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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 7 3057-3063
Copyright © 2003 by The Endocrine Society

Differential Menstrual Cycle Regulation of Hypothalamic-Pituitary-Adrenal Axis in Women with Premenstrual Syndrome and Controls

Catherine A. Roca, Peter J. Schmidt, Margaret Altemus, Patricia Deuster, Merry A. Danaceau, Karen Putnam and David R. Rubinow

Behavioral Endocrinology (C.A.R., P.J.S., D.R.R.) and Geriatric Psychiatry Branches (K.P.), National Institute of Mental Health, and Clinical Center Nursing Department (M.A.D.), National Institutes of Health, Bethesda, Maryland 20892; Department of Health and Human Services, Department of Psychiatry (M.A.), Weill Medical College, Cornell University, New York, New York 10021; and Department of Military and Emergency Medicine (P.D.), Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814

Address all correspondence and requests for reprints to: Catherine A. Roca, M.D., Building 10, Room 3N242, 10 Center Drive MSC 1277, Bethesda, Maryland 20892-1277. E-mail: rocac{at}intra.nimh.nih.gov.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
DYSREGULATION OF THE hypothalamic-pituitary-adrenal (HPA) axis is one of the most reliably observed physiologic abnormalities in major depression. Extensive studies in animals demonstrate that both gender and reproductive steroids regulate basal and stimulated axis function. In general, inhibition of HPA axis responses to stressors are seen with short-term, physiological levels of estradiol replacement in ovariectomized animals (1, 2, 3, 4), and higher doses and longer treatment regimens enhance HPA axis reactivity to stressors (5, 6, 7). The regulatory effects of changes in reproductive steroids or menstrual cycle phase on the HPA axis in women are far less well studied and understood. Although some studies using psychological stressors identified increased stimulated cortisol in the luteal phase (8, 9), others using psychological (10, 11) or physiological (e.g. insulin-induced hypoglycemia, exercise) (12, 13) stressors failed to find a luteal phase increase in HPA axis activity. Determination of the role of reproductive steroids in HPA axis regulation is of particular importance in efforts to understand the pathophysiology of premenstrual syndrome (PMS), a disorder characterized by affective symptoms and decreased stress adaptation in the luteal phase of the menstrual cycle.

Not surprisingly, data regarding the functioning of the HPA axis in women with PMS are conflicting. In general, no differences have been observed between PMS patients and controls in basal plasma cortisol levels, urinary-free cortisol, or the circadian pattern of plasma cortisol secretion (14). Basal plasma ACTH levels in PMS patients have been reported as both less than and similar to controls (15, 16, 17). Compared with controls, women with PMS had a blunted cortisol response to stimulation or stressors, either in the luteal phase or throughout the cycle, in some (18, 19, 20) but not other (21) studies. However, the inability to standardize stressors across individuals and across time points (i.e. as a repeated measure in the same individual) is a major limitation of such studies. To address this limitation, we employed an exercise stressor paradigm in which the stress delivered is individualized as a percentage of the subject’s maximum ventilatory capacity, thus assuring comparability across subjects and sessions (22). We used this paradigm to answer three questions: 1) Do stress-stimulated HPA axis responses differ as a function of menstrual cycle phase? 2) Do women with PMS display abnormalities in either their response to stress or in the impact of menstrual cycle phase on stress-stimulated physiology? 3) Can one identify a physiologic factor that mediates menstrual phase regulation of stress-stimulated HPA axis responses? Altemus et al. (23) recently published the answer to the first question (with subjects overlapping those in the present study) and demonstrated that exercise-stimulated HPA responses were increased in the midluteal, compared with the follicular, phase. This report, therefore, focuses on the last two questions.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subject selection

Women with PMS were self-referred in response to advertisements in local newspapers or referred by their physician. Normal volunteer women (controls in the PMS/menstrual cycle study and primary subjects in the leuprolide study) were recruited through local advertisement. All women were without current medical illness (as assessed by medical history, physical examination, laboratory tests, and electrocardiogram) and medication free and had no Axis I diagnosis within the past 2 yr, including alcohol and substance abuse, as determined by the structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders (DSM) III-R or IV (24, 25). PMS was confirmed by prospective ratings for three consecutive cycles. To be confirmed as having a diagnosis of PMS, subjects had to show at least a 30% increase in mean negative mood (e.g. depression, anxiety, or irritability), relative to the actual range of the analog rating scale (100 mm) used, in the week before menses compared with the week after menses (26) (unpublished NIMH premenstrual syndrome workshop guidelines, 1983). Patients also met DSM IV criteria for premenstrual dysphoric disorder (27), confirming that they suffered from a severe form of PMS associated with impairment. Normal volunteer women also completed 2 months of prospective ratings, had no evidence of premenstrual mood symptoms, and did not meet criteria for either current or past psychiatric illness as determined by the Structured Clinical Interview for DSM III-R or IV.

