Psychosomatic Medicine 61:292-296 (1999)
© 1999 American Psychosomatic Society
Testosterone, Gonadotropin, and Cortisol Secretion in Male Patients With Major Depression
Ulrich Schweiger, MD,
Michael Deuschle, MD,
Bettina Weber, MD,
Andreas Körner, MD,
Claas-Hinrich Lammers, MD,
Jürgen Schmider, MD,
Ulrike Gotthardt, MD and
Isabella Heuser, MD
From the Max-Planck-Institute of Psychiatry, Clinical Institute, Munich, Germany.
Address reprint requests to: Ulrich Schweiger, MD, Klinik für Psychiatrie, Medizinische Universität zu Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany. Email: schweiger.u{at}psychiatry.mu-Luebeck.de
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ABSTRACT
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OBJECTIVE: Previous studies of sex hormone concentrations in depression yielded inconsistent results. However, the activation of the hypothalamic-pituitary-adrenal system seen in depression may negatively affect gonadal function at every level of regulation. The objective of this study was to explore whether major depressive episodes are indeed associated with an alteration of gonadal function.
METHODS: Testosterone, pulsatile LH secretion, FSH, and cortisol were assessed using frequent sampling during a 24-hour period in 15 male inpatients with major depression of moderate to high severity and in 22 healthy comparison subjects (age range 22–85 years).
RESULTS: An analysis of covariance model showed that after adjustment for age only, daytime testosterone (p < .01), nighttime testosterone (p < .05), and 24-hour mean testosterone secretion (p < .01) were significantly lower in the depressed male inpatients. There was also a trend for a decreased LH pulse frequency in the depressed patients (p < .08).
CONCLUSIONS: Gonadal function may be disturbed in men with a depressive episode of moderate to high severity.
Key Words: major depression • testosterone • LH • FSH • cortisol • men
Abbreviations: ANCOVA = analysis of covariance; CRH =corticotropin-releasing hormone; DSM-III-R = Diagnostic andStatistical Manual of Mental Disorders, 3rd Edition-Revised; DST =dexamethasone suppression test; GnRH = gonadotropin-releasinghormone; HPA system = hypothalamic-pituitary-adrenal system; HPGsystem = hypothalamic-pituitary-gonadal system; FSH =follicle-stimulating hormone; LH = luteinizing hormone.
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INTRODUCTION
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The majority of pilot studies evaluating the hypothalamic-pituitary-gonadal (HPG) system in depression (for methodological reasons mostly limited to men with depression) were unable to consistently demonstrate any dysfunction. Sachar and co-workers (1), in a study of middle-aged and elderly men, found similar morning and evening concentrations of plasma testosterone during depressive illness compared with the recovered state. In contrast, Steiger and co-workers (2) reported higher nighttime (23.00–03.00 hours) testosterone concentrations in clinically depressed men after symptomatic recovery. And, Rupprecht and co-workers (3) reported a trend toward lower testosterone concentrations in six male patients during depression compared with the time after recovery. Levitt and Joffe (4) found similar morning plasma testosterone concentrations in 12 men with depression and a control group of similar age (mean 32 years). The most extensive null finding as of today comes from Rubin and co-workers (5): There was no difference between 16 male depressed patients (mean age 40 years) and their controls in 24-hour LH, FSH, and testosterone secretion, and there were no relevant correlations between these parameters and 24-hour cortisol secretion or results of the dexamethasone suppression test (DST). However, only six patients (but two controls) were DST- nonsuppressors in this study. The 10 DST-suppressors showed 24-hour cortisol concentrations nearly identical to the comparison group, a result that might indicate a relatively mild overall activation of the hypothalamic-pituitary-adrenal (HPA) system in the patients of this particular study (6). In contrast, Yesavage and co-workers (7) found a negative correlation between plasma testosterone concentration and severity of depression after correction for age in 15 male depressed patients. Furthermore, Unden and co- workers in a study of 14 depressed men including 8 DST-nonsuppressors (8) reported decreased testosterone in the DST-nonsuppressors during the acute episode when compared with the time of remission, whereas the DST-suppressors had similar concentrations at both points in time. Concerning the challenge tests, Amsterdam and co-workers (9) found similar LH and FSH concentrations before and after GnRH stimulation in 18 male depressed patients (mean age 33 years) and a comparison group. In contrast, Brambilla and co-workers (10) reported decreased baseline LH concentrations in nine depressed men compared with a control group, but no difference of the area under the curve after GnRH stimulation.
Physiological considerations about the interaction between the HPG and HPA system seem to support the hypothesis of gonadal dysfunction in depression: The majority of patients with moderate to severe depression are known to suffer from an activation of the HPA system (11). At this level of the hypothalamus, there is a close anatomical relationship between CRH and GnRH neurons (12). CRH has been shown to suppress pulsatile LH secretion after central application in rats (13) and glucocorticoids may negatively affect the HPG system at every level of regulation (14). This relationship between activation of the HPA system and suppression of gonadal function has also been observed with changes of social status in primates (15), in human stress models (16), hypothalamic amenorrhea (17, 18), and in bulimia nervosa (19).
