ORIGINAL ARTICLE Hypogonadism is associated with overt depression symptoms in men with erectile dysfunction

International Journal of Impotence Research (2008) 20, 157–161
                                                             & 2008 Nature Publishing Group All rights reserved 0955-9930/08 $30.00

Hypogonadism is associated with overt depression symptoms
in men with erectile dysfunction
AA Makhlouf1, MA Mohamed2, AD Seftel3 and C Neiderberger4
  Department of Urologic Surgery, University of Minnesota, Minneapolis, MN, USA; 2Urology Department El-Minia
University Hospital, El-Minia, Egypt; 3Department of Urology, Case Western Reserve University, University Hospitals
of Cleveland, Cleveland, OH, USA and 4Department of Urology, University of Illinois at Chicago, Chicago, IL, USA

          Depression and hypogonadism are associated with erectile dysfunction (ED). We evaluated the
          prevalence of both conditions in men presenting to an ED specialty clinic, and tested whether
          hypogonadism correlated with the presence of depressive symptoms using a validated ques-
          tionnaire. From July 2001 to June 2003, 157 men referred to an ED specialty clinic prospectively
          filled the Center for Epidemiologic Studies Depression Scale (CES-D), the abbreviated International
          Index of Erectile Function (IIEF-5) and had testosterone serum levels drawn. Median age was 53
          (range ¼ 21–85 years). Hypogonadism, defined as serum T (testosterone)o300 mg/dl, was present in
          36% of patients. This proportion was higher in men over the median age compared to younger
          patients (45 and 26%, respectively, P ¼ 0.002). Overt depression symptoms, defined as a CES-DX22,
          were found in 24% of men. Mean age of men with overt depression was 49.9710.1 years vs
          55.1715.8 years for those with CES-Do22 (P ¼ 0.02). Hypogonadal men were more likely to have
          overt depression scores compared to eugonadal counterparts (35 vs 18%, P ¼ 0.02). This association
          was statistically stronger after correcting for age in a multivariate linear model (P ¼ 0.005). The
          relative risk of having overt depression was 1.94 times higher in men with hypogonadal testosterone
          level (95% confidence interval: 1.13 to 3.7). We conclude that in an ED referral population,
          symptoms of hypogonadism and depression symptoms are fairly prevalent, and that overt
          depression symptoms are strongly associated with hypogonadism. Clinicians should consider
          testosterone measurements in all men with high depression symptom scores.
          International Journal of Impotence Research (2008) 20, 157–161; doi:10.1038/sj.ijir.3901576;
          published online 16 August 2007

          Keywords: depression; testosterone; erectile dysfunction; hypogonadism; diagnosis; IIEF

Introduction                                                   Depression was associated with 1.8-fold increase
                                                             in the prevalence of ED in the Massachussetts Male
Testosterone levels decline gradually in aging men,          Aging Study independent of age or the traditional
with about 20% of men over 60 years having total             organic comorbidities associated with ED.2,5 The
testosterone levels dip below the accepted normal            prevalence of depression in large epidemiological
threshold.1 This drop in androgen levels parallels an        studies of ED has been reported as ranging from 11
increase in the prevalence of erectile dysfunction           to 25%.6,7 Even higher rates (25–55%) were reported
(ED).2 Testosterone supplementation has been                 in men attending andrology clinics.8,9 Furthermore,
shown to improve erectile function and rescue                Shabsigh et al.8 found that patients with ED and
sildenafil failures.3,4 Thus, there is a clear incentive     concomitant depression were more likely to dis-
for urologists to identify men with hypogonadism.            continue therapy, making assessment of depression
                                                             symptoms an important aspect of ED evaluation.
                                                               There is an overlap between symptoms of hypo-
                                                             gonadism and depression. One study has found
                                                             that men with hypogonadal testosterone values are
Correspondence: Dr AA Makhlouf, Department of Urologic
Surgery, University of Minnesota, 420 Delaware St SE MMC
                                                             at higher risk of developing depression,10 while
394, Minneapolis, MN 55455, USA.                             others have not.5,11 In this paper, we examine
E-mail: makhl001@umn.edu                                     the correlation between depression symptoms and
Received 18 November 2006; revised 3 March 2007;             hypogonadsim in men attending an ED clinic. We
accepted 1 May 2007; published online 16 August 2007         specifically determine if men with hypogonadism
Depression and hypogonadism associated in ED
                                                                         AA Makhlouf et al
           and depression form an overlapping sub-population                                 Table 1 Summary data for all patients in the study
           of ED patients.
                                                                                                                                          Mean           Median          Range

