Normative hypogonadism and depression: Does 'andropause' exist?

The progressive decline in testosterone level has been demonstrated in both cross-sectional and longitudinal studies, and overall at least 25% of men over the age of 70 years 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, including sexual dysfunction and depression. Although, it has been difficult to establish correlations between 'andropausal' symptoms and plasma testosterone levels, there is some evidence that testosterone replacement leads to improvement in muscle strength, bone mineral density, and erectile dysfunction. There is little evidence of a link between HPG-axis dysfunction and depressive illness, and exogenous androgens have not been consistently shown to be antidepressant. This article reviews the relationship between androgens and depression in aging men.

Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men.

BACKGROUND: Testosterone (T) level declines progressively with age. Psychiatric symptoms of T deficiency (e.g., dysphoria, fatigue, irritability, low libido) are also symptoms of depression, and appear to be variably expressed. METHODS: We assessed independent measures of hypothalamic-pituitary-gonadal axis functioning, i.e., total T level and androgen receptor (AR) CAG repeat length (CAG RL), a genetic trait marker associated with AR function; and depression (diagnosed by above-threshold score on the Center for Epidemiologic Studies-Depression Scale [CES-D]) in 1000 men (mean age = 62.6 years; SD = 8.3) who participated in the Massachusetts Male Aging Study. RESULTS: There were 110 (11%) men with "depression" (CES-D score > or = 16) in the analysis sample. Neither total T level nor CAG RL was associated with depression in bivariate analyses. Among men with shorter CAG RLs, the percentage of men with depression was 21.6% in the lowest subgroup of total T (defined by quintiles) and 4.2% in the highest subgroup of total T. This was confirmed in simple logistic regression models with depression as the dependent variable and continuous total T as the predictor, run separately within the three CAG RL subgroups: depression was significantly and inversely associated with total T in men with shorter CAG RLs but not in men with moderate and longer CAG RLs. CONCLUSIONS: CAG isotype, a genetic trait marker of androgen receptor function, may mediate the expression of the central nervous system effects of T deficiency in men.

A review of sexual behavior in the United States.

OBJECTIVE: Knowledge of sexual behavior in the United States is necessary for 1) directing risk-reduction interventions aimed at preventing transmission of human immunodeficiency virus (HIV) and other sexually transmitted pathogens and 2) appreciating the current normative patterns of sexual behavior. METHODS: The authors reviewed American surveys that included measures of sexual behavior and analyzed the 1988-1990 General Social Surveys. RESULTS: Most American males have intercourse by 16-17 years of age, and females do so by 17-18 years of age. The majority of young adults aged 18-24 have multiple, serial sex partners. Among adults 25-59 years old, relative monogamy appears to be the norm: 80% of heterosexually active men and 90% of heterosexually active women in this age group report having had only one sex partner in the preceding year. The average frequency of intercourse among such monogamous individuals is one to three times per week. Approximately 25% of adults have had heterosexual anal intercourse. Up to 20% of adult men report that they have had a homosexual experience; 1%-6% report such an experience during the preceding year. CONCLUSIONS: Through accumulated studies, data are now available on normative sexual behavior across the life cycle. Such data should assist in psychiatric diagnosis and in the development of treatment goals that rely on assumptions regarding normative behavior. A large proportion of young heterosexual persons are at considerable risk for sexually transmitted disease. Sexual history taking and risk-reduction counseling should be integral components of psychiatric care.

Treatment of erectile dysfunction in men with depressive symptoms: results of a placebo-controlled trial with sildenafil citrate.