A factor only partially considered in the earlier studies concerns the covariant effects of age on the relationship between HPA and HPG system. The existence of age effects on both testosterone and cortisol secretion in humans is controversial. Some studies show similar levels of secretion in old and young individuals, and other studies show a positive association between age and cortisol and a negative association between age and testosterone (for review (20, 21)).
In summary, the literature on gonadal function in men with depression is ambiguous. However, due to methodological limitations of previous studies such as small sample sizes, reliance on single measurement, and inclusion of patients with only mild depression, the hypothesis of gonadal dysfunction in depression cannot be refuted at the present time. The available information and physiological considerations point to the possibility that gonadal dysfunction in depression is limited to severe depression with activation of the HPA system. For these reasons, we studied cortisol as well as LH, FSH, and testosterone secretion in a group of male inpatients who were severely depressed and a comparison group who was healthy with special emphasis on age effects and diurnal rhythms.
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METHODS
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Patients
We included 15 consecutively admitted men (age range 22–72 years), diagnosed with major depression according to DSM-III-R criteria using a standardized interview (22). The protocol had been approved by the local ethics committee. Written informed consent was obtained after the procedure had been fully explained to all participants. In addition to the standard DSM-III-R criteria, intensity of the disorder had to be rated moderate to severe at the time of the study, the disorder had to interfere markedly with social or occupational functioning, and DSM III-R criteria A1 to A4 had to be met. The Hamilton Rating Scale for Depression (21-items) was used to quantify the intensity of depression (23). The minimum score for inclusion was 18. Participants had no history of substance abuse or dependence. None of the men showed evidence of any major medical disorder as ascertained by a physical examination, routine laboratory examinations, including magnetic resonance imaging of the brain, electrocardiogram, and electroencephalogram. Participants were free of psychotropic medication for a minimum of 7 days before the study. They took part in the study within 3 to 7 days after hospitalization. Basic descriptive data are summarized in Table 1 .
Comparison Group
Twenty-two healthy men (age range 23–85) were recruited by announcements in local newspapers. They were only included if the standardized interview (22) yielded no evidence for a current or lifetime major psychiatric disorder and if no abnormalities in physical examination and routine laboratory tests were found. None of the men in the comparison group took any medication. A history of minor medical disorders was no exclusion criterion. Basic descriptive data are summarized in Table 1, also.
Procedure
24-Hour Blood Sampling.
At 7:45, an intravenous catheter was inserted into a forearm vein, connected to a long IV tubing system, and passed through a soundproof lock into the adjacent laboratory. Seven-milliliter blood samples were collected at half-hour intervals between 8:00 and 18:00 hours. Between 18:00 hours and 24:00 hours, blood was drawn every 10 minutes. Thereafter, from 0:00 to 7:30 hours the following morning, blood was drawn every 30 minutes again. Between sampling, the tubing was kept patent by saline infusion at a rate of 50 ml/hr. Samples were immediately centrifuged and aliquots were stored at -20°C. The every-10 minute samples between 18:00 and 24:00 hours were used for analysis of pulsatile LH and FSH secretion. Aliquots of all every-30 minute samples between 8:00 and 19:30 (daytime) and between 20:00 and 7:30 (nighttime) were pooled for analysis of testosterone and cortisol. During the entire 24-hour study, subjects were reclined on a bed in a single room. During daytime, they were not allowed to nap; they passed time by reading or watching television. Lights were switched off at 23:00 hours, and subjects were awakened at 7:00. Hospital meals were served at 8:00, 12:00, and 18:00 hours.
Hormone Analysis.
Cortisol was measured by radioimmunoassay using material from ICN Biomedical, Ceresa, CA. Intraassay variability was 6% and interassay variability was 9% at an average concentration of 120 nmol/L. Testosterone was measured by radioimmunoassay using material from Serono, Freiburg, Germany. All samples were measured using a single kit. Intraassay variability was 5% at 7 nmol/L. LH and FSH were measured with an immunoradiometric assay provided by Serono. Intraassay variability was less than 5% and interassay variability lay between 7% and 9% at 4.2 IU/L LH and 8.5 IU/L FSH.
Statistical Analysis
The LH data were analyzed by the Pulsar method (24). The G thresholds (1–5) for the pulsar method were 4.0, 3.5, 3.0, 2.5, and 2.0. As an additional pulse criterion for LH pulses, a minimum amplitude of 0.7 IU/L was required. Statistical analyses comprised ANCOVAs and t tests, all two-tailed. p-Values below .05 were considered significant. Results are expressed as means ± SD.
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RESULTS
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Table 1 presents basic descriptive data. Age and body mass index were similar in both groups. Mean endocrine data are also presented in Table 1. A comparison of the men with depression and the group that was healthy shows a trend for lower testosterone concentrations during daytime and significantly lower testosterone concentrations during nighttime as well as the 24-hour sampling. Although mean FSH and LH concentrations and LH amplitude are similar in the two groups, LH pulse frequency is lower in the depressed men. 24-hour mean cortisol concentration is 68% higher in the men with major depression relative to the comparison group.
