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Depression and hypogonadism are associated with erectile dysfunction (ED) and are common in elderly men. Would you describe recent research that explores the relationship between these comorbid conditions and discuss the clinical implications of screening and testosterone therapy?

Response by Antoine A. Makhlouf, MD, PhD
ED is associated with depression and hypogonadism. We determined the prevalence of depression and hypogonadism in men presenting to an ED specialty clinic and evaluated whether hypogonadism correlated with the presence of depression symptoms.1 Men who had been referred to the clinic (N=157; mean age, 53.8 years [range, 21-85 years]) were assessed for hypogonadism by serum testosterone evaluation.1 Validated, self-administered questionnaires—the abbreviated International Index of Erectile Function (IIEF-5) and the Center for Epidemiologic Studies Depression scale (CES-D)—were used to prospectively collect data on ED and symptoms of depression, respectively.1

Thirty-six percent of the patient cohort were hypogonadal (defined in this study as serum testosterone <300 mg/dL).1 Of the men younger than 53 years, 26% were hypogonadal, whereas 45% of the men 53 years or older were hypogonadal.1 A CES-D score ≥22 was used to define overt depression, found in 24% of the patient cohort.1 Men with overt depression were younger (mean age, 49.9 years) compared to men with mild depression (CES-D score <22; mean age, 55.1 years; P=.02).1 Analysis showed that men with hypogonadism were nearly twice as likely to have overt depression than eugonadal men (35% versus 18%, respectively; P=.02).1 Multivariate, linear-model age adjustment showed that this association was statistically stronger (P=.005) for men with hypogonadal testosterone levels, who have a relative risk of overt depression 1.94 times higher (95% confidence interval, 1.13, 3.7).1

The implications of this study may be significant: In a population of referred patients with ED, symptoms of hypogonadism and depression are prevalent, and overt depression is strongly associated with hypogonadism.1 This study provides further support that patients with ED should be screened for hypogonadism and depression, and patients with high depression symptom scores should be evaluated for hypogonadism.1

Response by Allen D. Seftel, MD
Hypogonadism is a serious medical condition that causes significant morbidity and is associated with depression, ED, and aging.2 Diagnosis remains the responsibility of the primary care clinician and the specialist, who must evaluate symptoms of low mood, depression, fatigue, and irritability that may be related to hypogonadism or attributed to another condition, particularly challenging in the context of the increased demands and greater time constraints of the clinical visit.2

The challenges in diagnosing hypogonadism are growing as life expectancies increase and more men seek treatment for an array of age-related medical conditions.2 Men with “classic” hypogonadism may have unequivocally low testosterone levels and exhibit unambiguous clinical signs and symptoms.3 However, particularly for older men, whose clinical manifestations of hypogonadism may be nonspecific and subtle, age-related declines in testosterone levels may obfuscate diagnosis of hypogonadism, potentially reduced to a “natural part of aging” or depression.2,3

In 2006, we published results of a study using an artificial neural network (ANN) programmed to predict hypogonadism (defined as a serum testosterone level <300 ng/dL) based on age and Sexual Health Inventory for Men (SHIM) and CES-D scores ascertained for each patient (N=218).2 The statistical significance of each risk factor was determined by reverse regression analysis, and the ANN successfully predicted hypogonadism.2 Because this model uses age, ED, and depression, which are easily screened for during the office visit, it may be an effective and helpful tool for clinicians evaluating whether to test for hypogonadism.2

Controlled studies evaluating the effect of testosterone therapy on symptoms of depression, dysthymia, and mood are limited.4-8 Results of two recent studies are described here.

A 2009 study by Jockenhövel et al evaluated the effects of testosterone therapy on sexual function and mood.7 Forty men with hypogonadism received either parenteral testosterone enanthate (TE) or testosterone undecanoate (TU) for 30 weeks, and the effects of treatment were assessed every 3 weeks.7 The impact on self-confidence appeared between 3 and 6 weeks after initiating testosterone therapy; over the course of 6 weeks of treatment, depression scores decreased; and mood improved after 6 to 9 weeks.7

Another investigation from 2009, a double-blind, placebo-controlled study by Shores et al, examined the effect of testosterone therapy in older hypogonadal men with subthreshold depression.8 Men aged 50 years or older with screening total testosterone levels of ≤280 ng/dL and dysthymia or minor depression (defined according to criteria from the 4th edition of Diagnostic and Statistical Manual of Mental Disorders
[DSM-IV]) were recruited to participate (N=33).8 Participants were randomized to receive 7.5 g of either testosterone gel or placebo gel daily for 12 weeks, followed by a 12-week open-label extension phase during which all participants received 7.5 g of testosterone gel.8 The primary outcome measure was the change in the Hamilton Rating Scale for Depression (HAM-D) score from baseline to the end of the double-blind phase.8 Secondary outcome measures were remission of subthreshold depression (defined as a HAM-D score ≤7) and changes in the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), the Hopkins Symptom Checklist (SCL) depression scale, and the 16-item Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q).8 Testosterone-treated men exhibited a greater reduction in HAM-D scores (P=.024) and a higher rate of remission of subthreshold depression (52.9% vs 18.8%, P=.041) than did men who received placebo by the end of the double-blind phase; there were no differences in other secondary outcome measures between groups.8 At the end of the open-label extension phase, the testosterone group exhibited sustained improvement and the control group exhibited improvement in HAM-D scores; no differences between groups were observed in primary or secondary outcome measures.8 These results suggest that testosterone therapy may be efficacious in the treatment of subthreshold depression in older men with hypogonadism.8 Large-scale studies are called for to corroborate these findings.8

Though not conclusive that testosterone therapy effects clinically meaningful changes in mood, dysthymia, or subthreshold depression, the study results described here and other preliminary findings do suggest this. Large-scale, placebo-controlled, longitudinal studies are needed to resolve this query definitively.


  1. Makhlouf AA, Mohamed MA, Seftel AD, Niederberger C. Hypogonadism is associated with overt depression symptoms in men with erectile dysfunction. Int J Impot Res. 2008;20(2):157-161.
  2. Kshirsagar A, Seftel A, Ross L, Mohamed M, Niederberger C. Predicting hypogonadism in men based upon age, presence of erectile dysfunction, and depression. Int J Impot Res. 2006;18(1):47-51.
  3. Tostain JL, Blanc F. Testosterone deficiency: a common, unrecognized syndrome [review]. Nat Clin Pract Urol. 2008;5(7):388-396.
  4. Seidman SN, Orr G, Raviv G, et al. Effects of testosterone replacement in middle-aged men with dysthymia: a randomized, placebo-controlled clinical trial. J Clin Psychopharmacol. 2009;29(3):216-221.
  5. Kanayama G, Amiaz R, Seidman S, Pope HG Jr. Testosterone supplementation for depressed men: current research and suggested treatment guidelines [review]. Exp Clin Psychopharmacol. 2007;15(6):529-538.
  6. Amiaz R, Seidman SN. Testosterone and depression in men [review]. Curr Opin Endocrinol Diabetes Obes. 2008;15(3):278-283.
  7. Jockenhövel F, Minnemann T, Schubert M, et al. Timetable of effects of testosterone administration to hypogonadal men on variables of sex and mood. Aging Male. 2009;12(4):113-118.
  8. Shores MM, Kivlahan DR, Sadak TI, Li EJ, Matsumoto AM. A randomized, double-blind, placebo-controlled study of testosterone treatment in hypogonadal older men with subthreshold depression (dysthymia or minor depression). J Clin Psychiatry. 2009;70(7):1009-1016.

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