Androgens and the Aging Male: A Review of Testosterone Deficiency and Its Effects
Author: Stuart N. Seidman, MD, Department of Psychiatry, College of Physicians and Surgeons, Columbia University; New York State Psychiatric Institute, New York.
Peer Reviewer: Laurence M. Demers, MD, Distinguished Professor of Pathology and Medicine, The Pennsylvania State University, MS Hershey Medical Center, Hershey.
This issue of Psychiatric Medicine Reports addresses the neglected but vital area of male hormones and their effect on the aging male. There is a large, growing body of literature on the effect of female hormones on the emotional and general medical health of women. Clinicians are becoming increasingly comfortable addressing psychiatric problems at various stages of the female life cycle with some understanding of how hormone therapy may have a role in treatment. For example, there are now specific therapies for premenstrual dysphoric disorder (PMDD), and some psychiatrists are using hormone replacement therapy to augment antidepressant therapy in postmenopausal women.
There is little attention paid to hormone changes in the male life cycle and how they relate emotional health, however. Most health care professionals are familiar with low testosterone affecting libido and sexual performance. However, few clinicians have an understanding of how testosterone levels may effect moods and behavior. Furthermore, little is known of the phenomenon of andropause that the author addresses in this issue. With an aging population and male patients becoming more open to receiving psychiatric intervention, this is an issue providers are more likely to encounter. Also of concern are the high rates of successful suicides in older men.
We now have highly effective and easier to administer pharmaceutical agents to deliver testosterone. Should clinicians be treating the aging male who has a psychiatric presentation with testosterone or other hormone therapy? Is there sufficient evidence to believe there is a menopause equivalent in men that has serious clinical implications for patients’ health?
The author is an acknowledged thought leader in this area and has written a thorough overview on the physiology of androgens and male hormone effects on mental and general health. He also gives a comprehensive review of the studies on the use of hormone therapy in treating psychiatric disorders in men.—The Editor
Abstract
In contrast to menopause in women, men do not experience a sudden cessation of gonadal function. 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. The progressive decline in testosterone level has been demonstrated in both cross-sectional and longitudinal studies, and overall at least 25% of men older than age 70 meet laboratory criteria for hypogonadism (i.e., testosterone deficiency). Such age-associated HPG hypofunctioning, which has been termed andropause, is thought to be responsible for a variety of symptoms experienced by elderly men, such as weakness, fatigue, reduced muscle and bone mass, impaired hematopoiesis, sexual dysfunction (including erectile dysfunction 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 leads to symptom relief, particularly with respect to muscle strength, bone mineral density, and erectile dysfunction. There is little evidence of a link between the 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.
Introduction
It long has been recognized that androgens exert potent pro-sexual effects, particularly in men. In the now-classic studies performed by Berthold in the mid-19th century, he demonstrated that implantation of testes into the abdominal cavity of castrated roosters restored the sexual behaviors that had disappeared following castration. He postulated that a blood-borne substance, acting on the brain, must be responsible.1 Modern endocrinological investigations have confirmed the role of gonadal steroids, particularly androgens, in the coordination of sexual behavior with physiologic events in the body related to fertility. Over the past century, androgens frequently have been used empirically to enhance sexual functioning.2,3 The role of the age-related HPG axis hypofunctioning in the development central nervous system (CNS) sequelae remains largely unexplored.
Androgen Physiology
The gonads (i.e., testes in males, ovaries in females) 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). Testosterone (T) is the most potent and abundant androgen. Gonadotropin-releasing hormone (GnRH) from the hypothalamus promotes anterior pituitary release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In males, LH stimulates the interstitial cells of Leydig in the testes to synthesize and secrete T; approximately 7 mg of T are secreted daily. Secretion occurs in pulsatile bursts, about six per day, with a morning peak and an early evening trough, and is regulated through a negative feedback on the hypothalamus and pituitary.4
In the circulation, approximately 98% of T molecules are protein-bound. Of this, about one-third are weakly bound to albumin, and the remainder are tightly bound to sex hormone-binding globulin (SHBG). SHBG, a beta-globulin produced primarily in the liver, consists of different protein subunits and one androgen binding site. Fluctuations in SHBG levels affect the bioavailability of T. In target cells, T is converted to two active metabolites: dihydrotestosterone (DHT) and estradiol (E2). There is tissue variability in the concentration of the cytoplasmic enzymes required for this conversion,5 alpha-reductase and aromatase, respectively, and differential tissue sensitivity to each of these metabolites. Both T and DHT bind to the androgen receptor (AR); estradiol binds to the estrogen receptor.5 The steroid-receptor complex binds to specific sequences of genomic DNA, which thereby influences messenger RNA production and modulates synthesis of a wide array of enzymatic, structural, and receptor proteins.4 T also influences cellular activity in a nongenomic manner through activation of membrane receptors, second messengers, and the membrane itself. Such nongenomic actions appear to be especially important in the CNS.6
Androgen Actions
During the male embryonal stage, T is responsible for the growth of the penis and scrotum, development of the prostate and seminal vesicles, descent of the testes, and suppression of the development of female genitalia.4,5 The T surge of puberty causes the genitalia to enlarge about eight-fold, promotes the development and maintenance of secondary sexual characteristics, and supports anabolic activity.
