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There is growing epidemiologic and clinical data that confirm progressive hypothalamic-pituitary-gonadal hypofunctioning in aging men. What role does the HPG axis play in the complex psychobiology of male sexual and affective disorders? The treatment rationale, clinical indications and risks in using exogenous testosterone for late-life depression are explored.
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Dr. Seidman is assistant professor of clinical psychiatry at Columbia University. His research focus is on the psychiatric aspects of hypothalamic-pituitary-gonadal functioning in men.Dr. Seidman has indicated he has nothing to disclose.
In contrast to women, men do not experience a sudden cessation of gonadal function comparable to menopause. However, there is a progressive reduction in male hypothalamic-pituitary-gonadal (HPG) axis function: Testosterone levels decline through both central (pituitary) and peripheral (testicular) mechanisms, and there is a loss of the circadian rhythm of testosterone secretion. Age-associated HPG axis hypofunctioning, which has been termed
, is thought to be responsible for a variety of symptoms experienced by elderly men, such as reduced muscle and bone mass, fatigue, sexual dysfunction (including erectile dysfunction [ED] and loss of libido), and depression. Although it has been difficult to establish correlations between these symptoms and plasma testosterone levels, there is some evidence that testosterone replacement in middle-aged men leads to symptom relief, particularly with respect to muscle strength, bone mineral density and sexual dysfunction. There is, however, limited evidence of a link between HPG axis hypofunctioning and depressive illness, and exogenous androgens have not been consistently shown to be antidepressant. This article reviews the relationship between androgens, depression and sexual function in aging men.
Background on HPG Axis Function in Aging Men
The gonads and adrenals secrete several male sex hormones called androgens. All are steroid hormones (i.e., derived from cholesterol and containing a basic skeleton of four fused carbon rings). Produced primarily in the Leydig cells, testosterone is the most potent and abundant androgen. Approximately 98% of testosterone molecules are protein-bound. Of this, about one-third are weakly bound to albumin, and the remainder is tightly bound to sex hormone-binding globulin. Free testosterone diffuses into target cells, where it is converted to dihydrotestosterone (DHT) and estradiol. Testosterone and DHT bind to the androgen receptor.
Symptomatic hypogonadism is generally diagnosed when the total testosterone level falls below a certain threshold, assumed by clinical consensus to be between 200 ng/dL and 300 ng/dL. Sequelae of testosterone deficiency include reduced musculoskeletal mass, increased adipose deposition and sexual dysfunction (Vermeulen, 2003; Villareal and Morley, 1994). Exogenous testosterone replacement consistently reverses these sequelae: body weight, fat-free muscle mass, muscle size and strength increase; continued bone loss is prevented; and sexual function and secondary sex characteristics (e.g., facial hair) are restored and maintained (Burris et al., 1992; Luisi and Franchi, 1980; Villareal and Morley, 1994).
Male HPG function declines progressively with age, and a substantial proportion of men older than 50 have testosterone levels below the threshold values used to define testosterone deficiency in younger men. Mild testosterone deficiency in elderly men can, therefore, be considered physiological (i.e., a para-aging phenomenon) or pathological (i.e., a deficit state). Since age-adjusted norms are not used, it is treated as pathological. Yet, even if it is considered physiological, this "normative" decline may be clinically significant, as it is with the age-associated decline in female gonadal hormones.
Whether the age-dependent decline in androgen levels leads to health problems in men is being debated vigorously (McKinlay et al., 1989; Morales et al., 2000; Seidman, 2003). Some investigators argue that age-associated testosterone deficiency is responsible for many of the typical signs of male aging, such as ED, decreased lean body mass, skin alterations, osteoporosis and increased visceral fat; as well as for neuropsychiatric problems, such as fatigue, loss of libido, depression, irritability, insomnia and memory impairment (Morales et al., 2000). Furthermore, the application of a testosterone replacement strategy for older men with low or low-normal testosterone levels is thought by some investigators to be especially promising for reversing such presumed "andropausal" sequelae (Morley, 2000). Yet, it has not only been difficult to correlate hormone levels with these age-related phenomena (McKinlay et al., 1989; Morales et al., 2000; Seidman, 2004), but testosterone replacement in elderly men is not especially effective in reversing these symptoms (Snyder et al., 1999a, 1999b). Although testosterone replacement in elderly men has been demonstrated to enhance upper limb strength (Bakhshi et al., 2000; Sih et al., 1997) and mass (Snyder et al., 1999b), improve bone mineral density (Snyder et al., 1999a), increase hematocrit (Hajjar et al., 1997), and reduce leptin levels (an effect that may improve visceral adiposity) (Sih et al., 1997), such effects appear to be weak and of questionable clinical significance. Moreover, there are few testosterone replacement studies in which psychiatric symptoms of mild hypogonadism have been considered in elderly men. Indeed, a report by the Board on Health Sciences Policy and the Institute of Medicine (2004) provides a comprehensive overview of these issues and has helped to better focus the research agenda regarding age-related testosterone deficiency.