                                                                                             Age (years)                                 53.8714.8         53            21–85
           Methods                                                                           IIEF-5                                      11.276.3          11             0–25
                                                                                             CES-D                                       15.178.8          15             0–40
                                                                                             Testosterone (ng/dl)                       414.47206         369            21–1182
           Total serum testosterone levels were obtained from
           185 consecutive patients presenting to an andrology                               Abbreviations: BPH, benign prostatic hyperplasia; CAD, coronary
           specialty clinic with a chief complaint of ED                                     artery disease; CES-D, Center for Epidemiologic Studies Depres-
           between July 2001 and June 2003. Samples were                                     sion Scale; HTN, hypertension; IIEF-5, International Index of
           drawn in the morning hours in most patients with                                  Erectile Function-5.
           rare exceptions. The Center of Epidemiologic Study                                Major comorbidites by patient-self report: diabetes, 21; Peyronie’s,
                                                                                             4; BPH, 3; depression, 3; CAD, 2; HTN, 2; prostate cancer, 1.
           Depression questionnaire (CES-D) and the five-
           question International Index of Erectile Function
           (IIEF-5) was administered as measures of depression
           and erectile function, respectively. The CES-D is an
                                                                                                                                  Hypogonadism by Age Group
           inventory of 20 questions on a 4-point scale, with a                                                             0.5
           score of 16–21 suggestive of mild or reactive                                                                                                             *
           depression, whereas a score of 22 or higher
           corresponding to signs of overt depression.12,13                                                                 0.4
           The IIEF-5 is widely used and validated measure
                                                                                              Proportion with T
Depression and hypogonadism associated in ED
                                                                                   AA Makhlouf et al
are fairly prevalent in an ED clinic population, and                                  Androgen deficiency is associated with a variety
that there is increased likelihood of finding depres-                              of symptoms in aging men.15 In addition to physical
sion among men with hypogonadism.                                                  signs such as loss of muscle mass and bone density,
                                                                                   low testosterone values are associated with forget-
                                                                                   fulness, insomnia, depressed mood and low sex
Table 2 2  2 contingency table showing the correlation of                         drive.15 Androgen blockade in prostate cancer
hypogonadism with presence or absence of overt depression                          patients leads to a rise in depression and anxiety
                                                                                   symptoms and weakening of verbal memory.16,17 In
                                     Mild or no depression Overt Sxs (CES-D 421;   contrast, testosterone supplementation leads to an
                                      symptoms (CES-D              n ¼ 38)         improvement in the sense of well being and a rise in
                                         p21; n ¼ 117)                             libido.18 Because of the effects of mood and libido
                                                                                   on sexual performance, we determined the rate of
Normal T                                  82 (82%)                     18 (18%)    hypogonadism in an ED referral population. Using a
Low T                                     37 (65%)                     20 (35%)    sensitive cutoff of 300 ng/dl, we found testosterone
(o300 ng/dl)
                                                                                   deficiency in 36% of men, while a more stringent
Abbreviations: CES-D, Center for Epidemiologic Studies Depres-
                                                                                   cutoff of 200 ng/dl gave a rate of 9.5%. Regardless of
sion Scale; CI, confidence intervals; T, testosterone.                             cutoff, hypogonadism was more common in men
The relative risk of having overt depression if hypogonadal group                  over the median age. Total testosterone levels did
is 1.95 higher than in eugonadal men (95% CI: 1.3–3.4).                            not correlate with severity of ED as measured by the
P ¼ 0.02 by w2 test.                                                               IIEF-5, even after correction for age (data not
                                                                                   shown). This agrees with Shabsigh et al.,3 who did
                                                                                   not find a correlation between Sexual Health
                                                                                   Inventory for Men (SHIM) score and testosterone
                                                   Normal T                        level in men supplemented with testosterone for ED.
                                                   T < 300 ng/dl                   Overall, our rate of hypogonadism was higher than
                                                                                   that reported for community men in general.1
                                                                                   Recognition of testosterone deficiency is important
                                                                                   since testosterone supplementation can rescue
                           0.5                                                     sildenafil failures.3 This effect of testosterone is
                                                                        p < 0.05
                                                                                   likely due to stabilization of neuronal nitric oxide
  Proportion of patients