Androgen-sensitive physiological effects occur at multiple levels, including metabolic processes, peripheral tissues (e.g., the penis and clitoris), the spinal cord, and the brain.1 Testosterone affects hair distribution (including baldness); stimulates prostatic secretion and growth; masculinizes the larynx and the skin; promotes protein anabolism, leading to muscular development, bone growth, calcium retention, and an increase in basal metabolic rate; and increases red blood cell production and hemoglobin synthesis.4,5
The sexual effects of T include perinatal organizing effects and post-pubertal activating effects. It has been established in many mammalian species that T, acting during a brief critical developmental period, permanently alters brain structure and function.1,4,5 Such organizing effects lead to behavioral predispositions in the setting of later re-exposure to T (i.e., T-sensitive neural networks are "wired"). This has been demonstrated most clearly in rodents. For example, perinatal androgen exposure of female rats leads to masculinized sexual, aggressive, and exploratory behavior post-pubertally (particularly when activated by T), and loss of the female pattern of gonadotropin secretion. In humans, prenatal exposure of female fetuses to excessive androgens (as a consequence of congenital adrenal hyperplasia) is associated with the development of male-like play behavior during childhood, male-like sexual imagery and preferences in adulthood, and more aggressive behavior compared to female relatives.7
Age-Related HPG-Axis Changes
In 1991, Gray and colleagues conducted a meta-analysis to evaluate the literature on the age-related changes in T levels among men.8 The analysis was designed to determine the source of discrepancies among previous studies and included the evaluation of sample characteristics (i.e., selection, health status, and medication usage) and design characteristics (i.e., time of blood sampling, hormone assessment technique, and hormone assessment quality). Of the 88 articles evaluated, 44 met specific rigorous inclusion criteria for predefined subgroups. The mean subgroup size was 25 subjects, and the average mid-age was 56 years. There were 12 subgroups with mean ages older than 80 years, and more than 75% of these subgroups were composed of subjects who had comorbid illnesses and were taking medications. One hundred fifty-seven mean T levels were obtained from the subgroups. Most sub-groups were comprised of samples drawn in the morning and assessed using radioimmunoassay. The overall weighted mean testosterone level was 479 ± 1.2 ng/dL; however, levels varied considerably depending on the sample and methodological characteristics examined. (See Table.) Likewise, general linear modeling revealed a significant relation between testosterone level and age (R2 = 0.29; p < .0001) and that some of the sample and methodological variables, including patient selection, health status, time of blood sampling, and type of hormone assessment, significantly affected this relationship. (See Table.) Finally, in a multiple regression analysis, the best predictors of both T level (i.e., higher) and the slope of the age-related decline (i.e., steeper) were good general health and morning serum sampling.
Similar results have been reported from a cross-sectional study of Austrian men age 20-89 years (N = 526), which demonstrated a gradual reduction in T level. The extent of the decline depended on health status; total T and free T levels were higher among men in the "super-healthy" group compared with their age-matched counterparts in less healthy groups.9 Finally, in two large longitudinal studies that assessed T levels in middle-aged men for 8-10 years, both demonstrated that the within-subject decline was even steeper than the cross-sectional declines (i.e., 1-3% reduction per year).10,11 Overall, these findings confirm that T level declines with age. The clinical significance of this decline remains an area of great controversy, particularly with regard to potential psychiatric sequelae of hypogonadism, such as depression.
