Randomized placebo-controlled trial of testosterone replacement in men with mild Leydig cell insufficiency following cytotoxic chemotherapy

Objective Testosterone deficiency is associated with significant morbidity, and androgen replacement in overt hypogonadism is clearly beneficial. Howe ver, there are few data concerning the response to therapy in young men wit h mild testosterone deficiency. Design and patients We have identified a cohort of 35 men, mean age 40.9 ye ars, with mild Leydig cell dysfunction, defined by a raised LH level (LH gr eater than or equal to8 IU/I) and a testosterone level in the lower half of the normal range or frankly subnormal (testosterone <20 nmol/l), following treatment with cytotoxic chemotherapy for malignancy. Patients were assign ed randomly to 12 months treatment with transdermal testosterone (n=16) (An dropatch 2.5 mg patches, 1-2 patches per day) or placebo patches (n=19) in a single blinded manner. Measurements Measurements of bone mineral density (BMD) and body compositio n were performed at baseline, 6 months and 12 months using single and dual energy X-ray absorptiometry (SXA, DXA). In addition, spinal BMD was assesse d at baseline and 12 months by quantitative CT (OCT). Subjects were reviewe d at 3-monthly intervals; at each visit blood was taken for measurement of testosterone, SHBG, LH, FSH, oestradiol, lipids and IGF-1 and patients comp leted three questionnaires which assessed energy levels, mood and sexual fu nction. Results Total testosterone and calculated free testosterone increased signi ficantly in the testosterone-treated group compared with the placebo-treate d group (13.3 nmol/l and 342.9 pmol/l at baseline compared with 17.3 nmol/l and 454.8 pmol/l during the study period in the testosterone-treated group ; P=0.05 and P=0.02, respectively). LH was suppressed into the normal range in 15 of the 16 testosterone-treated men and mean LH significantly reduced from 11.1 IU/I at baseline to 6.8 IU/I during the study. There was no sign ificant change in BMD at the hip, spine or forearm and no change in fat or lean body mass. There was a significant reduction in physical fatigue in th e testosterone-treated group compared with the placebo-treated group (P=0.0 08) and a borderline improvement in activity score (P=0.05). There were no significant effects of treatment on mood or sexual function. Neither oestra diol nor IGF-1 levels differed between the two groups during the study. The re was no significant change in mean total cholesterol, HDL cholesterol or triglyceride levels, but there was a small, but significant reduction in LD L cholesterol levels in the testosterone-treated group compared with the pl acebo group (P=0.02). Conclusions These results suggest that testosterone therapy in young men wi th raised LH levels and low/normal testosterone levels does not result in s ignificant changes in BMD, body composition, lipids or quality of life, apa rt from a reduction in physical fatigue and a small reduction in LDL choles terol. This implies that mild hypogonadism defined on this basis is not of clinical importance in the majority of men, and that androgen replacement c annot be recommended for routine use in these patients.