OBJECTIVE: Depressed men commonly have erectile dysfunction, and men with erectile dysfunction are frequently depressed. Since the etiologic and modulatory relationships between depression and erectile dysfunction have been poorly characterized, a 12-week, randomized, double-blind, placebo-controlled trial was conducted at 20 urologic clinics to evaluate the effects of sildenafil treatment in men with erectile dysfunction and mild-to-moderate comorbid depressive illness. METHOD: Men (N=152, mean age=56 years) with erectile dysfunction for > or =6 months (mean=5.7 years), a DSM-IV diagnosis of depressive disorder not otherwise specified, and a Hamilton Depression Rating Scale score > or =12 (mean at baseline=16.9) were randomly assigned to flexible-dose treatment with sildenafil citrate or matching placebo. Interviewer-rated and self-report instruments were used to assess changes in sexual function, depressive symptoms, and quality of life. Conservative criteria were used to classify erectile dysfunction treatment response and nonresponse. RESULTS: Sildenafil was strongly associated with erectile dysfunction treatment response. Fifty-eight men met the conservative criteria for response (48 given sildenafil, 10 given placebo), and 78 men did not respond (18 given sildenafil, 60 given placebo). Mean decreases of 10.6 and 2.3 in Hamilton depression scale scores were seen in treatment responders and nonresponders, respectively; 76% of treatment responders showed a > or =50% decline in Hamilton depression scale score versus 14% of nonresponders. Quality of life was similarly improved in treatment responders. CONCLUSIONS: Sildenafil is efficacious for erectile dysfunction in men with mild-to-moderate depressive illness. Improvement of erectile dysfunction is associated with marked improvement in depressive symptoms and quality of life.

Sexual activity and cardiac risk: is depression a contributing factor?

There is a well-documented association between depression, ischemic heart disease, and cardiovascular mortality. This association has a number of dimensions including: (1) depressed patients have a higher than expected rate of sudden cardiovascular death; (2) over the course of a lifetime, patients with depression develop symptomatic and fatal ischemic heart disease at a higher rate compared with a nondepressed group; and (3) depression after myocardial infarction (MI) is associated with increased cardiac mortality. Depression is also associated with sexual dysfunction, particularly erectile dysfunction. If depression is the primary illness, then erectile dysfunction can be considered a symptom of the depressive illness. However, if the erectile dysfunction is primary, men may develop a depressive syndrome in reaction to the loss of sexual function. Regardless of whether erectile dysfunction is a symptom of depression or depression is a consequence of erectile dysfunction, these conditions are frequently comorbid. Thus, the patient with ischemic heart disease who is depressed is more likely to have erectile difficulties. An attempt by this patient to engage in sexual activity is therefore more likely to be unsuccessful and, given the increase in cardiac mortality associated with depression, it may result in a serious cardiac event.

Testosterone replacement therapy for hypogonadal men with major depressive disorder: a randomized, placebo-controlled clinical trial.

BACKGROUND: Symptoms of male hypogonadism include low libido, fatigue, and dysphoria and are alleviated with testosterone replacement. The prevalence of major depressive disorder (MDD) in hypogonadal men is not known, nor is the antidepressant efficacy of testosterone replacement in depressed, hypogonadal men. METHOD: A 6-week double-blind, placebo-controlled clinical trial was conducted in 32 men with DSM-IV MDD and a low testosterone level, defined as total serum testosterone < or = 350 ng/dL. Patients were randomly assigned to receive weekly 1-mL intramuscular injections of either testosterone enanthate, 200 mg, or sesame seed oil (placebo). The primary outcome measure was the 24-item Hamilton Rating Scale for Depression (HAM-D). RESULTS: Thirty patients were randomly assigned to an intervention; 13 received testosterone, and 17 received placebo. Mean +/- SD age was 52+/-10 years, mean testosterone level was 266.1+/-50.6 ng/dL, and mean baseline HAM-D score was 21+/-8. All patients who received testosterone achieved normalization of their testosterone levels. The HAM-D scores decreased in both testosterone and placebo groups, and there were no significant between-group differences: reduction in group mean HAM-D score from baseline to endpoint was 10.1 in patients who received testosterone and 10.5 in those who received placebo. Response rate, defined as a 50% or greater reduction in HAM-D score, was 38.5% (5/13) for patients who received testosterone and 41.2% (7/17) for patients who received placebo. Patients receiving testosterone had a marginal but statistically significant improvement in sexual function (p = .02). CONCLUSION: In this clinical trial with depressed, hypogonadal men, antidepressant effects of testosterone replacement could not be differentiated from those of placebo.

Quality of life, mood, and sexual function: a path analytic model of treatment effects in men with erectile dysfunction and depressive symptoms.