Andropause
Proponents of the view that this condition exists assert that symptoms of testosterone deficiency are similar to those of the aging process itself: decreased musculoskeletal mass, increased adipose deposition, decreased hematopoiesis, decreased facial hair growth, and decreased libido, energy, mood, and memory.12,13 For support, they cite the established lore that testosterone replacement consistently reverses such sequelae in younger hypogonadal men (i.e., age 20-60): body weight, fat-free muscle mass, and muscle size and strength increase; continued bone loss is prevented; sexual function and secondary sex characteristics (e.g., facial hair) are restored and maintained; and hematocrit increases.14,15 Therefore, they contend, application of a testosterone replacement strategy for older men with low or low-normal androgen levels is capable of reversing the aging effects on bones and muscle mass, as well as enhancing mood, energy, cognition, and libido.16 Yet it has been difficult to correlate hormone levels with such age-related phenomena.13,17 Moreover, there are only limited controlled data on the effects of testosterone replacement in elderly men,18,19 and none that address psychiatric symptoms in this age group. Specific studies in aging men are particularly important, since age-related testosterone deficiency generally is more modest than the profound hypogonadism seen in the testosterone replacement trials with younger men.
Dehydroepiandrosterone
Dehydroepiandrosterone (DHEA) and its metabolite, DHEA sulfate (together abbreviated DHEAS), and androstenedione are the major androgenic steroids secreted by the adrenal cortex. Although not potent androgens themselves, they are converted in target organs to testosterone and dihydro-testosterone (DHT). This is likely of significant androgenic consequence in females.20 DHEAS also is produced in situ in brain tissue, and hence is termed a neurosteroid.21
Plasma and cerebrospinal fluid (CSF) DHEAS levels decline with age: at age 70, DHEAS levels are about 20% of those at age 20.20 In an eight-year, population-based longitudinal study, DHEAS levels declined 5.2% per year in middle-age men.10 Many, but not all, studies have reported lowered levels of DHEAS or lowered ratios of DHEAS-to-cortisol in patients with depression, chronic fatigue syndrome, post-partum depression, and anxiety.20 Similarly, in many population-based studies of the elderly, DHEAS level has been positively correlated with cognitive and general functional abilities, and negatively associated with mortality. Some investigators have, therefore, proposed DHEAS as a marker of successful aging.20,22 There is speculation that DHEAS buffers the deleterious effects of excessive glucocorticoid exposure. For example, it has been shown to prevent or reduce hippocampal neurotoxicity induced by the glutamate agonist N-methyl-D-glucamide (NMDA), corticosterone, and oxidative stressors. Overall, accumulating descriptive and epidemiological data suggest a relationship between DHEAS levels and functional abilities, memory, mood, and sense of well-being, though there are many inconsistencies in the literature.
Treatment studies to date—typically involving short treatments with DHEA—demonstrate that this treatment generally is well-tolerated and not associated with significant changes in physical examination, hepatic, thyroid, hematologic, and/or prostatic function. Relatively common side effects include acne, oily skin, nasal congestion, and headache. Less commonly reported side effects include insomnia, over-activation (including disinhibition, aggression, and mania), hirsutism, increased body odor, itching, irregular menstrual cycles, and voice deepening.20
Androgens and Male Sexual Function, Mood, and Age
Neuropsychiatric Effects of Testosterone. T’s influence occurs at multiple levels: metabolic processes, peripheral (particularly genital) tissues, the spinal cord, and the brain.6 Non-specific metabolic effects (e.g., increased hematocrit and anabolism) and/or stimulatory effects on genital tissue indirectly could influence neuropsychiatric functioning (e.g., via increased general arousal). Specific CNS activation occurs via binding of androgen receptors by testosterone or DHT, estrogen receptors by estradiol, and through membrane-associated actions.23
Sexual Function. Experimental evidence has demonstrated that androgens directly influence sexual behavior in mammals, including non-human primates. These direct effects appear to be more influenced by social factors in primates. For example, in a multi-male group of rhesus macaques (Macaca mulatta), castration leads to an immediate reduction in sexual behavior; in a single-male-multiple-female group, post-castration sexual behavior declines after one month; and in a male-female pair, reduced sexual activity does not occur until two months after T suppression.24 In human males, direct behavioral effects of androgens are less apparent, and likely to be even more influenced by social factors.
