DIFFERENTIAL RESPONSES OF BIOLOGICALLY-ACTIVE LUTEINIZING-HORMONE SECRETION IN OLDER VERSUS YOUNG MEN TO INTERRUPTION OF ANDROGEN NEGATIVE FEEDBACK

To investigate the responsiveness of the healthy aging male hypothalam o-pituitary-gonadal axis to short term interruption of androgen negati ve feedback, we administered a selective nonsteroidal competitive anta gonist of the androgen receptor, flutamide hydrochloride (250 mg, oral ly, three times daily for 3.5 days), to five older (aged 63-72 yr) and eight young (aged 21-30 yr) men. Pulsatile bioactive LH release was a ssessed by the rat interstitial cell testosterone bioassay in plasma s ampled at 10-min intervals for 8 h overnight at baseline and after flu tamide administration. Pituitary responsiveness was evaluated after tw o successive iv injections of 10 mu g GnRH. Deconvolution analysis was used to estimate the number, amplitude, duration, and mass of bioacti ve LH secretory bursts and the half-life of biologically active hormon e. At baseline, older men exhibited a significantly lower spontaneous bioactive LH secretory burst frequency than young men, with a median o f 5 events/8 h (older) vs. 7.5 bursts/8 h (younger, P < 0.05). In olde r men, mean 8-h plasma bioactive LH concentrations increased significa ntly in response to flutamide (P = 0.006), and the 8-h calculated secr etion rate of bioactive LH rose concomitantly. These increases were si milar to responses in young men. However, during antiandrogen administ ration, the frequency of bioactive LH secretory bursts failed to rise in older men to the baseline value seen in young men. Moreover, older (but not young) men showed a significant prolongation of the LH secret ory burst duration in response to flutamide treatment. On the other ha nd, the estimated half-life of endogenous bioactive LH increased Signi ficantly after flutamide ingestion in young compared to older individu als. After GnRH injections, older and young men secreted similar amoun ts of LH before flutamide administration, but during flutamide treatme nt, older men released more biologically active LH after the first GnR H stimulus [older men, 104 +/- 11 IU/L (median, 110); younger men, 44 +/- 8.4 IU/L (median, 40); P < 0.05]. Serum free testosterone concentr ations rose significantly during flutamide exposure in both young and older men, but estradiol concentrations increased significantly only i n young men. In summary, healthy older men exhibit a reduced (overnigh t) spontaneous bioactive LH secretory burst frequency. Pharmacological attenuation of androgen-mediated negative feedback increases mean ser um free testosterone concentrations and plasma bioactive LH concentrat ions to a similar degree in older and young individuals, but different mechanisms operate in the two age groups. In older men, flutamide tre atment amplifies the mass of bioactive LH secreted per burst by prolon ging the LH secretory burst duration, whereas in young men, flutamide administration increases the apparent half-life of biologically active LH significantly relative to values in older men. We conclude that co mpetitive nonsteroidal blockade of the androgen receptor unmasks quali tatively altered mechanisms of increased bioactive LH release in healt hy older men.