All patients and controls had cycle lengths between 26 and 31 d, with the exception of two patients, one with a cycle length of 21d and another with a cycle length of 33 d. All women participating in the menstrual cycle study had ovulation confirmed by LH testing. The protocols were reviewed and approved by the National Institute of Mental Health (NIMH) and Uniformed Services University of the Health Sciences (USUHS) institutional review boards, and all subjects gave both written and verbal consent to study participation.

Pregnancy tests were performed on all subjects before study entry, and all participants were required to use barrier forms of contraception throughout the course of the study. Normal volunteer women were paid for their participation according to the schedule of payment issued by the NIH Normal Volunteer Office.

Study design

Exercise procedure. Subjects were instructed to not eat the morning before 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 h and 0800 h.

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

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 slope 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, progesterone, testosterone, cortisol-binding globulin (CBG), lactate, and glucose was drawn at baseline along with cortisol, ACTH, and arginine vasopressin (AVP). Blood for subsequent measurements of cortisol, ACTH, AVP, lactate, and glucose was drawn at 10 min (70% VO2max), 20 min (90% VO2max), 30, 40, 50, and 60 min (during recovery from exercise.) Blood samples were drawn in prechilled tubes and stored at -70C until assayed, except for glucose and lactate samples, which were run on site within 1 h.

Menstrual cycle effects in PMS vs. controls (PMS/menstrual cycle study)

We studied six women with PMS and eight women without the syndrome (hereafter referred to as controls). Following the maximal treadmill exercise test, women participated in submaximal exercise tests (to 90% of the previously determined VO2max) during the early follicular (d 3–6 after the onset of menses) and midluteal [7–10 d after LH surge, determined by a home urine test kit (Clearplan Easy; Unipath Ltd., Bedford, UK)] phases of the menstrual cycle. Four of the six women with PMS and four of the eight control women had their first submaximal test in the follicular phase.

Effects of reproductive steroids in normal volunteer women (leuprolide study)

We studied 11 women without PMS recruited through local advertisements; eight were Caucasian and three were African-American. Women in the leuprolide study received five monthly injections of the GnRH agonist leuprolide acetate (Lupron, TAP Pharmaceuticals, Lake Forest, IL) (3.75 mg) after the 3-month screening period and a maximal treadmill exercise test. Women received leuprolide acetate injections alone (hypogonadal condition) during the first 8 wk of the study and then were randomly assigned to receive 5 wk of transdermal 17ß-estradiol (Alora, Watson Pharmaceuticals, Salt Lake City, UT) at a dose of 0.1 mg/d or progesterone vaginal suppositories (NIH, Pharmaceutical Development Service, Bethesda, MD) at a dose of 200 mg twice daily in a double-blind, placebo-controlled, cross-over study with a 2-wk washout between periods of hormone administration. All women received either active or placebo patches and suppositories every day for 10 wk. Women also received progesterone (1 wk) at the end of estradiol administration to induce shedding of the endometrium. Submaximal exercise tests (to 90% of VO2max, as described above) were performed during wk 5–8 (hypogonadal), 11–12 (2 wk after hormone add-back no. 1) and wk 17–18 (2 wk after hormone add-back no. 2).

Hormone assays

Samples were collected in prechilled test tubes containing EDTA. All assays were performed by Endocrine Sciences, Inc. (Calabasas Hills, CA). Individual patients had samples from all of their tests run in the same assay. In the PMS/menstrual cycle study, samples from patients were also run in the same assay with controls to reduce any variance secondary to interassay variability.

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 with LH20 column chromatography in a modification of the procedure by Wu and Lundy (28). The intraassay CV was 3.2% and the interassay CV was 9.2%. Progesterone was measured by RIA following organic extraction; intra- and interassay CV were 6.4% and 2%, respectively. Testosterone was measured by RIA following extraction with column chromatography, with an intraassay CV of 7% and an interassay CV of 9%.