In all male mammals studied, there is a dramatic reduction in sexual activity following the removal of T by either surgical ablation of the testes or through seasonal regression.25 In most male mammals, castration is followed first by loss of ejaculation, then intromission, and finally mounting; androgen replacement restores these sexual behaviors in reverse order. Although among humans the role of T 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. Males with an early onset of androgen secretion (i.e., precocious puberty) often develop in parallel an early interest in sexuality and erotic fantasies.26 Post-pubertal onset of hypogonadism is characterized by loss of libido and lack of vigor, and a loss in sleep-associated and spontaneous erections.27 T replacement in hypogonadal men leads to a dramatic increase in sexual desire, sexual activity, and frequency of erections.28 Finally, suppression of T secretion in eugonadal men leads to reduced sexual desire and activity, and a decrease in spontaneous and fantasy-driven erections, though no decrease in erectile response to erotic film (i.e., externally driven erections).29,30 Notably, T levels in eugonadal men generally do not correlate with sexual desire or performance, though studies have been inconsistent. The clinical consensus has been that among men there is a low T-threshold (which may vary from person to person), below which some aspects of sexual function are impaired, particularly internally driven erections and arousal.
Depression. The psychiatric symptoms of hypogonadism overlap with symptoms of depression, and include low libido, fatigue, loss of confidence, and irritability.31 Initial interest in this relationship has focused on whether men with major depressive disorder (MDD) have HPG abnormalities. However, most studies that assessed this relationship have been methodologically flawed. Specific limitations include the following: 1) endocrinological studies of hypogonadal men have not included methodologically rigorous neuropsychiatric assessments; and 2) the few psychiatric studies in which HPG axis functioning was assessed in men with MDD generally have not used rigorous endocrinological methods, and have not focused on older men or on milder depressive syndromes. Overall, in most epidemiological and clinical studies that have focused on the HPG axis in men, there is limited evidence that men with MDD at any age have significant HPG dysfunction, or that a low T level gives rise to depression.32
Epidemiological Studies. There were three large epidemiological studies in which the association between measures of male HPG-axis function and depressive symptoms was examined. The Veterans’ Experience Study was comprised of a representative sample of Vietnam-era veterans (mean age, 38 years).33 Subjects were administered a structured interview for depression (i.e., Diagnostic Interview Schedule [DIS]) and provided morning blood samples for testosterone assay. Overall, testosterone level was only weakly and negatively associated with depression (r = -02). However, in a later reanalysis of these data, Booth et al showed that the relation between testosterone level and MDD was nonlinear: below 600 ng/dL, men with lower T levels were more likely to be depressed, and above 600 ng/dL, men with higher T levels were more likely to be depressed. Still, the correlations were relatively low, and the clinical significance remains unclear.
The Massachusetts Male Aging Study (MMAS) was a community-based sample of men age 40-70 years (N = 1709).34 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 T levels were not associated with ED (OR 0.92; 95% CI 0.82-1.03) or CES-D-diagnosed depression (OR 0.90; 95% CI 0.75-1.09). However, in further MMAS analyses, we included an androgen receptor (AR) genetic polymorphism. The AR gene has a polymorphic CAG repeat sequence encoding a variable-length glutamine chain in the N-terminal transactivation domain of the AR protein. The length of the polymorphic CAG repeat is inversely correlated with the transactivation function of the AR, and inverse relations have been described between the number of CAG triplets in the AR gene and the risk of prostate cancer, younger age at diagnosis, and poor response to endocrine therapy. We found that in the MMAS cohort there was a significant interaction between AR CAG repeats, testosterone level, and CES-D, 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 CES-D-defined depression (i.e., CES-D ³ 16). In a model using all three variables, AR isotype and testosterone together predicted depression (significant effect for the interaction term).35 Thus, this AR trait marker may define a vulnerable group in whom depression is expressed when testosterone levels fall below a particular threshold.
Finally, in the Rancho Bernardo Study,36 adult residents of a southern California community were enrolled in a study of heart disease risk factors. In a 10-year follow-up study that included 82% of the surviving community residents, 856 men ages 50-89 years (mean age 70 years) 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 free, but not total, testosterone levels (B -0.302 ± 0.11, p = .007). That is, men with lower free T levels had higher BDI scores, which is indicative of increased depressive symptoms. This finding has not been replicated.