Erectile dysfunction (ED) is commonly associated with depressed mood and diminished quality of life (QoL), but few studies have investigated the causal associations involved. Therefore, we evaluated the correlation between several measures of mood, QoL, and sexual function in a retrospective analysis of a sample of depressed men (n=152), with ED enrolled in a clinical trial of sildenafil citrate (VIAGRA). Strong correlations were observed at baseline among measures of erectile function (EF), mood, and overall QoL. Significant treatment effects were observed on all three domains, with significant interactions between changes in mood and QoL. Based on multiple regression and path analysis, a model was developed in which EF changes were associated with improved mood and quality of sexual life, which resulted in improved partner satisfaction, family life, and overall life satisfaction. These data suggest that QoL changes associated with ED therapy may be mediated by changes in sexual function, mood, and family relationships.

Testosterone replacement therapy for hypogonadal men with SSRI-refractory depression.

BACKGROUND: Testosterone replacement therapy is an effective treatment of some depressive symptoms in hypogonadal men, and may be an effective augmentation treatment for SSRI-refractory major depression in such men. METHODS: We treated five depressed men who had low testosterone levels and had not responded to an adequate SSRI trial with 400 mg testosterone replacement biweekly for 8 weeks. Four patients underwent single-blind placebo discontinuation. Patients were assessed at baseline and biweekly thereafter using the Hamilton Depression Rating Scale (HAM-D) and the Endicott Quality of Life Enjoyment and Satisfaction Scale (Q-LES-Q). RESULTS: Patients' mean age was 40 years, and mean testosterone level 277 ng/dl. All had a rapid and dramatic recovery from major depression following testosterone augmentation: mean 21-item HAM-D decreased from 19.2 to 7.2 by week 2, and to 4.0 by week 8; mean Q-LES-Q increased from 45% to 68%. Three of four subjects who underwent discontinuation of testosterone under single-blind placebo treatment began to relapse. CONCLUSION: Testosterone replacement therapy may be an effective treatment of depressive symptoms in some men, and warrants further research.

Predictors of high-risk behavior in unmarried American women: adolescent environment as risk factor.

BACKGROUND: Heterosexual intercourse with two or more partners in a short time period represents a high-risk behavior for acquisition and transmission of sexually transmitted pathogens (STDs). Identification of factors that may predict high-risk sexual behavior can help to focus primary prevention strategies on women at risk for future acquisition of infection. METHODS: We analyzed survey data obtained in 1988 from a nationally representative sample of 8,450 American women of reproductive age in order to identify such factors. RESULTS: Of all sexually experienced unmarried women, 6.6% reported having had two or more sexual partners in the preceding three months. Earlier age at first sexual intercourse was associated with multiple recent partners, and with lower reports of abstinence. Birth region in the West, lack of attendance at religious services as an adolescent, and having a mother who had her first child before she was 25 years of age were factors associated with multiple recent partners. Among unmarried white women having a mother who worked full time and not living with both parents during adolescence were associated with multiple recent partners; among unmarried black women, the inverse was true (p for racial difference < .05). Multivariate analysis showed western birth region and earlier age at first sexual intercourse to be significant predictors of having multiple recent sex partners. CONCLUSIONS: Early environment and race influence later sexual behavior. These factors should be considered in targeting and planning education for STD prevention.

Hormonal aspects of sexual dysfunction: the therapeutic use of exogenous androgens in men and women.

Hormones exert a pervasive influence on sexual activity. Androgens are involved in the initiation and maintenance of libido and spontaneous arousal. In recent years, the clinical use of exogenous androgens for treatment of sexual dysfunction has received a great deal of attention. Good evidence exists that such treatment is effective for arousal difficulties in men and women in the setting of a hypo-androgenic state. This article reviews the relationship between androgens and sexual function.

The relationship between depression and erectile dysfunction.

Normal sexual function is a biopsychosocial process; sexual dysfunction almost always has organic and psychologic components, and it requires multidisciplinary, goal-directed evaluation and treatment. Factors such as aging, declining testosterone levels, medical illness, certain medications, and comorbid depressive illness can contribute to sexual dysfunction. Erectile dysfunction (ED) is the most common male sexual dysfunction encountered in the clinical setting. Comorbidity between ED and depressive illness is high, but the causal relationship is unclear, and likely bidirectional. In this article, we review the existing literature on the relationship between depression and ED.

