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Authors Finkelstein JS, Lee H, Burnett-Bowie SM, Pallais JC, et al
Review Date November 2013
Citation N Engl J Med 2013; 369: 1011-1022
Despite the burgeoning use of testosterone (see October journal review), its mechanism of action is not well understood. Testosterone acts both directly and indirectly (through conversion to oestradiol). More than 80% of circulating oestradiol in men is derived from the aromatisation of testosterone. When testosterone levels decline so do serum oestradiol levels. Distinguishing the mechanism of action of testosterone is not straightforward and it has recently become apparent that oestrogen deficiency may be important in some effects of male hypogonadism, such as bone loss.
The current approaches to diagnosing testosterone deficiency do not consider the physiological consequences of various testosterone levels or whether deficiencies of testosterone, oestradiol, or both are responsible for clinical manifestations.
The study was designed to suppress endogenous testosterone and then add back one of four different doses of testosterone (or placebo), with half also receiving an aromatase inhibitor to block synthesis of oestradiol. The aim was to tease out the separate or combined effects of testosterone deficiency and oestradiol deficiency on body composition, strength and sexual function, and to determine the level of androgen deficiency at which adverse changes begin to occur.
The study included 400 healthy men 20 to 50 years of age with normal serum testosterone levels. 198 men were given goserelin acetate to suppress endogenous testosterone and oestradiol and were randomly assigned to receive a placebo gel or 1.25 g, 2.5 g, 5 g, or 10 g of testosterone gel daily for 16 weeks. Another 202 healthy men received goserelin acetate, placebo gel or testosterone gel, and anastrozole to suppress the conversion of testosterone to oestradiol.
Primary outcome measures were change in percentage body fat and change in lean mass measured by DXA. Subcutaneous and intra-abdominal fat areas (measured by CT), thigh muscle area (measured at mid-femur) and strength (leg press weight), and sexual function (measured with HR-QOL questionnaire and divided into erectile function and sexual desire) were secondary outcomes.
Modified intention-to-treat statistical analyses were done.
There was some loss to follow-up in both cohorts: the men not given (cohort 1) and the men given (cohort 2) aromatase inhibitors. Numbers included in analyses of various outcomes ranged from 184 to 166 in cohort 1 and 174 to 158 in cohort 2. The percentage of body fat increased in groups receiving placebo or 1.25 g or 2.5 g of testosterone daily without anastrozole (mean testosterone level, 44±13 ng/dL, 191±78 ng/ dL, and 337±173 ng/dL, respectively). Lean mass and thigh-muscle area decreased in men receiving placebo and in those receiving 1.25 g of testosterone daily without anastrozole. Leg-press strength fell only with placebo administration. In general, sexual desire declined as the testosterone dose was reduced.
The study showed that the amount of testosterone needed for maintenance of lean mass, fat mass, strength, and sexual function varied widely; however the current diagnosis of androgen deficiency relies on a single measure of testosterone (2SD below the mean in normal young men). Androgen deficiency accounted for decreases in lean mass, muscle size, and strength; oestrogen deficiency primarily accounted for increases in body fat; and both contributed to the decline in sexual function. The clinical implications of the study suggest a change in the evaluation and management of hypogonadism in men.
Points to Note
- This study makes a significant contribution to understanding the degree of hypogonadism in men at which adverse changes occur and the role of androgens and oestrogens in specific outcomes.
- The finding that oestrogen deficiency is largely responsible for some of the main consequences of androgen deficiency suggest that measuring oestradiol may be helpful in assessing risk of fat accumulation or sexual dysfunction.
- The study was limited by a relatively short follow-up (16 weeks) whereby the possible longer term effects of the higher dose testosterone may have been missed. Also, acute gonadal steroid deprivation may induce different effects to those from gradual decline over years.
- Other limitations include the characteristics of the participants (age 20-50 years, healthy men), limited outcome measures, and inclusion of four discrete doses of testosterone (effects are likely to be on a continuum).
- Future studies should include longer time-frames and inclusion of other outcome measures such as bone density and fractures, cardiovascular function and cerebral function.