Clinical Studies. In young men, symptomatic hypogonadism develops when the total T level falls below a certain threshold, assumed to be 200-300 ng/dL by clinical consensus. Neuroendocrine studies of HPG-axis functioning among men with MDD have been cross-sectional (i.e., mean T levels in a group of depressed men are compared with a group of non-depressed control subjects); and longitudinal, in which T levels during acute depressive illness are compared with hormone levels after remission. Findings from such studies have been inconsistent. Comparable numbers of studies have demonstrated lower levels of T in depressed men, as have those showing no difference in plasma T levels between depressed vs. controls (although importantly, none have demonstrated higher testosterone levels in the depressed state).37 The inconsistent results may be due to a number of factors, including small sample sizes, different diagnostic assessments of depression, and heterogeneity in depressive symptoms in different study samples. There also is likely to be considerable diurnal, seasonal, situational, and age-related variability in T secretion from study to study.
In a few elaborate neuroendocrine studies, investigators have attempted to control for diurnal variability in hormone levels by using indwelling catheters to obtain multiple serum samples over 24 hours. Such labor-intensive methods have, however, had limited numbers of subjects. In one of the largest and most rigorous, Rubin, Poland, and Lesser38 enrolled 16 RDC-diagnosed depressed men (mean age 39 years) and 16 paired, age-matched controls. They assessed multiple measures of HPG functioning for 26 hours, with serum sampling every 30 minutes, and found that the T level was significantly more negatively correlated with age among depressed men (r = -0.70) than among controls (r = -0.10); and was correlated positively with DSM-III-diagnosed melancholia (r = 0.58). There were no significant correlations between T level and depressive symptoms. Schweiger and colleagues compared 18 consecutively admitted male inpatients with major depression (mean 21-item HAM-D = 29, mean age 47 years) to 22 age- and BMI-matched controls (mean age 53 years).39 They collected blood every 30 minutes, and pooled samples for analysis of 24 hour, daytime (8:00-19:30), and nighttime (20:00-7:30) T levels, as well as evening (18:00-24:00) pulsatile lutenizing hormone (LH) secretion. Compared to the control group and after controlling for age, the depressed group had a significantly lower mean total T level (p < 0.01)—particularly during nighttime hours—and a trend toward lower LH pulse frequency (p < 0.07). Finally, Steiger and colleagues40 studied 12 men hospitalized with DSM III-R major depression (mean age 46 years) with hourly serum sampling while sleeping. They demonstrated that nocturnal T secretion— particularly between 11 p.m. and 3 a.m.—was significantly lower during the acute phase than after remission.40
Some 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. In a sample of elderly depressed men who presented to our geriatric depression clinic, we found that the median total testosterone level in 32 men with dysthymia (295 ng/dL; range, 180-520 ng/dL) was significantly lower than that of 13 age-matched men with MDD (425 ng/dL; range, 248-657 ng/dL) or 175 age-matched, non-depressed men from the MMAS sample (423 ng/dL; range, 9-1021 ng/dL). Notably, 56% of these elderly dysthymic men had testosterone levels in the hypogonadal range (i.e., £ 300 ng/dL).41 These data suggest that dysthymia (and not MDD) may be the depressive illness linked to hypogonadism.
In summary, most of these HPG-depression studies were small and cross-sectional, and did not adequately control for the multi-determined variability in T level found among normals. It is possible that a sub-group of depressed men in these studies were symptomatic due to hypogonadism alone (i.e., that their depressive symptoms are sequelae of low T levels). Alternatively, blunting of T secretion might have been a consequence of a depressive symptom, such as caloric restriction (a known inhibitor of GnRH), sleep disturbance, stress, or the experience of defeat. Overall, it remains unclear whether lower T levels among depressed men represent state-dependent HPG dysfunction or artifact.
Exogeonous Androgen Administration. In 1889, Brown-Sequard reported that self-injections of the extracts of crushed animal testicles were rejuvenating, and improved "all the functions depending on the power of action of the nervous centers."3 Thereafter, thousands of men received exogenous T to reverse senescence. Although many of these treatments could not have been endocrinologically active, men who received them routinely reported improved energy, mood, and memory. In more recent years, controlled studies have demonstrated that T replacement in hypogonadal men leads to improved libido, energy, and well-being, and reduced irritability.14,31,42,43 Administration of supraphysiologic doses of T to men who have normal T levels (i.e., eugonadal men) has been inconsistently associated with elevated mood and increased sexual arousal.44 Because of such psychiatric effects of low T and excess T states, and additionally because there has been a presumed relationship between depression and low T, the use of exogenous T to treat MDD and/or depressive symptoms that evolve with age has long been used clinically.3 Yet few studies have systematically assessed the efficacy of exogenous T using modern psychiatric diagnostic criteria or accepted clinical trials methodology.