Male HPG Axis: Androgens and Sexual Function
Gonadal steroids are necessary for mating in most mammals. In all male mammals studied, a dramatic reduction in sexual activity occurs in parallel to testosterone depletion (either via surgical ablation of the testes or through seasonal regression) (Davidson and Rosen, 1992). Castration is typically followed first by loss of ejaculation, then intromission and finally mounting; androgen replacement (peripherally or via intracerebral implant) restores these sexual behaviors in reverse order (Davidson and Rosen, 1992). Although among humans the role of testosterone in the maintenance of male sexual function is more complex, a large body of evidence supports a strong influence. For example, increasing plasma androgens at puberty is correlated with the onset of nocturnal emission, masturbation, dating and infatuation (Kemper, 1990), and free testosterone is correlated with sexual thoughts (Meston and Frohlich, 2000). Males with an early onset of androgen secretion (i.e., precocious puberty) often develop in parallel an early interest in sexuality and erotic fantasies (Feder, 1984). Hypogonadism is characterized by loss of libido and a loss in sleep-associated and spontaneous erections; testosterone replacement leads to a dramatic increase in sexual desire, sexual activity and frequency of erections (Anderson et al., 1992). Finally, suppression of testosterone secretion in eugonadal men leads to reduced sexual desire and activity, and a decrease in spontaneous and fantasy-driven erections (though it has no demonstrable effect on erectile response to erotic film [i.e., externally driven erections]) (Bagatell et al., 1994; Davidson and Rosen, 1992; Rosler and Witztum, 1998).
Testosterone levels in eugonadal men exhibit a wide inter-individual variability and do not generally correlate with sexual desire or performance. The clinical consensus has been that among men, there is a "low testosterone threshold" (which may vary from person to person) below which there is impairment of some aspects of sexual functioning (e.g., internally driven erections). However, such a threshold is not well established (Kelleher et al., 2004).
Male HPG Axis and Depression
Testosterone and mood. There appears to be a clinical consensus among andrologists that testosterone replacement enhances mood in hypogonadal men (Morley, 2001; Vermeulen, 2003). Yet, until recently, few testosterone replacement studies considered mood as an outcome to be systematically measured. Two influential clinical trials did include self-reported mood assessments during testosterone replacement (McNicholas et al., 2003; Wang et al., 2000). In both, investigators demonstrated that compared to hypogonadal baseline, testosterone replacement was associated with improved mood and "well-being," and reduced fatigue and irritability. Notably, Wang et al. (2004) reported that in the 123 men followed on testosterone replacement for three years, improvements in mood persisted. No placebo controls (or placebo substitutions) were included in these studies, leaving the question open as to whether the reported mood improvements might have been equally detectable in a placebo group of hypogonadal men who thought they might be receiving testosterone.
Indeed, a negative picture emerges from the only two placebo-controlled testosterone replacement studies in which mood was systematically assessed (Sih et al., 1997; Steidle et al., 2003). Neither had a testosterone-placebo difference distinguishable with respect to mood.
For example, Steidle and colleagues (2003) randomized 99 hypogonadal men to placebo and 307 hypogonadal men to different doses of testosterone replacement. Patients rated positive moods (alert, full of energy, friendly, well or good) and negative moods (angry, irritable, sad or blue, tired, nervous) on a 0-to-7 categorical scale. The one sentence describing the mood results is the following: "Although all treatments resulted in mean improvements from baseline in both positive and negative mood scores, no significant differences among the treatment groups were observed."
In a well-designed experiment, Schmidt et al. (2004) examined the mood effects of a one-month suppression of testosterone secretion with Lupron (leuprolide), followed by double-blind, placebo-controlled testosterone replacement in 31 healthy men. They demonstrated that overall there was a minimal effect of induced testosterone deficiency on mood.
Investigators have also used population-based studies to examine the relationship between testosterone level and depressive symptoms. The Massachusetts Male Aging Study (MMAS) was a community-based sample of men ages 40 to 70 (n=1,709) (Araujo et al., 1998). Participants completed a self-report depression inventory--the Center for Epidemiologic Studies Depression Scale (CES-D)--and provided a morning blood sample for hormone measurement. In a multiple logistic regression analysis, serum testosterone levels were not associated with depression diagnosed with CES-D.