Sexual dysfunction and depression.

Sexual functioning is generally impaired during depression. Interest in the relationship between sexual dysfunction and depression has risen substantially, prompted primarily by 1) the 1998 Food and Drug Administration approval of sildenafil citrate as the first oral therapy of erectile dysfunction, and 2) the widespread clinical use of selective serotonin reuptake inhibitors, which prominently impair orgasm, and possibly libido and arousal. In this paper, we first review the phenomenology of sexual dysfunction and important contributing factors, such as age and illness, and then focus on the clinical assessment and therapeutic interventions used for sexual dysfunction in depressed individuals.

Testosterone and depression in aging men.

In men, testosterone secretion affects neurobehavioral functions such as sexual arousal, aggression, emotional tone, and cognition. Beginning at approximately age 50, men secrete progressively lower amounts of testosterone; about 20% of men over age 60 have lower-than-normal levels. The psychiatric sequelae are poorly understood, yet there is evidence of an association with depressive symptoms. The authors reviewed 1) the physiology of the hypothalamic-pituitary-gonadal axis and its changes with age in men; and 2) the evidence linking testosterone level and major depression in men. Data on this relationship are derived from two types of studies: observational studies comparing testosterone levels and secretory patterns in depressed and non-depressed men, and treatment studies using exogenous androgens for male depression. The data suggest that some depressed older men may have state-dependent low testosterone levels and that some depressed men may improve with androgen treatment.

Women with multiple sexual partners: united states, 1988.

Women who have multiple sexual partners in a short time period are appropriate targets for sexually transmitted disease (STD) prevention. We analyzed survey data collected in 1988 from a nationally representative sample of 8450 American women aged 15 to 44 to identify markers of such behavior. Among sexually active persons, 0.4% of married women and 8.4% of unmarried women had two or more sexual partners in the 3 months preceding the interview; unmarried marital status, early age at first sexual intercourse, lack of religious affiliation, and young age were associated with this behavior. All except young age were predictive after multivariate analysis. Such factors may help define women at elevated STD risk and allow better targeting of STD prevention.

High-risk sexual behavior among drug-using men.

BACKGROUND AND OBJECTIVES: Drug-using men are at high risk for acquisition and transmission of STD, presumably due to the risky behaviors practiced in environments of drug use. GOAL OF THIS STUDY: To study behaviors associated with STD transmission among drug-using men. STUDY DESIGN: Drug outreach workers distributed vouchers to self-identified drug-using men in urban Atlanta. Vouchers could be redeemed for cash at a storefront clinic where subjects provided urine for a urethritis screening test (leukocyte esterase test) and a drug screen, and were interviewed. RESULTS: Of 382 voucher recipients, 252 (66%) came to the clinic. Subjects were predominantly black (92%), homeless (70%), and aged 20 to 40 (88%). All used illicit drugs; none were currently receiving drug abuse treatment. Urine drug screen confirmed recent cocaine use in 63%, and recent opiate use in 4%. Three-fourths reported a history of STD, mostly gonorrhea. In the preceding 3 months, 14% had not had sex, 80% had sex exclusively with women, 4% had sex with both men and women, and 2% had sex exclusively with men. Of the heterosexually active men, 29% had 5 or more recent partners. Compared to other heterosexually active men, these men were more likely to always use alcohol or crack before having sex (prevalence ratio [PR] = 2.0, 95% CI = 1.3-2.5) and to drink alcohol every day (PR = 2.0, 95% CI = 1.2-3.3). Daily crack use was associated with choosing partners at elevated STD risk; daily alcohol use with having more partners. Positive drug screen for cocaine was associated with self-reported crack use. Urethritis, detected in 16%, was not correlated with behavior. CONCLUSION: A substantial number of drug-using men practice high-risk sexual behavior and should be targeted for intervention. Monetary and other incentives should be considered for recruitment. Further study is needed to clarify the relationship between sexual behavior, cocaine use, and STD.