Specific methodologic limitations in existing studies include the following: 1) no investigation has addressed the neuropsychiatric or medical implications of the normative gonadal hypofunction in aging men—especially including men who do not seek medical or psychiatric treatment; 2) endocrinological studies of hypogonadal men have not included methodologically rigorous neuropsychiatric assessments; 3) the few psychiatric studies that have assessed hypothalamic-pituitary-gonadal (HPG) axis functioning in depressed men have generally not used rigorous endocrinological methods and have not focused on older men or on milder depressive syndromes; and 4) no published controlled study has evaluated the clinical utility of T for psychiatric illnesses as replacement (i.e., at physiologic doses in hypogonadal men) or as an independent psychotropic agent (e.g., as antidepressant augmentation at supra-physiologic doses) to synthesize and secrete T. Secretion occurs in pulsatile bursts, about six per day, with a morning peak and an early evening trough. Secretion is regulated through a negative feedback on the hypothalamus and pituitary.
Sexual Dysfunction. There are a few well-controlled studies of T administration to eugonadal men with sexual dysfunction.45-47 In general, they have demonstrated that administration of physiologic doses of T is: 1) no more effective than placebo for erectile dysfunction, 2) leads to a modest increase in sexual interest, and 3) does not lead to a change on self-report measures of mood. For example, Schiavi and colleagues45 enrolled 18 eugonadal men (age range 46-67 years) who presented with the chief complaint of erectile dysfunction in a double-blind, placebo-controlled, cross-over study of T 200 mg or placebo every two weeks for six weeks. They found that during the T 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.45 Most subjects could not correctly identify the phase in which they received T, and felt it was not helpful. Notably, the authors were unable to demonstrate that this schedule of T administration led to an increase in circulating levels two weeks after each intramuscular injection-suggesting that this dose may have been too low to override the compensatory feedback mechanisms operating in eugonadal men.
O’Carroll and Bancroft47 administered T to men with erectile dysfunction (n = 10) and hypoactive sexual desire (n = 10). There was no demonstrable effect of T on erectile function, and a clinically significant effect on desire in only three patients in the low-desire group. Carani and colleagues48 administered T to 14 men with sexual dysfunction and demonstrated it to be helpful only for those who were mildly hypogonadal. Finally, Anderson et al28 randomized 31 eugonadal men, single blind, to receive T 200 intramuscularly for eight weeks or placebo weekly for four weeks followed by T 200 IM weekly for four weeks. A significant effect of T was demonstrated on the psychosexual stimulation test (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.
Depression. In most clinical trials in which exogenous testosterone was administered to non-depressed eugonadal men, significant effects on mood were not detected. For example, Tricker et al randomized 43 eugonadal men age 19-40 to double-blind treatment with either testosterone or placebo injections weekly for 10 weeks. They found no change in self- or observer-reported measures of hostility, anger, or mood during testosterone treatment.49 Matsumoto and colleagues50 administered T 100 mg and T 300 mg weekly for six months to 20 young eugonadal men, and Janowsky and colleagues51 randomized 56 elderly men to receive T or placebo patches for three months. In both studies, there were no differences between T and placebo groups in self-reported measures of mood.
Reports from the older psychiatric literature (1935-1960) on the antidepressanteffects of T suggested that a substantial number of so-called "depressed" men responded immediately and dramatically to hormone replacement therapy and subsequently relapsed when treatment was discontinued.37 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 limits interpretation of the results.
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 Diagnostic and Statistical Manual of Mental Disorders and systematically followed depressive symptoms. (See Table.)
Most used the oral androgen mesterolone, which is a derivative of DHT, and therefore lacks T’s non-DHT actions (i.e., T-specific and estrogenic activity), and three used DHEA.
