused by differences across sexes in circulating gonadal steroid levels. Whether these sex differences represent organizational effects, perhaps mediated through sex differences in feedback, or differential vasopressinergic regulation of the axis cannot be determined from our data. Fourth, our findings with pharmacological and physiological stimuli in younger men and women are in contrast to the increased cortisol secretion often seen in older women compared with men in studies using similar stimuli. As such, they reinforce observations that age and sex interact in determining the HPA axis response to stimuli. Finally, the kinetics of the response to stimulation were different in the men, who showed a more robust and rapid increase in ACTH for the 30 min after both CRH and exercise than the women. This may in part account for the increased cortisol to ACTH ratios in women reported elsewhere, although gonadal steroid-dependent differences in adrenal sensitivity cannot be ruled out. Notwithstanding the considerable interindividual differences in HPA axis response, the sex differences identified under relatively hypogonadal conditions may help further illuminate stress axis physiology and the mechanisms underlying sex differences in stress-related pathophysiology.


   Acknowledgments
 
We gratefully acknowledge the tireless and careful efforts of Kristen Dancer in the analysis of data and preparation of figures and the helpful editorial suggestions of Katya Rubinow.


   Footnotes
 
First Published Online May 10, 2005

Abbreviations: ANOVA-R, Repeated-measures ANOVA; AUC, area under the curve; AVP, arginine vasopressin; CBG, cortisol-binding globulin; CV, coefficient of variation; HPA, hypothalamic-pituitary-adrenal; MAX, stimulated peak value; {delta} MAX, difference between peak value and baseline; o-CRH, ovine CRH; VO2max, maximal oxygen uptake.

Received December 23, 2004.

Accepted April 22, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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