The longitudinal relationship of sexual function and androgen status in older men: the Concord Health and Ageing in Men Project.

ORIGINAL

ARTICLE

The Longitudinal Relationship of Sexual Function and Androgen Status in Older Men: The Concord Health and Ageing in Men Project Benjumin Hsu, Robert G. Cumming, Fiona M. Blyth, Vasi Naganathan, David G. Le Couteur, Markus J. Seibel, Louise M. Waite, and David J. Handelsman School of Public Health (B.H., R.G.C.), University of Sydney, Sydney, New South Wales, Australia 2139; and Centre of Education and Research on Ageing (B.H., R.G.C., F.M.B., V.N., D.G.L.C., L.M.W.), and ANZAC Research Institute (R.G.C., D.G.L.C., M.J.S., D.J.H.), University of Sydney and Concord Hospital, Sydney, New South Wales, Australia 2139

Context: It is unclear whether declining sexual function in older men is a cause or consequence of reduced androgen status. Objective: Longitudinal associations were examined between reproductive hormones and sexual function in older men. Design, Setting, and Participants: Men aged 70 years and older from the Concord Health and Ageing in Men Project study were assessed at baseline (n ⫽ 1705) and 2-year follow-up (n ⫽ 1367), with a total of 1226 men included in the final analyses. Main Outcomes and Measures: At both visits, serum testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, and SHBG, LH, and FSH were measured by immunoassay. Sexual functions (erectile function, sexual activity, and sexual desire) were self-reported via standardized questions. Results: In longitudinal analyses, although baseline hormones (T, DHT, E2, and E1) did not predict decline in sexual function, the decline in serum T (but not DHT, E2, or E1) over 2 years was strongly related to the change in sexual activity and desire (but not erectile function). For each 1-SD decrease in T from baseline to 2-year follow-up, there was a multivariate-adjusted odds ratio of 1.23 (95% confidence interval, 1.12–1.36) for an additional risk of further decline in sexual activity. However, the magnitude of the decrease in serum T was strikingly small (⬍10%). Similar associations were found for changes over 2 years in serum T and decline in sexual desire, but not for erectile function. Conclusions: We found a consistent association among older men followed over 2 years between the decline in sexual activity and desire, but not in erectile function, with a decrease in serum T. Although these observational findings cannot determine causality, the small magnitude of the decrease in serum T raises the hypothesis that reduced sexual function may reduce serum T rather than the reverse. (J Clin Endocrinol Metab 100: 1350 –1358, 2015)

n older men, declining sexual function and androgen status are both widely understood to be related to aging; however, the relationship between these two aspects of male aging remains uncertain (1). Specifically,

I

it remains unclear whether reduced sexual function in older men is a cause or a consequence of reduced androgen status, as indicated by a low circulating testosterone (T) level.

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2015 by the Endocrine Society Received November 14, 2014. Accepted January 23, 2015. First Published Online January 28, 2015

Abbreviations: BMI, body mass index; cFT, calculated free T; DHT, dihydrotestosterone; E1, estrone; E2, estradiol; LC-MS/MS, liquid chromatography-tandem mass spectrometry; T, testosterone.

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J Clin Endocrinol Metab, April 2015, 100(4):1350 –1358

doi: 10.1210/jc.2014-4104

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doi: 10.1210/jc.2014-4104

Major reasons for this uncertainty are the lack of relevant longitudinal studies and the narrowed appraisal of androgen status due to failure to investigate concurrently the bioactive T metabolites, dihydrotestosterone (DHT) and estradiol (E2). Placebo-controlled clinical trials of T treatment of older men with sexual dysfunction but without disorders of the reproductive system have shown little consistent improvement in sexual function (2– 4). The objectives of this longitudinal study over 2 years are to examine temporal and predictive relationships between reproductive hormones and decline in sexual function. This is the first study to examine this relationship with a comprehensive focus on androgen (T and DHT) and estrogen (E2 and estrone [E1]) status using serum steroids measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), which is not only more accurate than direct steroid immunoassays but also has the multianalyte capabilities that are necessary for comprehensive evaluation of androgen status (5).

Subjects and Methods Study participants The Concord Health and Ageing in Men Project (CHAMP) is a longitudinal, observational study of the epidemiology of male aging conducted among men living within the three local government areas (Burwood, Canada Bay, and Strathfield) surrounding Concord Hospital in Sydney, New South Wales, Australia (6). Men were selected from the New South Wales electoral roll; enrollment is compulsory in Australia. Participants were community-dwelling men aged at least 70 years, but no other inclusion or exclusion criteria were required (6). Letters were sent to 3627 men, of whom 2815 were successfully contacted and confirmed eligible, and 1511 participated in the study. An additional 194 eligible men living in the study area heard about the study from friends or the local media and were recruited before receiving a letter, yielding a total cohort of 1705 participants. The study design has been reported in detail elsewhere (6). Baseline measurements were conducted between January 2005 and June 2007; data were collected using self-reported questionnaires, interviewer-administered questionnaires, and a wide range of clinical assessments. Follow-up assessments were conducted between January 2007 and October 2009, with identical measurements as at baseline.

Reproductive hormone measurement The participants had an early morning fasting blood sample taken, with serum stored at ⫺80ºC until assay. Measurements of serum T, DHT, E2, and E1 were by LC-MS/MS as described elsewhere (7), with between-run coefficients of variation at three levels (low, medium, high) of quality control specimens of 1.9 – 4.5, 3.8 –7.6, 2.9 –13.6, and 5.7– 8.7%, respectively, over 184 runs (109 baseline, 75 follow-up) for this study. Serum LH, FSH, and SHBG were measured by automated immunoassays (Roche Diagnostics Australia) subject to ongoing external quality con-


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trol program calibration, with between-assay coefficient of variation for three levels of quality control specimens in each run of 2.1–2.2% for LH, 2.7–3.0 for FSH, and 2.0 –2.8% (two quality control levels only) for SHBG. The calculated free T (cFT) levels were computed using an empirical formula validated in two large data sets consisting of more than 6000 blood samples (8, 9).

Sexual function measurement Men were invited to complete a self-reported sexual health questionnaire during the study clinic visit. These questionnaires were completed in private and put in sealed envelopes by study participants and were not seen by clinic interviewers. The men were asked about erectile dysfunction, sexual activity, and sexual desire. A standard, validated question for erectile dysfunction was used: “How often are you able to get and keep an erection that is firm enough for satisfactory sexual activity?” (10). Erectile function was dichotomized into either adequate erectile function (reporting always or usually) or erectile dysfunction (reporting sometimes or never) (10). Sexual activity was based on the question: “How many times over the LAST MONTH have you had sexual activity (including intercourse and masturbation) reaching ejaculation?” Responses were dichotomized into sexually active (reporting having had sexual activity at least once) or sexually inactive (reporting no intercourse or masturbation). Sexual desire was determined by the question: “How much desire for sex do you have now, compared with when you were 50?” Responses were dichotomized into not decreased sexual desire (reporting much more, more, or about the same) and decreased sexual desire (reporting less or much less).

Statistical analysis Of the 1705 men, a total of 1226 who completed the sexual health questionnaire at baseline and follow-up were included in the cross-sectional analyses. This excluded men who declined to complete the questionnaire at baseline and/or follow-up clinic visit (n ⫽ 447; 26%). Additionally, 32 men were excluded from analyses in this paper because they were receiving either androgens or antiandrogen treatments. Losses to follow-up comprised 99 men who died before the 2-year follow-up visit and 222 living men who declined to attend the follow-up visit. Descriptive characteristics were generated for the baseline analytic sample. Categorical data on erectile dysfunction, sexual activity, and sexual desire were assessed by logistic regression models. Two separate sets of longitudinal analyses using logistic regression models were conducted. The first analyses examined associations between (prevalent) baseline levels of reproductive hormones and subsequent (incident) onset of erectile dysfunction and declines in sexual activity and sexual desire over the 2-year study follow-up period. The second set of longitudinal analyses examined associations between changes in reproductive hormone levels from baseline to 2-year follow-up and onset of erectile dysfunction and declines in sexual activity and sexual desire over the same period. Men with erectile dysfunction (n ⫽ 774), no sexual activity (n ⫽ 665), or decreased sexual desire (n ⫽ 854) at baseline were excluded from relevant longitudinal analyses to avoid floor effects in sexual function measures. After the exclusions, this resulted in total numbers in each longitudinal analysis of 392 men for sexual activity, 258 men for sexual desire, and 302 men for erectile function. Analyses of the relationships between reproductive hormones and sexual function were further analyzed for curvature effect.


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Androgen Status and Sexual Function

The model building for all analyses included covariates known to have independent impact on sexual function: age, body mass index (BMI), smoking status, alcohol consumption, depression (Geriatric Depression Scale), diabetes, cardiovascular disease, and marital status. Models were fitted using SPSS software version 20 (IBM Corp) and SAS software 9.3 (SAS Institute Inc).

Results Descriptive characteristics The 1241 men included for analyses at baseline had a mean age of 76.7 ⫾ 5.5 years and mean BMI of 27.8 ⫾ 4.0 kg/m2 (Table 1). At both baseline and 2-year follow-up, men with sexual inactivity, erectile dysfunction, and decreased sexual desire were older compared to men with satisfactory sexual function in each respective sexual domain (see Supplemental Tables 1 and 2). The mean fasting glucose was 5.5 ⫾ 1.2 mmol/L, with 13% (n ⫽ 156) of men taking diabetes medication. Fifty-eight percent (n ⫽ 719) of men self-reported cardiovascular disease, and the mean measured systolic/diastolic blood pressure was 148 ⫾ 19.2/79 ⫾ 10.0 mm Hg. Nearly 9% (n ⫽ 116) had no comorbidity, 22% (n ⫽ 267) had one comorbidity, 25% (n ⫽ 303) had two comorbidities, and 44% (n ⫽ 555) had three or more comorbidities. Of the 1241 men at baseline, 12% (n ⫽ 149) had no children, 8% (n ⫽ 106) had tried for more than 12 months to have children but were unsuccessful, and nearly 7% (n ⫽ 83) had had medical tests or seen a doctor for infertility. At baseline, a total of 12% (n ⫽ 155) of men had at Table 1. Cross-sectional Characteristics of Participants in the Study

Age, y BMI, kg/m2 T, ng/mL DHT, ng/mL SHBG, nmol/L E2, pg/mL E1, pg/mL FSH, IU/L LH, IU/L cFT, pmol/L Current smoker Excessive drinkera Depression Cardiovascular disease Diabetes Living with a partner Erectile dysfunction Sexual inactivity Low sexual desire

Baseline

2-Year Follow-Up

76.9 (5.5) 27.8 (4.0) 4.3 (1.9) 0.4 (0.2) 50.2 (20.8) 25.3 (12.4) 40.4 (16.2) 14.8 (14.9) 9.6 (8.8) 59.6 (22.4) 101 (6%) 245 (15%) 239 (15%) 953 (57%) 266 (16%) 1286 (77%) 774 (64%) 665 (56%) 854 (70%)

79.0 (5.2) 27.8 (4.0) 4.2 (1.9) 0.4 (0.2) 52.1 (21.0) 24.2 (9.5) 39.9 (15.7) 15.4 (14.9) 10.1 (8.3) 58.4 (22.3) 52 (4%) 191 (14%) 199 (15%) 769 (57%) 235 (18%) 1007 (76%) 609 (67%) 541 (59%) 642 (70%)

Data are expressed as mean (SD) or number (percentage). a

⬎14 drinks per week.


one time had treatment or taken medication for erection difficulties. Of the men in the longitudinal analyses, nearly 25% (n ⫽ 96) became sexually inactive, 39% (n ⫽ 101) had lower sexual desire, and 32% (n ⫽ 96) had declining erectile function. There were no differences between the men who declined to complete the sexual health questionnaire (n ⫽ 447) and those in the analytic sample for age (76.8 ⫾ 5.6 y), blood pressure (146 ⫾ 18.7/77 ⫾ 10.7 mm Hg), and number of comorbidities (data not shown). Men who declined to complete the sexual health questionnaire had slightly higher BMI (28.3 ⫾ 4.0 kg/m2), were more likely to be living with a partner, and were more likely to be depressed or on diabetes medication (data not shown). Longitudinal analyses The longitudinal associations between reproductive hormones and decline in sexual activity are shown in Table 2. None of the studied hormones at baseline predicted a subsequent decline in sexual activity. However, the changes in T and cFT over 2 years were strongly associated with a decline in sexual activity over the same time period (Table 2). For each 1-SD decrease in T and cFT levels from baseline to follow-up, men had an unadjusted odds ratio for decline in sexual activity of 1.23 (95% confidence interval [CI], 1.11–1.36) for T and 1.23 (95% CI, 1.09 –1.34) for cFT; these findings were unchanged by multivariate adjustment (1.23 [95% CI, 1.12–1.36], for T; 1.24 [95% CI, 1.14 –1.35], for cFT). Men were 13% more likely to be sexually inactive at baseline for every 0.55 ng/mL lower level of T, and were 23% more likely to become sexually inactive for every 0.71 ng/mL decline in T from baseline to 2-year follow-up (data not shown). The mean change in serum T plotted against the change in categorical frequency of sexual activity (ejaculation) from baseline to 2-year follow-up revealed a significant trend (P ⫽ .003; one-way ANOVA) with men experiencing a larger decline in mean T having a greater decline in the frequency of sexual activity (Figure 1A). For men with a one or two category decline in ejaculation frequency, serum T decreased by 5 and 9%, respectively, whereas men who became sexually inactive during the 2-year follow-up period had a 7% decline in circulating T levels. In addition, changes in both E2 and E1 were statistically significantly associated with decline in sexual activity over time. For each 1-SD decrease in estrogen (E2 and E1) levels from baseline to follow-up, men had a multivariate-adjusted odds ratio for decline in sexual activity of 1.19 (95% CI, 1.08 –1.31) for E2 and 1.15 (95% CI, 1.06 –1.30) for E1. The longitudinal associations between reproductive hormones and decline in sexual desire were similar to those for sexual activity and are shown in Table 3. None


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Table 2. Longitudinal Associations Between Reproductive Hormones and Decline in Sexual Activity Odds Ratio (95% CI)

Table 2.

P Value

1.06 (0.96 –1.17) 1.07 (0.97–1.18) 1.04 (0.94 –1.16)

.26 .17 .41

1.23 (1.11–1.36) 1.22 (1.11–1.34) 1.23 (1.12–1.36)

⬍.001 ⬍.001 ⬍.001

0.95 (0.85–1.06) 1.01 (0.91–1.10) 0.99 (0.88 –1.09)

.29 .83 .79

1.06 (0.96 –1.16) 1.05 (0.95–1.17) 1.06 (0.94 –1.19)

.23 .29 .26

1.01 (0.92–1.11) 1.00 (0.91–1.11) 0.99 (0.90 –1.09)

.89 .95 .84

1.06 (0.96 –1.17) 1.07 (0.97–1.18) 1.07 (0.97–1.18)

.26 .17 .20

0.92 (0.84 –1.01) 0.94 (0.87–1.02) 0.94 (0.87–1.04)

.08 .20 .23

0.96 (0.88 –1.05) 0.98 (0.84 –1.13) 0.97 (0.87–1.10)

.44 .74 .61

0.90 (0.81– 0.99) 0.95 (0.85–1.04) 0.94 (0.85–1.04)

.04 .26 .21

1.01 (0.93–1.09) 1.03 (0.93–1.16) 1.02 (0.93–1.13)

.91 .50 .65

0.99 (0.90 –1.09) 1.01 (0.94 –1.08) 1.01 (0.94 –1.07)

.89 .80 .81

1.17 (1.06 –1.29) 1.18 (1.08 –1.29) 1.19 (1.08 –1.31)

.002 .001 .001

1.00 (0.92–1.09) 1.01 (0.92–1.09) 1.00 (0.92–1.09)

.93 .91 .93 (Continued)

Continued Odds Ratio (95% CI)

P Value

1.12 (1.01–1.25) 1.15 (1.06 –1.28) 1.15 (1.06 –1.30)

.03 .005 .005

1.09 (0.99 –1.19) 1.08 (0.99 –1.17) 1.06 (0.94 –1.27)

.08 .11 .27

1.23 (1.09 –1.34) 1.23 (1.08 –1.33) 1.24 (1.14 –1.35)

⬍.001 ⬍.001 ⬍.001

b

Change Unadjusted ⫹Age ⫹Multivariablec cFT Baselinea Unadjusted ⫹Age ⫹Multivariablec Changeb Unadjusted ⫹Age ⫹Multivariablec

T Baselinea Unadjusted ⫹Age ⫹Multivariablec Changeb Unadjusted ⫹Age ⫹Multivariablec SHBG Baselinea Unadjusted ⫹Age ⫹Multivariablec Changeb Unadjusted ⫹Age ⫹Multivariablec DHT Baselinea Unadjusted ⫹Age ⫹Multivariablec Changeb Unadjusted ⫹Age ⫹Multivariablec FSH Baselinea Unadjusted ⫹Age ⫹Multivariablec Changeb Unadjusted ⫹Age ⫹Multivariablec LH Baselinea Unadjusted ⫹Age ⫹Multivariablec Changeb Unadjusted ⫹Age ⫹Multivariablec E2 Baselinea Unadjusted ⫹Age ⫹Multivariablec Changeb Unadjusted ⫹Age ⫹Multivariablec E1 Baselinea Unadjusted ⫹Age ⫹Multivariablec

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Plus signs indicate the addition of age and multivariable. a

Odds ratio per 1-SD decrease in baseline hormone concentrations.

b

Odds ratio per 1-SD decrease in hormone concentrations between baseline and 2-year follow-up. c Multivariable model was adjusted for age, BMI, smoking status, alcohol consumption, depression, diabetes, cardiovascular disease, and marital status.

of the studied hormones at baseline, except SHBG, were associated with decline in sexual desire over the 2-year study period. Men with lower SHBG were less likely to have a decline in sexual desire, with a multivariate-adjusted odds ratio of 0.87 (95% CI, 0.79 –1.00) for each 1-SD decrease in SHBG (Table 3). Changes in T and cFT over the 2-year study period were significantly associated with changes in sexual desire. For each 1-SD decline in T levels, there was an adjusted odds ratio of 1.19 (95% CI, 1.05–1.35) for decline in sexual desire. Similar associations were found for changes in cFT (Table 3). The mean change in serum T plotted against change in the category of sexual desire from baseline to 2-year follow-up (Figure 1B) also showed a significant relationship (P ⬍ .001; oneway ANOVA). For men with a one or two category decline in sexual desire, serum T decreased by 9 and 17%, respectively. Men who declined in sexual desire over the 2-year follow-up period had nearly a 10% decline in circulating T levels. All studied hormones, other than E1, were not associated longitudinally with the onset of erectile dysfunction (Table 4). Baseline E1 was statistically significantly associated with the onset of erectile dysfunction, with a multivariate-adjusted odds ratio of 1.19 (95% CI, 1.06 –1.31) for each 1-SD decline in E1. The test for curvature effect was not statistically significant in all the analyses conducted between the reproductive hormones and each of the sexual domains (data not shown). Subanalyses were conducted by adjusting for other potential confounders that may influence sexual function in older men, as suggested in previous studies (11). In the multivariate-adjusted model for each relevant sexual func-


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these potential confounders was added into the model (data not shown). Cross-sectional snapshot Cross-sectional analyses at baseline and 2-year follow-up and the pooled data (see Supplemental Table 3) showed consistently that men with low T and cFT were more likely to have no sexual activity. For each 1-SD decrease in T, in univariate analysis for sexual inactivity men had an unadjusted odds ratio of 1.18 (95% CI, 1.12–1.25) and a multivariate-adjusted odds ratio of 1.15 (95% CI, 1.03–1.21) for T and 1.17 (95% CI, 1.08 –1.21) for cFT. Similar associations were observed between T and sexual desire (see Supplemental Table 3). Low levels of estrogen (both E2 and E1) and high levels of FSH were associated with low sexual desire after multivariate adjustment (see Supplemental Table 3). For erectile function, in univariate analyses, T, cFT, LH, and FSH had significant associations with prevalent erectile dysfunction (see Supplemental Table 3). However, only cFT remained statistically significantly associated with erectile dysfunction (after adjusting for age, BMI, smoking status, alcohol consumption, depression, diabetes, cardiovascular disease, and marital status) with an odds ratio of 1.04 (95% CI, 1.01– 1.22) for each 1-SD decrease in cFT.

Figure 1. Average change in serum T plotted against the change in sexual function (sexual activity and sexual desire) from baseline to 2-year follow-up. A, Mean change in serum T plotted against the change in categorical frequency of sexual activity (ejaculation) from baseline to 2-year follow-up. B, Mean change in serum T plotted against the change in category of sexual desire from baseline to 2-year follow-up.

tion analysis, frailty, medication use (␤-blockers, ␣-blockers, and diuretics), and a series of other self-reported medical comorbidities (thyroid dysfunction, osteoporosis, Paget’s disease, stroke, Parkinson’s disease, kidney stone, dementia, epilepsy, chronic lung disease, liver disease, chronic kidney disease, and arthritis) were adjusted for. However, the findings remained the same when each of

Discussion

To our knowledge, this study provides the first comprehensive examination of longitudinal associations between all the major bioactive reproductive hormones and declining sexual function in older men. Consistent with previous studies, in cross-sectional analyses, men with low T tended to have low sexual activity and desire, but there was no association between T and erectile dysfunction. However, interpreting the direction of causality of this cross-sectional finding is difficult, and longitudinal analyses are helpful to shed impor-


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Table 3. Longitudinal Associations Between Reproductive Hormones and Decline in Sexual Desire Odds Ratio (95% CI)

Table 3.

P Value

0.93 (0.82–1.05) 0.94 (0.83–1.06) 0.92 (0.80 –1.05)

.24 .29 .20

1.15 (1.01–1.30) 1.15 (1.02–1.30) 1.19 (1.05–1.35)

.03 .03 .008

0.85 (0.76 – 0.96) 0.87 (0.78 – 0.99) 0.87 (0.79 –1.00)

.01 .03 .04

0.98 (0.86 –1.11) 0.97 (0.84 –1.12) 0.97 (0.86 –1.11)

.70 .65 .69

0.87 (0.77– 0.98) 0.88 (0.78 –1.00) 0.87 (0.76 –1.00)

.03 .05 .05

1.12 (0.99 –1.27) 1.12 (0.99 –1.27) 1.14 (1.01–1.30)

.07 .07 .04

0.92 (0.79 –1.04) 0.94 (0.80 –1.07) 0.93 (0.81–1.06)

.17 .30 .25

0.95 (0.86 –1.07) 0.96 (0.82–1.10) 0.93 (0.83–1.05)

.47 .47 .26

0.89 (0.79 –1.01) 0.91 (0.80 –1.03) 0.91 (0.80 –1.04)

.07 .14 .16

1.00 (0.87–1.16) 1.01 (0.90 –1.12) 1.01 (0.91–1.11)

.98 .92 .93

0.98 (0.80 –1.16) 0.99 (0.89 –1.10) 1.01 (0.89 –1.15)

.69 .82 .91

1.09 (0.97–1.23) 1.09 (0.97–1.23) 1.11 (0.97–1.26)

.17 .16 .13

1.02 (0.94 –1.12) 1.02 (0.94 –1.01) 1.05 (0.93–1.16)

.73 .74 .44 (Continued)


P Value

1.01 (0.89 –1.14) 1.02 (0.92–1.10) 1.03 (0.88 –1.26)

.88 .80 .62

0.96 (0.86 –1.08) 0.96 (0.86 –1.08) 0.94 (0.74 –1.13)

.54 .54 .39

1.15 (1.02–1.28) 1.15 (1.04 –1.29) 1.21 (1.08 –1.35)

.03 .02 .004

b



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b


tant new light on this uncertainty. In our longitudinal analyses, baseline T levels per se were not associated with decline in sexual function over the 2-year follow-up period. However, analyses revealed associations between a decline in T levels and a decline in sexual activity and sexual desire from baseline to 2 years. The consistent change in sexual activity and desire was accompanied by an equally consistent but quantitatively minor decrease in serum T. These changes in serum T are mostly (⬍10%) too small to explain the decrease in sexual activity or desire because well-designed placebo clinical trials show that reducing serum T by 75% (12) or 80% (13) is required to reduce male sexual function, whereas reductions of 50% (12) or 60% (13) have no impact on sexual function in young (mean age, 32 y) or older men (mean age, 66 y) (12–14). The Massachusetts Male Aging Study (MMAS) is to our knowledge the only population-based study to have longitudinally examined male hormones with sexual function; however, the MMAS only studied serum T measured by immunoassay and sexual desire (15). Both the CHAMP and MMAS have reported that low T is longitudinally associated with low sexual desire. Our study has further investigated the longitudinal relationship between T and other major reproductive hormones with other sexual domains. Our cross-sectional findings are consistent with several previous large, population-based studies in which circulating T level was associated with sexual desire and sexual activity, but not with erectile dysfunction (15–18). These studies have all shown cross-sectional associations between low T and low sexual desire in aging men, but none


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Table 4. Longitudinal Associations Between Reproductive Hormones and Onset of Erectile Dysfunction


Table 4.


P Value

0.97 (0.84 –1.12) 0.97 (0.85–1.12) 0.96 (0.89 –1.06)

.64 .65 .54

1.03 (0.94 –1.10) 1.02 (0.95–1.07) 0.99 (0.88 –1.14)

.61 .69 .87

1.01 (0.89 –1.12) 1.01 (0.90 –1.12) 1.02 (0.94 –1.09)

.91 .94 .73

b

Odds Ratio (95% CI)

P Value

1.07 (0.95–1.20) 1.06 (0.94 –1.20) 1.03 (0.91–1.15)

.29 .31 .70

0.99 (0.87–1.12) 0.99 (0.88 –1.11) 1.00 (0.84 –1.18)

.85 .83 .96

1.14 (1.02–1.30) 1.17 (1.04 –1.31) 1.12 (0.99 –1.26)

.03 .01 .08

0.94 (0.82–1.06) 0.94 (0.82–1.06) 0.92 (0.81–1.05)

.35 .36 .21

1.08 (0.96 –1.22) 1.07 (0.96 –1.21) 1.06 (0.94 –1.20)

.20 .22 .35

0.97 (0.86 –1.10) 0.97 (0.86 –1.10) 0.97 (0.86 –1.10)

.62 .63 .64

1.01 (0.89 –1.15) 1.02 (0.94 –1.08) 1.03 (0.90 –1.14)

.91 .80 .68

0.97 (0.88 –1.08) 0.98 (0.89 –1.09) 0.97 (0.83–1.11)

.68 .70 .59

1.04 (0.92–1.18) 1.05 (0.94 –1.17) 1.05 (0.93–1.21)

.53 .39 .42

1.02 (0.89 –1.18) 1.03 (0.91–1.15) 1.01 (0.86 –1.20)

.73 .69 .85

1.12 (0.98 –1.02) 1.11 (0.98 –1.26) 1.13 (1.01–1.28)

.07 .07 .04

0.98 (0.81–1.15) 0.98 (0.81–1.15) 0.95 (0.85–1.08)

.71 .70 .46



1.21 (1.06 –1.37) 1.20 (1.06 –1.36) 1.19 (1.06 –1.31)

.002 .002 .003 (Continued)



b


has examined the relationships with circulating DHT, E2, or E1. This neglect of the bioactive metabolites of T is problematic because consideration of DHT is required to fully evaluate androgen status, and E2 is reported to be required to maintain male sexual function in one (12) but not another (19) study of selective estrogen deficiency. The European Male Ageing Study (EMAS) has further shown associations between T and other sexual function domains, including sexual thoughts and morning erections (16, 20, 21). The role of T in sexual function is complex, but the present data suggest that among otherwise healthy men in the general population, where the prevalence of reproductive system disorders is ⬍1% (22), low sexual activity may be a cause rather than an effect of low circulating T level. This is supported by a recent meta-analysis of 29 studies comparing T therapy vs placebo that found no evidence of positive effects on male sexual function in men with normal T (2). Our findings for endogenous T are consistent with these clinical trials. The role of DHT in these relationships has been inadequately explored (19, 23). Taken together, this evidence confirms that T therapy should be considered hormonal replacement for men with reproductive system pathology and not as an empirical treatment for men without reproductive system pathology complaining of sexual dysfunction. These findings allow a different interpretation of the EMAS study, which aimed to define “andropause” (late onset hypogonadism) from an observational study relating serum T thresholds to physical, psychological, and sexual symptoms in community-dwelling middle-aged and older European men (20). After finding no T thresh-


doi: 10.1210/jc.2014-4104

olds for physical or psychological symptoms, shallow thresholds were observed for symptoms of sexual dysfunction, which was interpreted to mean that the reduction in serum T led to the sexual dysfunction symptoms. Our present findings favor the reverse interpretation—that is, the sexual inactivity led to the mild reduction in serum T observed. This interpretation is also consistent with other studies showing that sexual activity can induce similar magnitude increases in serum T (24 –27). For example, during the run-in phase of a randomized, placebo-controlled clinical trial of T added to twiceweekly sildenafil therapy for erectile dysfunction, both sexual function and serum T increased (26, 27). The consistently increased serum T is unlikely to be due to the very brief effect (⬍1 h) of direct stimulation of Leydig cell T secretion (28, 29) when sildenafil was taken at 3- to 4-day intervals. Additionally, experimental bilateral cavernous neurotomy in rats significantly reduces serum T levels, proving that purely mechanical failure of sexual function can reduce circulating T (30), a finding that is borne out in observational clinical studies (24, 25). Nevertheless, the exact psychobiological mechanism behind this finding remains unclear. In our study, low circulating E1 was associated with onset of erectile dysfunction over the 2-year follow-up study period. Current research on estrogen action in men mainly focuses on E2, the only potent bioactive circulating estrogen, whereas the impact of E1 has been little studied, although it has been implicated in longitudinal study as a risk factor for diabetes (31). Our findings for E2 are consistent with the cross-sectional Olmstead County Study and EMAS—which found no cross-sectional associations between E2 and erectile dysfunction (16, 17). Given the relationship of erectile failure as a sentinel feature of atherosclerotic cardiovascular disease (32, 33), which is accelerated by diabetes, further studies of E1 and cardiovascular disease as well as a novel biomarker for male sexual function are warranted. A major strength of our study is its longitudinal framework, providing a temporal dimension that sheds additional light on the possible causal direction of the relationship between reproductive hormones and sexual dysfunction. Furthermore, the application of general estimating equations for analysis of longitudinal data (34) is robust against data missing at random (35), although the impact of systematic factors such as healthy survivor bias may still be underestimated (36). Another strength is that we used LC-MS/MS, the current “gold standard” for steroid assays, together with comprehensive steroid profiling rather than the limited monoanalyte approach of steroid immunoassays (5). Direct (nonextraction) steroid immunoassays are inaccurate when measuring low levels of reproductive hormones, which is problematic for measuring circulating T in older men, and


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cannot provide a comprehensive multianalyte appraisal of androgen status (37, 38). In addition, our study provides an analysis of the dynamic effect of a change in T over time. A further strength is that CHAMP includes a large and representative group of older Australian men, as demonstrated by similar sociodemographic and health characteristics in CHAMP men and older men in the nationally representative Men in Australia Telephone Survey (MATeS) study (39). Limitations of our study include the follow-up period of 2 years and the 20% loss to follow-up. However, loss to follow-up in cohort studies of older people is inevitable because of the high mortality rate, explaining nearly onethird of the loss to follow-up in our cohort. Diurnal variation and seasonal variation in hormone concentrations could also have influenced our results (40). We have obtained a single morning fasting blood sample to minimize any possible variations. The measurement of sexual function was through self-reported questionnaire and did not include information on sexual partners (11); therefore, responses to its questions may not have captured all the details of each participant’s sexual function. Although our present observational findings cannot ascribe causality, in the light of placebo-controlled clinical trials that find little effect of T therapy on male sexual function in the absence of reproductive system disorders and the small magnitude of the decrease in serum T compared with that required to impair sexual function in older men, we propose the hypothesis that declines in sexual activity and desire in older men may be important contributors to the lowering of circulating T levels. Further studies aiming to test this hypothesis are warranted.

Acknowledgments Address all correspondence and requests for reprints to: David J. Handelsman, ANZAC Research Institute, Sydney, New South Wales, Australia 2139. E-mail: [email protected]. The CHAMP study is funded by the National Health and Medical Research Council Project Grant (no. 301916), the Sydney Medical School Foundation, and the Ageing and Alzheimer’s Institute. B.H is funded by the Sydney Medical School Foundation. R.G.C., D.J.H., M.J.S., L.M.W., V.N., D.G.L.C., and F.M.B. contributed to the formulation of the study concept, design, methods, subject recruitment, and data collection. B.H. performed the analyses and wrote the manuscript. R.G.C. and D.J.H. wrote portions of the manuscript. F.M.B., V.N., D.G.L.C., M.J.S., and L.M.W. reviewed the manuscript and contributed to discussion. Disclosure Summary: B.H., F.M.B., V.N., D.G.L.C., M.J.S., L.M.W., and D.J.H. have nothing to declare. R.G.C. received an honorarium from Eli Lilly Australia for an education event.


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Alcohol consumption and tobacco smoking among community-dwelling older Australian men: the Concord Health and Ageing in Men Project.

Swimming and other sporting activities and the rate of falls in older men: longitudinal findings from the Concord Health and Ageing in Men Project.

Longitudinal relationships of circulating reproductive hormone with functional disability, muscle mass, and strength in community-dwelling older men: the Concord Health and Ageing in Men project.

Associations between circulating reproductive hormones and SHBG and prevalent and incident metabolic syndrome in community-dwelling older men: the Concord Health and Ageing in Men Project.

Relative Validity of a Diet History Questionnaire Against a Four-Day Weighed Food Record among Older Men in Australia: The Concord Health and Ageing in Men Project (CHAMP).

Reproductive Hormones and Longitudinal Change in Bone Mineral Density and Incident Fracture Risk in Older Men: The Concord Health and Aging in Men Project.

Sexual Health and Well-being Among Older Men and Women in England: Findings from the English Longitudinal Study of Ageing.

Associations between serum 25-hydroxyvitamin D concentrations and multiple health conditions, physical performance measures, disability, and all-cause mortality: the Concord Health and Ageing in Men Project.

Perceived effects of health status on sexual activity in women and men older than 50 years.

Education, marital status, and risk of hip fractures in older men and women: the CHANCES project.

Eating alone and depression in older men and women by cohabitation status: The JAGES longitudinal survey.

Perceived health status and mortality among older men and women.

The relationship between daily hassles and sexual function in men and women.

Prevalence and risk factors for falls in older men and women: The English Longitudinal Study of Ageing.

Androgen Therapy and Rehospitalization in Older Men With Testosterone Deficiency.

Sexual health status of women who have regular sexual relations with men who have sex with men in mainland China.

The relationship between health-related quality of life, obesity and testosterone levels in older men.

Insulin resistance and depressive symptoms in older men: the health in men study.

Physical function in older men with hyperkyphosis.

Health, Economic Resources and the Work Decisions of Older Men.

Sexual identity and HIV status influence the relationship between internalized stigma and psychological distress in black gay and bisexual men.

Sexual and reproductive health and rights of older men and women: addressing a policy blind spot.

Testosterone deficiency, cardiac health, and older men.

HIV status and sexual behaviour among gay men in Ottawa: considerations for public health.