However, in a follow-up analysis of these data, Seidman et al. (2001a) included data regarding an androgen receptor (AR) genetic polymorphism. The AR gene has a polymorphic CAG repeat sequence whose length is inversely correlated with transactivation; inverse relations have been described between the number of CAG triplets in the AR gene and the risk of prostate cancer (Nelson and Witte, 2002). In the MMAS cohort there was a significant interaction between AR CAG repeats, testosterone level and CES-D scores, suggesting that these HPG axis state and trait features may interact to produce depressive symptoms. That is, whereas neither testosterone level nor AR isotype alone were associated with depression as defined by CES-D, in a model using all three variables, AR isotype and testosterone together predicted depression (significant effect for the interaction term) (Seidman et al., 2001a). Thus, this AR trait marker may define a vulnerable group in whom depression is expressed when testosterone levels fall below a particular threshold. A similar vulnerability based on the interaction of these HPG markers has recently been described with regard to risk for Alzheimer's disease (Lehmann et al., 2004).
In the Rancho Bernardo Study, adult residents of a Southern California community were enrolled in a study of heart disease risk factors (Barrett-Connor et al., 1999). In a 10-year follow-up study that included 82% of the surviving community residents, 856 men ages 50 to 89 (mean age=70) completed the Beck Depression Inventory (BDI) and had a morning blood sample drawn for hormone assays. Multiple linear regression analysis revealed a significant inverse correlation between BDI score and bioavailable, but not total, testosterone levels (p=0.007). That is, men with lower free testosterone levels had higher BDI scores, which is indicative of increased depressive symptoms.
Testosterone and clinical depression. Neuroendocrine studies of HPG axis functioning among men with major depressive disorder (MDD) have been cross-sectional (i.e., mean testosterone levels in a group of men with depression are compared with a group of nondepressed control participants); and longitudinal, in which testosterone levels during acute depressive illness are compared with hormone levels after remission. Findings from such studies have been inconsistent, except for the demonstration that early morning luteinizing hormone (LH) and testosterone release is blunted in men with melancholic depression (Rupprecht et al., 1988; Schweiger et al., 1999). Overall, comparable numbers of studies have demonstrated lower testosterone levels in men with depression versus controls as have those showing no difference in testosterone levels between depressed versus controls; none have demonstrated higher testosterone levels in the depressed state (Seidman, 2003). Inconsistencies in this literature may be due to small sample sizes, different diagnostic assessments of depression, and heterogeneity in depressive symptoms or diagnoses in different study samples. There is also likely to be considerable diurnal, seasonal, situational and age-related variability in HPG axis functioning from study to study. However, data are most consistent with the interpretation that there is virtually no functional effect of MDD on the male HPG axis.
Clinical data suggest that the normative age-related decline in testosterone level, persisting over years, may lead to a chronic, low-grade, depressive illness such as dysthymia, but not to MDD. In a sample of elderly men with depression who presented to a geriatric depression clinic, Seidman et al. (2002) demonstrated that the median total testosterone level in 32 men with dysthymia (295 ng/dL; range=180 ng/dL to 520 ng/dL) was significantly lower than that of 13 age-matched men with MDD (425 ng/dL; range=248 ng/dL to 657 ng/dL) or 175 age-matched, "nondepressed" men from the MMAS sample (423 ng/dL; range=9 ng/dL to 1,021 ng/dL). Notably, 56% of the elderly men with dysthymia had testosterone levels in the hypogonadal range (≤300 ng/dL).
Two epidemiological studies provide indirect support for the hypothesis that the testosterone-mood relationship is curvilinear. In a study completed in Belgium, Delhez et al. (2003) evaluated morning hormone levels and self-reported psychiatric symptoms in 153 men ages 50 to 70. They found that free testosterone was negatively correlated with a Carroll rating scale (CRS) for depression score (r=0.17, p=0.04). Yet, when 25 frankly depressed participants (CRS=15) were removed from the analysis, the association was stronger (r=-0.33, p
In the Veterans' Experience Study, a representative sample of Vietnam War veterans (mean age=38) were administered the Diagnostic Interview Schedule (DIS) and provided morning blood samples for testosterone assay (Booth et al., 1999; Dabbs et al., 1990). Booth et al. (1999) demonstrated that the relationship between testosterone level and depression was nonlinear: Below 600 ng/dL, men with lower testosterone levels were more likely to be depressed whereas above 600 ng/dL, men with higher testosterone levels were more likely to be depressed.