Itil and colleagues performed three mesterolone trials.52,53 First, they administered variable doses of mesterolone to 17 depressed men openly for three weeks, and found that eight (47%) improved, particularly in mood and anxiety level.53 Then, in a randomized, double blind, four-week trial, low dose mesterolone (i.e., 75 mg/day) or placebo was administered to 38 dysthymic men. They reported that treatment led to improvement in symptoms such as anxiety, lack of drive, lack of desire, and impaired satisfaction.53 Finally, they administered high dose mesterolone (i.e., 450 mg/day) or placebo in a six-week randomized trial to 52 men (mean age 40 years) with dysthymia, unipolar depression, and bipolar depression.52 Both the mesterolone and placebo groups improved significantly, and there was no statistically significant difference demonstrable between the two. Mesterolone treatment led to a significant decrease in LH and T levels—likely due to feedback inhibition at the hypothalamus and pituitary. Notably, of those patients who improved on mesterolone (initial drug responders, and placebo non-responders who were crossed over and responded), improvement in psychopathology was correlated positively with the decrease in T levels during weeks 3-6 of treatment.
Vogel, Klaiber, and Broverman54 administered mesterolone openly for seven weeks to 13 eugonadal men (mean age 39 years) with refractory, chronic unipolar depression. Eleven responded, most by the second week, with a mean HAM-D decrease (in these 11) from 21.1 to 5.6 (p < 0.001). The same investigators, in a 12-week randomized, double-blind trial, gave mesterolone or amitriptyline to 34 chronically depressed, eugonadal men age 27-62 years.55 Mesterolone was as effective as amitriptyline in reducing depressive symptoms; mean HAM-D score decreased by 8 in both groups.
Seidman and Rabkin56 administered T replacement to five men who had SSRI-resistant MDD and T level below 350 ng/dL. In this six-week open trial, all five achieved remission, with a mean HAM-D decrease from 19.2 to 4.0. Of the four patients who were followed after the trial, three relapsed when treatment was discontinued.
In a double-blind, randomized clinical trial of testosterone replacement versus placebo in 30 men with MDD and hypogonadism, our group demonstrated that testosterone replacement was indistinguishable from placebo in antidepressant efficacy: 38% responded to testosterone, and 41% responded to placebo.57 Notably, following the blinded phase, most non-responders received moderately supraphysiologic T (i.e., 400 mg every two weeks) in four weeks of open treatment. Four of seven (57%) non-responders to physiologic T responded to the higher dose; seven of nine (78%) of the non-responders to placebo responded to T in open treatment. However, a more recent study of testosterone replacement as an augmentation to antidepressant partial response suggests that this strategy may be more promising,58 although our unpublished findings do not support this. Overall, although initial anecdotal reports have been favorable, systematic trials of androgen replacement for depression have provided inconsistent support for its efficacy.
In summary, androgens have psychoactive properties. There is limited, though suggestive, evidence that exogenous androgen treatment has antidepressant effects in some male depressives. Such effects may be more prominent among men who are hypogonadal, though this is not well-established. In general, the evidence is too limited to evaluate whether the presumed antidepressant efficacy is related to T replacement, symptomatic improvement (e.g., increased libido or energy), or nonspecific placebo effects.
Conclusion
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. For example, the suicide rate in elderly white males triples from the sixth decade to the ninth decade; in comparable women, it remains unchanged after age 40.42 Dysthymia especially is common among elderly men, and moreover, appears to be a distinct disorder from dysthymia in young adults, and in elderly women.59 It is possible that such age-associated, male-specific psychiatric problems are related to untreated hypogonadism. Prange, in an excellent review of modern psychoendocrinology, posits that among the most compelling areas of investigation is the elucidation of the role of subclinical endocrin opathies in subthreshold mental disorders.60 The role of male hypogonadism in low-grade depression is one such area.
Future research should focus on the possible CNS 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 for his valuable contributions to this work, and gratefully acknowledges the thoughtful critiques of B. Timothy Walsh, MD; Donald F. Klein, MD; Judith G. Rabkin, PhD; Davangare P. Devanand, MD; and Harold A. Sackeim, PhD.)
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There is little attention paid to hormone changes in the male life cycle and how they relate emotional health. Most health care professionals are familiar with low testosterone affecting libido and sexual performance. However, few clinicians have an understanding of how testosterone levels may effect moods and behavior. Furthermore, little is known of the phenomenon of andropause. With an aging population and male patients becoming more open to receiving psychiatric intervention, this is an issue providers are more likely to encounter. Also of concern are the high rates of successful suicides in older men.
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