Introduction: As men age, the prevalence of sexual dysfunction, low vitality, poor physical function, and low total and free testosterone (TT and FT) levels increases. However, it is unclear whether low sex hormone levels are independently related to age-related changes in sexual function, vitality, and physical function in older men.
Methods: Researchers analyzed baseline data from 788 older men (age ≥65 years) with low testosterone levels (<275 ng/dL on 2 readings) participating in the cross-sectional Testosterone Trials (TTrials). All the participants had self-reported sexual dysfunction, decreased vitality, and/or mobility limitations. Baseline measures of TT, FT, estradiol, and sex hormone-binding globulin (SHBG) levels were included in the analysis.
Vitality was assessed using the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale and physical function was measured using the Physical Function Subscale of the Medical Outcomes Study Short Form-36 Health Survey Questionnaire and the 6-minute walk test. Sexual desire was measured using the Sexual Desire Domain of the Derogatis Interview for Sexual Function (DISF), erectile function was measured using the Erectile Function Domain of the International Index of Erectile Function, and sexual activity over 7 days was measured using the question 4 of the Psychosexual Daily Questionnaire.
Results: A significant, independent, positive association was found between TT and FT levels (but not estradiol or SHBG) and sexual desire (P=0.03), erectile function (P=0.004), and sexual activity (P=0.02). In contrast, TT and FT levels were not associated with FACIT-Fatigue, PHQ-9 Depression or Physical Function-10 scores, or gait speed.
Conclusion: A small yet statistically significant positive association was found between TT and FT levels and sexual desire, erectile function, and sexual activity, but not with vitality or physical function in older men with symptomatic low testosterone levels.
Cunningham GR, Stephens-Shields AJ, Rosen RC, et al. Association of sex hormones with sexual function, vitality, and physical function of symptomatic older men with low testosterone levels at baseline in the testosterone trials. J Clin Endocrinol Metab. 2015;100(3):1146-1155.
Commentary by Tamara L Wexler MD, PhD
Tamara L. Wexler, MD, PhD, is an endocrinologist specializing in neuroendocrinology and reproductive endocrinology. She is the Director of the NYU Langone Medical Center Pituitary Center in New York, NY, as well as an Attending in Medicine at Massachusetts General Hospital, Boston, MA.
As men age, they may experience changes in sexual function, energy, and physical strength. In addition, testosterone levels have been observed to decrease over time. Whether there is a causal relationship between testosterone levels and the above-noted symptoms has not been conclusively determined. Population studies differ as to the association between sexual symptoms such as libido and erectile function and testosterone level, with some studies showing an association with testosterone level1,2 and others only with other factors such as age or body mass index (BMI).3,4
The Testosterone Trials (TTrials) was designed as a multicenter randomized clinical effort to investigate the effects of testosterone replacement in 800 men 65 years and older. The study, as a whole, encompasses ongoing trials in seven domains: physical function, vitality, sexual function, cognitive function, anemia, bone, and cardiovascular risk. This article describes baseline characteristics of the 788 participants in the trials with regard to sexual function, vitality, and physical function.
The cohort enrolled in the TTrials was carefully delineated: community-dwelling men ≥65 years old; two early-morning low T levels (<275 ng/dL and <300 ng/dL; none <100 unless further testing was consistent with primary and not secondary hypogonadism); self-reported sexual dysfunction, decreased vitality and/or mobility. Enrollment in specific trials—the Sexual Function Trial (n=470), Vitality Trial (n=474), and Physical Function Trial (n=390)—was based on further criteria. Primary outcomes analysis in each trial included only those men who qualified, with participants being able to participate in more than one trial; however, outcomes were collected across the entire study cohort.
Metrics included self-reported measures and scoring on validated questionnaires. Hormone levels measured included total testosterone (TT), free testosterone (FT), estradiol (E2), and sex hormone-binding globulin (SHBG). Baseline testosterone and estradiol levels did not differ between the groups. The authors were careful to specify which tests were used for both hormone measurements and outcomes. Multivariable regression adjusted for potential confounders of age and BMI, and for Sexual Function Trial-specific factors of waist circumference, diabetes, and hypertension. Results were not corrected for multiple comparisons, as noted by the authors, thus adding power to detect real changes but increasing the potential for false positives.
Those men whose self-assessment and questionnaire results qualified them for the Physical Function Trial tended to be slightly older (73.3 years vs 71.6 or 71.9 years) and a higher percentage had diabetes (42.6% vs 35 and 35.7%). BMI and average baseline hormone levels were similar across trials.
Given the higher rate of diabetes in the Physical Function group, it may be of interest to determine whether diabetes served as a confounder in those results, as well as in the Sexual Function trial results.
Results of the baseline analysis indicate a statistically significant relationship between testosterone levels and sexual desire, sexual activity, and erectile function. The clinical significance of those changes is not discussed [ie, whether the 0.63 point increase in DISF score correlated with a 1 standard deviation increase (70 ng/dL) in testosterone is clinically meaningful]. There was no association between testosterone or estradiol levels and measures of physical function and vitality.
An association between estradiol levels and sexual desire and activity only reached statistical significance within the entire study cohort. An inverse association with SHBG and sexual desire was also seen only across the entire study cohort; that association is not surprising, given that a higher binding protein level suggests lower free testosterone. No significant association was noted between estradiol and measures of sexual function within the Sexual Function Trial.
This contrasts with the findings of Finklestein and colleagues (2013),5 as discussed in our March 2014 issue of EndoScan. That group studied the level of testosterone and/ or estradiol deficiency at which deficiencies in body composition, strength, and sexual function begin to occur by controlling the testosterone and estradiol levels of healthy men 20-50 years old. They found that testosterone levels appeared to regulate lean body mass, muscle size and strength, while estradiol levels regulated fat accumulation, and both testosterone and estradiol regulated sexual function (desire and erectile function).
The absence of associations of baseline estradiol and sexual function in the TTrials, and between testosterone or estradiol levels and vitality and physical function, may be due to the specific enrollment criteria in the study. The TTrials focus on men 65 years and older; Finkelstein and colleagues studied men 20-50 years old. It may be that the threshold hormone levels at which symptoms occur are different in different age groups.6,7 In addition, Cunningham and colleagues measured baseline estradiol and a set range of baseline testosterone levels. Finkelstein and colleagues carefully controlled estradiol and testosterone levels in their study (suppressed estradiol and testosterone levels in both Finkelstein study cohorts, with testosterone replacement accompanied by anastrozole in one cohort to block conversion to estradiol). The TTrial criteria were chosen to ensure that testosterone levels were not so low as to limit generalizability, but were clearly below normal values,8 excluding most men with testosterone <100 ng/dL. Finkelstein and colleagues included men (those given placebo after goserelin acetate) with fully suppressed testosterone levels.
As we were going to press, the results of one year of testosterone replacement (vs placebo) were published, as described next in this EndoScan.
1. Gades NM, Jacobson DJ, McGree ME, et al. The associations between serum sex hormones, erectile function, and sex drive: The Olmsted County Study of Urinary Symptoms and Health Status among Men. J Sex Med. 2008;5(9):2209-2220.
2. O'Connor DB, Lee DM, Corona G, et al. The relationships between sex hormones and sexual function in middle-aged and older European men. J Clin Endocrinol Metab. 2011;96(10):E1577–1587.
3. Marberger M, Wilson TH, Rittmaster RS. Low serum testosterone levels are poor predictors of sexual dysfunction. BJU Int. 2011;108(2):256–262.
4. Bhasin S, Pencina M, Jasuja GK, et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J Clin Endocrinol Metab. 2011;96(8):2430–2439.
5. Finkelstein JS, Yu EW, Burnett-Bowie SA. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013;369(25):2457.
6. Scovell JM, Ramasamy R, Wilken N, et al. Hypogonadal symptoms in young men are associated with a serum total testosterone threshold of 400 ng/dL. BJU Int. 2015;116(1):142-146.
7. Ramasamy R, Wilken N, Scovell JM, et al. Hypogonadal symptoms are associated with different serum testosterone thresholds in middle-aged and elderly men. Urology. 2014;84(6):1378-1382.
8. Snyder PJ, Ellenberg SS, Cunningham GR, et al. The testosterone trials: Seven coordinated trials of testosterone treatment in elderly men. Clin Trials. 2014;11(3):362-375.