Exogenous Testosterone Administration
Nondepressed men. Testosterone has variable effects on mood. In most clinical trials in which exogenous testosterone was administered to nondepressed eugonadal men at physiological and moderately supraphysiological doses, significant effects on mood were not detected. For example, Tricker et al. (1996) randomized 43 eugonadal men ages 19 to 40 to double-blind treatment with intramuscular injections of either testosterone 600 mg or placebo weekly for 10 weeks. The researchers found no change in self- or observer-reported measures of hostility, anger or mood during testosterone treatment. Matsumoto (1990) randomized 51 young men to received placebo or testosterone 25 mg, 50 mg, 100 mg or 300 mg, intramuscular (IM), weekly for six months. Janowsky et al. (1994) randomized 56 elderly men to receive testosterone or placebo patches for three months. In both studies, there were no differences between testosterone and placebo groups in self-reported measures of mood.
Administration of supraphysiological doses of testosterone to eugonadal men has been associated with mania in a small proportion of men. For example, Yates et al. (1999) administered testosterone (100 mg/week, 250 mg/week or 500 mg/week) for 14 weeks to 18 men; one participant became manic. Su et al. (1993) administered methyltestosterone or placebo for a short time (three days of 40 mg/day then three days of 240 mg/day) to 20 eugonadal men; one man became manic and one hypomanic. Notably, overall change in aggressiveness (i.e., anger, violent feelings and irritability) was correlated with the change in free thyroxine (T4) (r=0.5, p=0.02); changes in total testosterone correlated only with changes in specific cognitive functions (i.e., forgetfulness and distractibility) (r=0.52, p=0.02) (Daly et al., 2003).
In a double-blind study, Pope et al. (2000) enrolled 66 men (age range=20 to 50) who did not have psychiatric histories to receive testosterone in doses rising to 600 mg per week or matching placebo for six weeks, followed by a six-week no-treatment period, and then cross-over to the alternate treatment. They found that testosterone administration significantly increased the mean manic score on the Young Manic Rating Scale (YMRS) (p=0.002) and on daily diaries (p=0.003), the "like the way I feel" score on daily diaries (p=0.008), and aggressive responses on the Point Subtraction Aggression Paradigm (PSAP) (p=0.03). Notably, two participants became markedly hypomanic (YMRS=20) after testosterone administration.
There are also well-controlled studies of testosterone administration to eugonadal men with sexual dysfunction (Benkert et al., 1979; O'Carroll and Bancroft, 1984; Schiavi et al., 1997). In general, they have demonstrated that administration of physiologic doses of testosterone: 1) is no more effective than placebo for ED; 2) may lead to a modest increase in sexual interest in some men; and 3) does not have a demonstrable effect on mood. For example, Schiavi et al. (1997) enrolled 18 eugonadal men (age range=46 to 67) who presented with the chief complaint of ED in a double-blind, placebo-controlled, cross-over study of testosterone 200 mg or placebo biweekly for six weeks. They found that during the testosterone compared to placebo phase: ejaculatory frequency doubled; other measures of sexual arousal increased, but this was not statistically significant; erectile function and sexual satisfaction were unaffected; and mood, assessed by self-report instruments, was unaffected. Most participants could not correctly identify the phase in which they received testosterone and felt it was not helpful. Notably, the authors were unable to demonstrate that this schedule of testosterone administration led to an increase in circulating levels two weeks after each IM injection--suggesting that this dose may have been too low to override the compensatory feedback mechanisms operating in eugonadal men.
O'Carroll and Bancroft (1984) administered testosterone to men with ED (n=10) and hypoactive sexual desire (n=10). There was no demonstrable effect of testosterone on erectile function and a clinically significant effect on desire in only three patients in the low-desire group. Carani et al. (1990) administered testosterone to 14 men with sexual dysfunction and demonstrated it to be helpful only for those who were mildly hypogonadal. Finally, Anderson et al. (1992) randomized 31 eugonadal men to receive weekly testosterone 200 mg IM for eight weeks or weekly placebo for four weeks followed by weekly testosterone 200 mg IM for four weeks. A significant effect of testosterone was demonstrated on the Psychosexual Stimulation Scale of the Sexual Energy Scale (SES 2), which measures the extent to which an individual seeks sexual stimuli. There was no effect on measures of sexual behavior, including intercourse frequency, erectile function or masturbation, and no apparent effect on mood. Overall, the data suggest that in eugonadal men, exogenous androgen treatment has no effect on erectile dysfunction but may help hypoactive desire. In hypogonadal men, androgen replacement clearly improves desire and some aspects of erectile functioning. It is not known whether mild, age-related HPG hypofunctioning is associated with any sexual dysfunction, and if it is, whether androgen replacement is effective.