Age and the 24-hour mean mean testosterone and cortisol are plotted in Figures 1 and 2 . ANCOVA revealed that after adjustment for age, daytime testosterone (df = 1,33; F = 11.5; p < .01), nighttime testosterone (df = 1,33; F = 5.3; p < .05), and 24-hour mean testosterone (df = 1,33; F = 8,5; p < .01) were significantly lower in depressed patients. Concerning the daytime testosterone, a significant interaction between age and depression (df = 1,33), F = 5,7; p < .05) emerged.
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Fig. 1. Age and 24-hour testosterone secretion in men with major depression and a healthy comparison group. Linear regression analysis shows an absence of significant correlation between age and 24-hour testosterone secretion in the patient group (r = .11). In the comparison group there is a trend toward a negative correlation between age and 24-hour testosterone (r = -.39; p < .08). ANCOVA reveals significantly lower concentrations in depressed patients (df = 1,33; F = 8.5; p < .001) and a trend for an interaction between age and diagnosis (df = 1,33; F = 3.7; p < .07).
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Fig. 2. Age and 24-hour cortisol secretion in men with major depression and a healthy comparison group. Linear regression analysis shows an absence of significant correlation between age and 24-hour cortisol in the patient group (r = .26). In the comparison group there is a significant positive correlation between age and 24-cortisol (r = .56; p < .01). ANCOVA reveals significantly higher concentrations in depressed patients (df = 1,34; F = 93.5; p < .01) and a significant correlation with age (df = 1,34; F = 4,9; p < .05).
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ANCOVA revealed that FSH correlated with age (df = 1,34; F = 5.0; p < .05). However, after adjustment for age, mean FSH, mean LH, and LH amplitude concentrations were similar in the depressed patients and the comparison group. After adjustment for age, LH pulse frequency tended to show lower values in depression (df = 1,34; F = 3.4; p < .08). ANCOVA of 24-hour mean cortisol concentrations revealed a positive correlation with age (df = 1,34; F = 4,9; p < .05). After adjustment for this covariate, cortisol concentrations were significantly higher in the depressed group (df = 1,34; F = 93.5; p < .01).
Linear regression analysis shows an absence of significant correlation between both age and 24 hours-mean testosterone (r = .11) and age and 24-hour mean cortisol concentrations (r = .26) in the patient group. In the comparison group, there is a trend toward a negative correlation between age and 24-hour mean testosterone (r = -.39; p < .08) and a significant positive correlation between age and 24-hour mean cortisol concentrations (r = .56; p < .01). No significant correlation can be found between 24-hour mean cortisol and 24-hour mean testosterone concentrations in the two groups (patients r = -.17, comparison group r = -.33). When both groups are pooled (Figure 3 ), there is a significant negative correlation between 24-hour cortisol and 24-hour testosterone (r = -.49; p < .01).
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Fig. 3. Relationship between 24-hour cortisol and 24-hour testosterone in men with major depression and a healthy comparison group. No significant correlation can be found between 24-hour cortisol and 24-hour testosterone concentrations in the two groups (patients r = -.17, comparison group r = -.33). When both groups are pooled there is a significant negative correlation (r = -.49; p < .01).
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DISCUSSION
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The study succeeded in selecting patients with a high severity of depressive disorder, which is reflected by high Hamilton scores and a high 24-hour cortisol secretion in the patient group. In the study by Rubin et al. (5, 6), only the DST-nonsuppressers showed a comparable difference between the patient group and controls; the other studies cannot be compared in this respect. Our data suggest that men who suffer from severe major depression have disturbance of gonadal function as reflected by decreased testosterone concentration. This effect is particularly apparent in the age group below 55 years, where there is practically no overlap between the patient and the comparison groups. The effects of depression on testosterone secretion remain stable when they are corrected for age. Our data suggest that previous null findings may be attributed to insufficient methodological and statistical power of these studies.
Correlational analysis shows the predicted negative relationship between cortisol and testosterone. This may be a function of diagnostic status. The mechanism of this association certainly cannot be derived from this study. Gonadal as well as pituitary and hypothalamic mechanisms may play a role. The trend for decreased LH pulse frequency supports a hypothalamic mechanism, but does not exclude additional testicular or pituitary effects of cortisol and other potential factors.
Another question that a cross-sectional study like ours cannot address is what role in the pathophysiology of depression low testosterone might play and whether symptoms of depression can be explained by the low testosterone concentrations observed in our patients. Candidates are sexual disturbances, reduced energy and vegetative symptoms. Apart from these symptoms, low testosterone may contribute to low bone mass in depression (25) and may increase the risk for the development of diabetes and myocardial infarction (26). This way the disturbance of gonadal function in major depression may constitute a link between disturbed psychological function and poor general health.
Received for publication January 22, 1998.
Revision received November 3, 1998.
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TOP
ABSTRACT
INTRODUCTION