                           0.4                                                     synthase expression,19 although other mechanisms
                                                                                   such as prevention of smooth muscle cell loss
                           0.3                                                     through apoptosis have been proposed.20
                                                                                      Previous epidemiological studies have found a
                                                                                   strong correlation between the presence of ED and
                                                                                   depression. In a multinational survey of over 27 000
                                                                                   men, Rosen et al.21 found depression to be twice as
                           0.1                                                     common in men with ED than in their potent
                                                                                   counterparts. Conversely, the presence of depression
                            0                                                      correlated with a high prevalence of ED (25%),
                                 None              Mild                 Overt      similar to the prevalence in men with hypertension
Depression and hypogonadism associated in ED
                                                                         AA Makhlouf et al
           with the present findings. These large epidemiolo-                                question of whether depression contributes to the
           gical surveys have been borne out in studies of men                               development of ED, or whether depression itself is
           attending ED specialty clinics. Shabsigh et al.8                                  the result of organic ED. Similarly, it does not
           reported that 55% of men presenting to an ED clinic                               establish a cause–effect relationship between hypo-
           had significant depression symptoms as measured                                   gonadism and depression. In fact, Schmidt et al.25
           by the Beck Depression Inventory. Finally, treatment                              have found that experimental androgen deprivation
           of ED with phosphodiesterase 5 (PDE5) inhibitors                                  leads to depression in only a minority of men, while
           has been shown to improve depressive symptoms in                                  Seidman et al.26 found no benefit to testosterone
           two randomized controlled trials.22,23                                            injections in treating depression in a small trial of
              It should be noted that the prevalence of depres-                              men with concomitant major depression and low
           sive symptoms in our cohort was significantly                                     testosterone. Both studies therefore cast some doubt
           higher than that found in epidemiological sur-                                    on the hypogonadism-depression linkage. Second,
           veys.5,6 In the Massachusetts Male Aging Study                                    the present study is limited by the accuracy of the
           (MMAS) sample, the overall prevalence of depres-                                  CES-D in diagnosing clinically relevant depression.
           sive symptoms defined as CES-D416 was 12%,                                        The CES-D was designed as a population screening
           much lower than in our study.5 This can be                                        tool and not a diagnostic instrument in a clinical
           explained by two factors. First, in the MMAS                                      setting, and the optimal cutoff of the CES-D varies
           sample, the presence of depression increased the                                  according to the population at hand. Unfortunately,
           odds of ED twofold. Therefore, the prevalence of                                  the criterion validity of the CES-D in a population
           depressive symptoms among the ED subgroup of the                                  similar to ours (clinic-based, middle-aged, North
           MMAS is necessarily higher than 12%. Second, not                                  American males with ED) has not been established.
           all men with ED in the MMAS sought treatment for                                  Studies of other populations have found the optimal
           ED, and one would expect patients presenting to a                                 cut point to be higher than the traditional value of
           clinic to be more distressed about ED and therefore                               16, with most being between 18 and 22.13,27–31 In the
           score was higher on the CES-D. This is supported by                               present work, we analyzed the data using both the
           the fact that another study of ED in an andrology                                 traditional cutoff of 16, as well as the more stringent
           clinic setting revealed similarly high prevalence of                              cutoff of 22 recommended by Haringsma et al.,13 and
           depressive symptoms.8 Still, we cannot discount the                               found an association of hypogonadism with the
           possibility that our cohort represents a slightly                                 more overt depression scores. This finding agrees in
           skewed population of severe or refractory cases,                                  part only with that of Delhez et al.,32 who also found
           especially that the clinic is a known tertiary referral                           that hypogonadism was associated with depressive
           center. Thus, one should be careful in generalizing                               scores, but reported that this association was
           our findings to a non-ED clinic population, such as                               strongest in men with mild depression symptoms,
           one presenting for screening at a health fair or for an                           as opposed to pathological cases. Because the two
           unrelated problem at a primary care clinic.                                       studies used different questionnaires, a direct
              Since both depression and hypogonadism are                                     comparison is not possible in the absence of
           associated with ED, and since men with hypogona-                                  clinician-verified diagnosis of depression.
           dal testosterone levels are at threefold increased risk                              In conclusion, depression symptoms and low
           of developing depression symptoms,10 we examined                                  testosterone are prevalent in ED patients referred
           the possibility that men with depression and low                                  to specialized clinics. Although limited in some
           testosterone form a single subgroup in ED patients.                               respects, the present study shows a significant
           We found that hypogonadal men were almost twice                                   association between the two conditions, and sug-
           as likely to have high depression scores. Mild                                    gests that men with hypogonadism and depression
           elevations on the depression scale, however, were                                 form a distinct subgroup of ED patients.
           not good correlates of hypogonadism. The relation-
           ship of depression and hypogonadism is even more
           striking considering that they vary in inverse ways
           with aging (hypogonadism more common in older                                     References
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