Depressed men. Reports from the older psychiatric literature (1935-1960) on the "antidepressant" effects of testosterone suggested that a substantial number of "depressed" men responded immediately and dramatically to hormone replacement therapy and subsequently relapsed when treatment was discontinued (Seidman and Walsh, 1999). However, standardized, syndromal, psychiatric diagnoses were not used in these studies, and baseline testosterone levels were not assessed. Moreover, the lack of a control group prevents considering such results any more than promising.
More recent anecdotal reports have suggested that in some hypogonadal men, comorbid MDD remits with testosterone replacement (Ehrenreich et al., 1999; Heuser et al., 1999; Rinieris et al., 1979) or augmentation to partially effective antidepressant treatment (Seidman and Rabkin, 1998) and that in hypogonadal, HIV-infected men, testosterone replacement is associated with improved mood, libido and energy (Grinspoon et al., 2000; Rabkin et al., 2000). Based on such reports, it had been assumed that testosterone replacement in hypogonadal men with MDD would conform to the "hypothyroid" model (i.e., hormone axis normalization as an effective antidepressant). Systematic study suggests that this is not the case.
In the past two decades there have been at least 10 published studies of androgen treatment for men with depression in which investigators used criteria for MDD from the DSM and systematically followed depressive symptoms. Many used the oral androgen mesterolone, which is a derivative of DHT and therefore lacks testosterone's non-DHT actions (i.e., testosterone-specific and estrogenic activity).
In a double-blind, randomized clinical trial of testosterone replacement versus placebo in 30 men with MDD and hypogonadism, Seidman et al. (2001b) found testosterone replacement indistinguishable from placebo in antidepressant efficacy: 38.5% responded to testosterone, and 41.2% responded to placebo. However, a more recent study of testosterone replacement as an augmentation to antidepressant partial response suggested that this strategy may be more promising (Pope et al., 2003), though our recent findings do not support this (Seidman et al., in press). Overall, although initial anecdotal reports have been favorable, systematic trials of androgen replacement for depression have provided little support for its efficacy. Currently, treatment of depression with testosterone, either as replacement (i.e., in hypogonadism) or as an antidepressant supplement, should be considered experimental.
See Table 1 and Table 2 for studies that evaluated depressive symptoms in eugonadal and hypogonadal men treated with exogenous androgens. (Due to copyright concerns, the tables cannot be reproduced online. Please see pp83-84 in the print edition--Ed.)
Exogenous Testosterone: Clinical Considerations
Exogenous testosterone, even at supraphysiological doses, rarely produces side effects, though there is a remote risk of developing gynecomastia (i.e., breast tenderness and breast enlargement), truncal acne (particularly for those with a history of acne), hair loss or hair growth, and/or weight gain. Since there is always a modest increase in hematocrit, complete blood count (CBC) should be checked pre-treatment and followed (Rolf and Nieschlag, 1998; Seidman and Roose, 2000). Via the negative feedback mechanism, exogenous testosterone suppresses LH and follicle-stimulating hormone (FSH), which leads to reduced testicular sperm production and, consequently, reduced testicular volume. Since mania and hypomania have been precipitated by testosterone administration (Pope et al., 2000; Yates et al., 1999), bipolar disorder should be considered a relative contraindication.
The primary concern regarding potential adverse effects of testosterone treatment is related to the prostate gland. Androgens play a permissive role in the growth of prostate cancer and benign prostate hyperplasia (BPH); however, there are no data to indicate that testosterone administration can lead to the progression of preclinical prostate cancer or to worsening BPH (Rolf and Nieschlag, 1998). Prostate cancer is an absolute contraindication to treatment with exogenous testosterone and should be excluded in all men older than 50 (or 40 if a positive family history of prostate cancer) via pretreatment prostate-specific antigen (PSA) and digital rectal exam of the prostate (Rolf and Nieschlag, 1998).
Delineation of the role of the HPG axis in the psychiatric problems of aging men may be of substantial public health importance. The sequelae of age-related gonadal hypofunction in women (i.e., menopause) are well characterized and substantial. Yet, there is no parallel characterization of the psychophysiology of age-related male hypogonadism, despite potential implications for the treatment of psychiatric and sexual problems in this population. Future research should focus on the central nervous system effects of mild age-related HPG axis hypofunctioning with an emphasis on mild mood problems (e.g., dysthymia), mild cognitive impairment and sexual dysfunction.
The author wishes to thank Steven P. Roose, M.D., for his valuable contributions to this work, and Donald F. Klein, M.D., for his review of an earlier version of the manuscript; and the Partnership for Gender-Specific Medicine and the National Institutes of Mental Health for salary support, GRANT No. MH01740.
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