Cortisol, ACTH, and AVP were measured in 10-min intervals throughout the test as previously described. Cortisol was measured directly by RIA with intra- and interassay CV of 3.9% and 8.3%, respectively. The ACTH-immunoradiometric assay uses paired monoclonal and polyclonal antibodies, reactive respectively with the N-terminal and the C-terminal regions of ACTH. The intraassay CV was 6.2%, and the interassay CV was 11%. AVP was measured by a double-antibody RIA using a modification of the method developed by Glick and Kagan (29). The intraassay CV was 8.8%, and the interassay CV was 7.1%.

Plasma lactate and glucose concentrations were determined in duplicate (analyzer model 27, YSI, Inc., Yellow Springs, OH). The intraassay and interassay CV for lactate and glucose were less than 2%.

Statistics

Age of subjects in the PMS/menstrual cycle study groups was compared with Student’s t test. Basal and exercise-stimulated hormonal data were analyzed by ANOVA for repeated measures. In the PMS/menstrual cycle study, diagnosis (PMS vs. controls) was the between-subject factor and menstrual cycle phase (follicular, luteal) and time [baseline, 10–60 min (seven levels)] were the within-subject factors. Dependent measures were hormone levels and areas under the curve (AUCs) (with phase as the only repeated measure) for AVP, ACTH, and cortisol. AUC was determined by a baseline-corrected trapezoidal integration method. The effects of diagnostic group and menstrual cycle phase on the ratio of cortisol to ACTH levels was also assessed with ANOVA for repeated measures. In the leuprolide study, two within-subject factors were examined: gonadal condition [hypogonadal (leuprolide alone); leuprolide and estradiol; leuprolide and progesterone]; and time (seven levels as described above). Significant differences found on ANOVA were explored with post hoc Bonferroni t tests (two-tailed).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
PMS/menstrual cycle study

Women with PMS and controls were Caucasian and did not differ in age (37.7 ± 1.6 yr vs. 34 ± 1.8 yr, respectively, P = NS). Two of the women with PMS had a past history of major depressive disorder.

Exercise-stimulated hormone levels did not differ between patients and controls (i.e. there were no significant diagnostic effects). However, significant phase by time by diagnosis effects were observed for exercise-stimulated cortisol (F(6,72) = 2.9, P = 0.02), ACTH (F(6,72) = 2.3, P = 0.04), and AVP (F (6,72) = 2.8, P = 0.02). These findings reflected different effects of menstrual cycle phase on stimulated HPA axis hormones in women with PMS and controls (Fig. 1Go, A and B). Post hoc testing in controls demonstrated that values of ACTH at 30 min (T30 t = 3.3, df = 84, P < 0.05) and cortisol at 40 min (T40 t = 3.2, df = 84, P < 0.05) were significantly increased in the luteal compared with the follicular phase; no significant menstrual cycle phase effects were seen in women with PMS. A significant diagnosis by phase interaction was also seen with an integrated measure of hormone secretion, AUC, for cortisol (F(1,12) = 5.8, P = 0.03), reflecting significantly increased stimulated cortisol during the luteal phase compared with the follicular phase (Bonferroni t = 2.8, df = 12, P < 0.05) in controls only. Similarly, a significant diagnosis by phase interaction (F(1,12) = 6.1, P = 0.03) for ACTH reflected a significant increase in stimulated ACTH during the luteal phase (compared with the follicular phase) in controls (Bonferroni t = 3.9, df = 12, P < 0.01) but not patients (Bonferroni t = 2.2, df = 12, p= NS). No significant effect of menstrual cycle phase was seen on exercise-stimulated levels of any of the three hormones (AVP, ACTH, cortisol) studied in women with PMS. In fact, hormonal secretory curves and AUCs were greater, albeit not significantly, in the follicular phase in these women (Fig. 1AGo). Women with PMS and controls did not differ in baseline plasma levels of estradiol, progesterone, testosterone, or CBG during either menstrual cycle phase (Table 1Go). There was a trend for a lower cortisol: ACTH ratio, a measure of adrenal sensitivity, in women with PMS across the menstrual cycle (F(1,12) = 3.8, P = 0.08), with lower ratios seen in patients compared with controls at every time point (Fig. 2Go). Finally, although both glucose and lactate levels significantly increased (as expected) during exercise (F(6,72) = 12.4, P = 0.001, F(6,76) = 31.8, P = 0.00, respectively), no significant effects of diagnosis, menstrual cycle phase, or interactive effects were observed.



