Androgen-receptor blockade enhances pulsatile luteinizing hormone production in late pubertal males: evidence for a hypothalamic site of physiologic androgen feedback action.
To determine potential mechanisms by which androgens alter gonadotropin secretion and elimination in the pubertal male, we administered the potent nonsteroidal androgen receptor blocking agent, flutamide, to eight males with Tanner IV or V genital development. Venous blood samples were obtained every 10 min for 24 h and assayed for LH by a sensitive and high-precision fluorimmunoassay. Subjects were studied before and after the administration of flutamide. Deconvolution analysis was used to assess specific pulsatile LH secretory characteristics and estimate LH production and metabolic clearance rates quantitatively. After antagonism of endogenous androgen action, mean 24-h serum LH concentrations increased significantly. An increased mean 24-h LH production rate, without evident changes in serum LH half-life, accounted for the increase in average serum LH levels. The increased daily secretion rate of LH was in turn due to both an augmented mass of LH released per secretory episode and increased frequency of secretory events. There was no demonstrable change in the maximal rate of LH secretion attained within each secretory event. Serum concentrations of total testosterone, free-testosterone, and 17 beta-estradiol all increased during blockade of androgen action. Administration of the antiandrogen had no measurable effect on the pituitary response to a single maximally effective dose of exogenous gonadotropin releasing hormone (GnRH). These results indicate that, in the late pubertal male, endogenous androgen exerts negative feedback control of gonadotropin secretion primarily at a hypothalamic site reflected by regulation of the frequency of pulsatile LH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Kerrigan
J R
JR
Department of Pediatrics, University of Virginia Health Sciences Center, Charlottesville 22908.
Veldhuis
J D
JD
Rogol
A D
AD
D000293:Adolescent; D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000378:metabolism; D004958:Estradiol / Q000097:blood; D005246:Feedback; D005485:Flutamide / Q000494:pharmacology; D005640:Follicle Stimulating Hormone / Q000097:blood; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D008297:Male; D011627:Puberty / Q000378:metabolism*; D013739:Testosterone / Q000097:blood
D059002:Androgen Receptor Antagonists; D000728:Androgens; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D004958:Estradiol; D005485:Flutamide; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone