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In secondary hypogonadism, free testosterone levels may predict sexual function in men

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July 5, 2018

Giulia Rastrelli
Giulia Rastrelli

The onset of secondary hypogonadism is associated with the development or worsening of androgen deficiency symptoms only when total testosterone and free testosterone are low, according to findings published in Clinical Endocrinology.

“This information is important in confirming that only a minority (27.3%) of obese men have low free testosterone, implying that most obese men with low total testosterone associated with low sex hormone-binding globulin do not have symptomatic hypogonadism,” Giulia Rastrelli, MD, PhD, assistant professor in the sexual medicine and andrology unit at the University of Florence, Italy, told Endocrine Today.

In a prospective, observational study, Rastrelli and colleagues analyzed data from 2,019 men aged 40 to 79 years participating in the European Male Aging Study, a population-based survey of eight European countries: Belgium, Estonia, Hungary, Italy, Poland, Spain, Sweden and the United Kingdom (mean age, 58 years). At baseline and follow-up, men provided fasting blood samples to measure testosterone, luteinizing hormone, SHBG, free testosterone (calculated using the Vermeulen formula), total testosterone (lower limit was defined as 0.05 ng/mL) and serum insulin. Men also completed the Sexual Function Questionnaire, the SF-36 and the Beck Depression Inventory to assess sexual function, physical and psychological symptoms associated with androgen deficiency, with changes in symptoms at follow-up defined as developing or worsening.

Eugonadism was defined as a total testosterone of at least 10.5 nmol/L and secondary hypogonadism was defined as a total testosterone of less than 10.5 nmol/L and luteinizing hormone of 9.4 U/L or less. Men identified as having incident secondary hypogonadism were further stratified by free testosterone levels, including normal free testosterone ( 170 pmol/L) and low total testosterone and low free testosterone (< 170 pmol/L) with low total testosterone. Researchers used binary logistic regression analyses to assess the relationship between change in gonadal status and change in clinical features of hypogonadism, with nine putative symptoms of hypogonadism as outcomes.

Median follow-up was 4.3 years. At baseline, all men had total and free testosterone levels within the normal range.

Within the cohort, 1,880 men were eugonadal and 139 developed secondary hypogonadism at follow-up. Among men with incident secondary hypogonadism, 101 (72.7%) had a free testosterone of at least 170 pmol/L and 38 men (27.3%) had a free testosterone of less than 170 pmol/L. During follow-up, cumulative incidence for secondary hypogonadism with normal and low levels of free testosterone were 4.9% and 1.9%, respectively. The researchers found that baseline obesity status predicted secondary hypogonadism in the setting of both low and normal free testosterone; however, men with normal levels of free testosterone tended to be younger.

Additionally, researchers found that secondary hypogonadism with low free testosterone was associated with new and worsening sexual symptoms, including low desire (OR = 2.67; 95% CI, 1.27-5.6), erectile dysfunction (OR = 4.53; 95% CI, 2.05-10.01) and infrequent morning erections (OR = 3.4; 95% CI, 1.48-7.84). Researchers observed no differences between eugonadal men and men with secondary hypogonadism with normal free testosterone levels with respect to sexual, physical or psychological symptoms at baseline or follow-up, persisting after adjustment for age, country, comorbidities and smoking status.

During follow-up, recovery from secondary hypogonadism to eugonadism occurred in 46.2% of men with normal levels of free testosterone and in 27.5% of men with low free testosterone; however, analyses on possible predictors of recovery did not yield meaningful information due to the small sample size, according to the researchers.

The incidence rate of secondary hypogonadism in the population is relatively low at 0.4% per year, Rastrelli said, and the findings provide strong evidence to support the use of free testosterone, either obtained directly by equilibrium dialysis measurement or derived by validated calculation formula, in the accurate diagnosis of hypogonadism and to avoid overdiagnosis — and overtreatment — in symptomatic men with obesity.

“Further studies in different research context are needed for confirming the relevance of the assessment of free testosterone in the definition of hypogonadism,” Rastrelli said. – by Regina Schaffer

For more information:

Giulia Rastrelli, MD, PhD, can be reached at the University of Florence, Department of Experimental and Clinical Biomedical Sciences, Sexual Medicine and Andrology Unit, Viale Pieraccini, 6, 50139 Florence, Italy; email:

Disclosures: Rastrelli reports no relevant financial disclosures. Please see the study for the other authors’ relevant financial disclosures.

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