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  		FIG. 1. A and B, Exercise-stimulated AVP, ACTH, and cortisol levels in the follicular and luteal phases in women with PMS (A) and normal women (B). Normal women demonstrated significantly greater stimulated levels of ACTH and cortisol (at 30 min and 40 min after initiation of exercise, respectively) in the luteal phase, compared with the follicular phase. In contrast, no significant differences in stimulated hormone levels were seen between menstrual cycle phases in women with PMS (whose values were uniformly, but not significantly, lower in the luteal phase). *, Bonferroni t, P < 0.05

 

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  		TABLE 1. Basal hormone levels (means ± SD) in PMS/menstrual cycle and leuprolide (Lupron) studies

 


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  		FIG. 2. Ratio of exercise-stimulated cortisol and ACTH values during the luteal and follicular phases in normal women and women with PMS. A trend is seen for lower cortisol: ACTH ratios in the women with PMS, compared with normal women, in both cycle phases. This trend suggests a decreased adrenal response in women with PMS.

 
Leuprolide study

Subjects were three African-Americans and eight Caucasians, mean age 31.7 ± 6.5 yr.

As seen in Table 1Go, the three intended hormonal conditions, hypogonadal, estradiol replaced, and progesterone replaced, were achieved.

Examination of exercise-stimulated hormones under these three induced hormonal conditions showed significant increases (hormone condition by time effect) in AVP (F(12,108) = 2.4, P = 0.01), ACTH (F(12,108) = 4.2, P < 0.001), and cortisol (F(12,108) = 6.5, P < 0.001) during progesterone replacement compared with hypogonadism or estradiol (Fig. 3Go). Values during estradiol were not significantly different from those seen during leuprolide alone for any measure. On post hoc testing, stimulated AVP during progesterone was significantly greater at 20 min (T20) than hypogonadism (t = 6.5, df = 126, P < 0.01) or estradiol (t = 3.4, df = 126, P < 0.05), stimulated ACTH was greater at T20 (t = 4.4, df = 126, P < 0.01), T30 (t = 5.6, df = 126, P < 0.01), and T40 (t = 3.0, df = 126, P < 0.05) [than estradiol only at T30 (t = 3.6, df = 126, P < 0.05)], and stimulated cortisol was greater at T50 (t = 3.8, df = 126, P < 0.05) and T60 (t = 3.8, df = 126, P < 0.05) than hypogonadism or estradiol. A significant effect of hormone condition was also observed for AUC ACTH (F(2,18) = 7.0, df = 18, P < 0.001) and AUC cortisol (F(2,18) = 15.0, df 18, P = 0.001), reflecting increased secretion during progesterone (but not estradiol) compared with hypogonadism (t = 3.4, P < 0.05; df = 18, t = 5.1, df = 18, P < 0.01, respectively). The stimulated hormonal peaks during each of the three hormonal conditions occurred in the same temporal sequence as observed in the PMS/menstrual cycle study. No effect of hormone condition was seen on lactate or glucose, both of which significantly increased during the exercise stress (F(6,54) = 18.2, P < 0.0001, and F(6,54) = 9.1, P < 0.0001, respectively).



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  		FIG. 3. Exercise-stimulated AVP, ACTH, and cortisol levels during hypogonadism (leuprolide [Lupron] alone), estradiol (E2) replacement, or progesterone (P4) replacement. Exercise-stimulated AVP, ACTH, and cortisol were all significantly greater during P4 replacement than during the hypogonadal (leuprolide) or E2 replacement conditions. Bonferroni comparisons: ++, P4 > leuprolide, P < 0.01; +P4 > leuprolide, P < 0.05; *, P4 > E2, P < 0.05.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study yielded two major findings: 1) women with PMS fail to show the luteal phase enhancement of exercise-stimulated HPA axis activity seen in normal control women; and 2) in normal control women, it is progesterone, not estradiol, that appears to amplify HPA axis responses to the stress of exercise. The differential HPA axis response to exercise stimulation in women with PMS provides strong additional evidence for the dysregulation of stress response physiology in this disorder. PMS patients failed to show the luteal phase increase in AVP, ACTH, and cortisol seen in controls; indeed, stimulated hormone levels in women with PMS were higher (albeit nonsignificantly) in the follicular phase, militating against simple type II error as the explanation for the absence of luteal phase increase in women with PMS. Differences seen were not attributable to differences in the level of stress achieved, because similar stimulated levels of lactate were obtained in both menstrual cycle phases in patients and controls. In addition to the abnormal response to menstrual cycle phase, women with PMS showed (at a trend level) reduced adrenal response to ACTH in both cycle phases. The failure of prior studies to demonstrate these significant differences in HPA axis function may reflect the nature of the stimulation paradigms employed: Graded exercise stimulation is a more robust activator of the axis than most others used [e.g. CRH, m-chlorophenylpiperazine (m-CPP)] and additionally permits a similar degree of stress across individuals by indexing the stimulus parameters to those required to elicit 90% of the individual’s maximal aerobic capacity.

Our data are, nonetheless, consistent with several earlier observations. Blunted stimulation of cortisol during the luteal phase in women with PMS has been described following m-CPP (18), a psychological stressor (19), and CRH or naloxone (30). Additionally, the trend that we noted for decreased cortisol to ACTH ratios in women with PMS throughout the cycle suggests an adrenal hyposensitivity, a potential explanation for several earlier observations including decreased evening plasma cortisol levels (21, 31, 32) and blunted tryptophan-stimulated cortisol (20) in women with PMS across the menstrual cycle. Such hyposensitivity could reflect decreased bioactive ACTH, decreased adrenal ACTH receptors, decreased postreceptor signaling, or decreased adrenal size or capacity. Irrespective of the mechanism, these data provide a striking contrast to those seen in major depressive disorder, which is characterized by adrenal hypertrophy and hyperresponsivity (33, 34). The validity and physiologic significance of the current findings are suggested by the following: 1) identical significant diagnostic group by phase by time interactive effects were observed for all three hormones examined rather than a single component of the HPA axis response; and, 2) the timing of the peaks of the stimulation curves showed the predicted sequence: AVP followed by ACTH followed by cortisol.

The AVP levels obtained in plasma primarily represent the product of supraoptic nuclear magnocellular neurons rather than the paraventricular nuclear parvocellular neurons that play a direct role in the modulation and amplification of CRH action at the corticotrope. However, a possible role of AVP in the disturbed menstrual cycle effect on HPA axis activity in the women with PMS is suggested by several prior observations. First, magnocellular activity may reflect parvocellular neuronal activation, and considerable evidence suggests that the magnocellular system influences ACTH secretion, particularly under stressful conditions that elevate peripheral AVP (35, 36); second, repeated or chronic stress enhances HPA response to subsequent stressors, at least in part by shifting to enhanced AVP modulation of the axis (37). As such, it has been proposed that AVP plays a key role in the ACTH response to a novel or heterotypic stimulus that occurs in the context of chronic or repeated stress (38). Third, Keck et al. (39) have proposed that the enhanced ACTH response to the dexamethasone-CRH test in depression reflects [like the response in the context of repeated stress (37, 40) or aging in women (41)] the effect of increased vasopressin stores and release. Because the enhanced ACTH response to exogenous AVP in the dexamethasone/CRH test is not seen in those who are believed to have up-regulated AVP levels (e.g. depressed or older women) (41), it is possible that chronically up-regulated AVP in women with PMS consequent to their recurrent distress may prevent the luteal phase increase in AVP and pituitary-adrenal activation seen in normal women.

To clarify the nature of the abnormal HPA axis response in women with PMS, we attempted to determine the hormonal constituents of the luteal phase responsible for the enhanced response seen in control women by exercising women during three pharmacologically mediated hormone conditions: hypogonadism (leuprolide alone), estradiol (leuprolide and estradiol), and progesterone (leuprolide and progesterone). The hormone condition significantly affected the stress responses of all three HPA axis hormones. In contrast to a large animal literature documenting the ability of estradiol to increase basal and stimulated HPA axis secretion, we found that progesterone, but not estradiol, significantly increased exercise-stimulated AVP, ACTH, and cortisol secretion, compared with a leuprolide-induced hypogonadal condition or estradiol replacement. Although surprising, these stimulatory effects of progesterone are not without precedent. Keller-Wood et al. (42) have described the ability of progesterone to actively interfere with feedback inhibition of the HPA axis. Additionally, Lindheim et al. (43) found that progesterone reversed estradiol-induced blunting of the stress axis (norepinephrine and systolic blood pressure but not ACTH or cortisol) and increased adrenal sensitivity to ACTH. [The latter finding is inconsistent with our observation of increased adrenal sensitivity (increased cortisol to ACTH ratios) in the follicular phase in control women.] The mechanism by which progesterone augments stimulated HPA axis activity is currently unknown but could include the following: modulation of cortisol feedback restraint of the axis (1, 44, 45, 46); neurosteroid-related down-regulation of {gamma}-aminobutyric acid receptors (47); and up-regulation of AVP (consistent with luteal phase reductions in the threshold for AVP release) (48). Additionally, Aguilera et al. (Ochedalski, T., P. Wynn, and G. Aguilera, unpublished manuscript) have shown that progesterone enhances oxytocin-induced CRH, a model for how progesterone might increase the response to stimulated activity without affecting basal function. The importance of progesterone as a neuroendocrine modulator is further supported by our observation that progesterone, but not estradiol, significantly increases m-CPP-stimulated prolactin (49), consistent with the reported ability of progesterone to modulate serotonergic function in rhesus macaques (50). Independent of the mechanism involved, progesterone modulation of the stress response in humans might influence behavioral adaption (and hence psychiatric phenomenology) and contribute to the susceptibility to affective disturbance seen in some women in association with reproductive endocrine change.

Several caveats are necessary in the interpretation of our data. First, the exercise stimulation test was performed in the morning, at a time when increased variability may have been introduced because of the increased endogenous activity of the HPA axis at this time. This confound would not be expected to affect results unless there were a systematic alteration in the circadian activity of the axis in women with PMS, evidence for which is currently lacking. Second, although mean estradiol levels achieved during the estradiol add-back with leuprolide were higher than follicular levels in the PMS study, they were lower than those seen in controls during the luteal phase in that study (although similar to luteal phase values in the women with PMS). We cannot, therefore, rule out the possibility that a modulatory effect of estradiol on HPA axis function would be seen with substantially elevated estradiol levels. Third, the results that we observed were obtained with a strong physiologic stressor and may not be observed in a variety of different stress paradigms. Finally, given the co-occurrence of progesterone and estradiol during the normal luteal phases, we cannot directly extrapolate our findings and conclude that progesterone is the sole factor responsible for the enhanced stimulated HPA axis function we observed during the luteal phase in normals during the cycle study.

These caveats notwithstanding, several conclusions can be drawn. First, despite the ubiquity of affective symptoms in PMS, the function of the HPA axis is distinctly different from that seen in major depression: Women with PMS, if anything, show a decrease in stimulated HPA axis response when symptomatic (compared with the increased response seen in major depressive disorder) and blunted (instead of enhanced) adrenal sensitivity. In this regard, it is of interest that several animal studies demonstrate that stressors repeated at 3- to 5-wk intervals can generate adrenal hyporesponsivity or hypocortisolism, which in turn may contribute to stress-related pathology (51, 52). The role of repeated dysphoric episodes occurring on a monthly basis in PMS can, as such, be regarded as potentially impacting stress physiology. Second, although we cannot be certain whether menstrual cycle-related variation in HPA axis function reflects effects of progesterone alone or progesterone in combination with estradiol, it does appear that estradiol alone is not the relevant factor. Third, as in our earlier examination of the effects of induced gonadal states on mood (53), women with PMS appear to have an abnormal response to normal levels of progesterone, compared with normal women. Although the mechanism underlying the abnormal response to progesterone is unknown, as is the possible contribution of abnormalities in the stress axis to the symptomatology of PMS, our data strongly suggest that PMS is characterized by stress axis physiology that clearly distinguishes it from major depressive disorder.


   Acknowledgments
 
Material support (estrogen and placebo patches) supplied by Watson Pharmaceuticals. We thank Philip W. Gold, M.D., for expert consultation and advice; Wendy A. Koss, M.S., for preparation of the figures; and the women who gave their time and efforts to participate in this study.


   Footnotes
 
Abbreviations: AUC, Area under the curve; AVP, arginine vasopressin; CBG, cortisol-binding globulin; CV, coefficient of variation; HPA, hypothalamic-pituitary-adrenal; m-CPP, m-chlorophenylpiperazine; PMS, premenstrual syndrome; VO2max, maximal oxygen uptake.

Received October 7, 2002.

Accepted March 16, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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