Objective: The present study was designed to explore further the mechanism for the decline in androgen production as men age by studying the influence of ageing on testosterone negative feedback control of gonadotrophin secretion.
Design: Circulating testosterone, dihydrotestosterone, oestradiol, SHBG and LH concentrations were measured during long-term treatment of men with primary hypogonadism using transdermal testosterone via scrotal skin.
Patients: Results were compared in 12 hypogonadal men below age 40 years (34 +/- 1.1 years; mean +/- SEM), 13 middle-aged men, aged 51 +/- 2.2 years, and 10 men age 64 years or older (68 +/- 1.4 years).
Results: During the course of therapy, circulating LH levels were suppressed 48% (F = -2.42, P = 0.018) from 19.6 +/- 6.0 IU/I at baseline to 10 +/- 7.7 IU/I during month 15 in elderly men. By contrast, LH levels were unchanged (F = 0.31; P = 0.97) in young men (20.3 +/- 7.4 IU/I at baseline and 17.7 +/- 14.9 IU/I during treatment month 15). Intermediate results were observed in middle-aged men in whom LH levels declined slightly (F = 1.34; P = 0.24). Transdermal testosterone treatment produced similar circulating testosterone levels (F = 1.49; P = 0.24) and oestradiol levels (F = 0.60; P = 0.42) in elderly and young men. Mean plasma DHT levels were approximately 20% higher (F = 9.91; P = 0.01) during treatment in elderly men overall mean values of 8.03 +/- 0.37 nmol/l) than in young men (6.68 +/- 0.08 nmol/l). When total DHT was adjusted for higher plasma SHBG levels in elderly men, the free DHT index during treatment was similar (F = 0.23; P = 0.64) in both groups.
Conclusions: These data provide further evidence that the set point for androgen negative feedback control of gonadotrophin accretion in men is altered by ageing. Taken together with previous findings, these results provide a potential explanation for the unchanged or slightly increased plasma LH levels and reduced testosterone production characteristic of elderly men. Accordingly, ageing-associated Leydig cell insufficiency leads to a decline in testosterone production, but circulating LH levels do not rise appropriately because the set-point for negative feedback is decreased.