Age disrupts androgen receptor-modulated negative feedback in the gonadal axis in healthy men.
Testosterone (T) exerts negative feedback on the hypothalamo-pituitary (GnRH-LH) unit, but the relative roles of the CNS and pituitary are not established. We postulated that relatively greater LH responses to flutamide (brain-permeant antiandrogen) than bicalutamide (brain-impermeant antiandrogen) should reflect greater feedback via CNS than pituitary/peripheral androgen receptor-dependent pathways. To this end, 24 healthy men ages 20-73 yr, BMI 21-32 kg/m2, participated in a prospective, placebo-controlled, randomized, double-blind crossover study of the effects of antiandrogen control of pulsatile, basal, and entropic (pattern regularity) measurements of LH secretion. Analysis of covariance revealed that flutamide but not bicalutamide 1) increased pulsatile LH secretion (P = 0.003), 2) potentiated the age-related abbreviation of LH secretory bursts (P = 0.025), 3) suppressed incremental GnRH-induced LH release (P = 0.015), and 4) decreased the regularity of GnRH-stimulated LH release (P = 0.012). Furthermore, the effect of flutamide exceeded that of bicalutamide in 1) raising mean LH (P = 0.002) and T (P = 0.017) concentrations, 2) accelerating LH pulse frequency (P = 0.013), 3) amplifying total (basal plus pulsatile) LH (P = 0.002) and T (P < 0.001) secretion, 4) shortening LH secretory bursts (P = 0.032), and 5) reducing LH secretory regularity (P < 0.001). Both flutamide and bicalutamide elevated basal (nonpulsatile) LH secretion (P < 0.001). These data suggest the hypothesis that topographically selective androgen receptor pathways mediate brain-predominant and pituitary-dependent feedback mechanisms in healthy men.
Veldhuis
Johannes D
JD
Mayo School of Graduate Medical Education, Mayo Clinic, 200 First St. SW/Mayo Clinic, Rochester, MN 55905, USA. veldhuis.johannes@mayo.edu
Takahashi
Paul Y
PY
Keenan
Daniel M
DM
Liu
Peter Y
PY
Mielke
Kristi L
KL
Weist
Suanne M
SM
D000328:Adult; D000367:Age Factors; D000368:Aged; D000726:Androgen Antagonists / Q000097:blood / Q000494:pharmacology*; D000813:Anilides / Q000097:blood / Q000494:pharmacology; D002490:Central Nervous System / Q000187:drug effects / Q000502:physiology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004958:Estradiol / Q000097:blood; D005246:Feedback / Q000187:drug effects; D005485:Flutamide / Q000097:blood / Q000494:pharmacology; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology*; D016014:Linear Models; D007986:Luteinizing Hormone / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000097:blood / Q000494:pharmacology; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology*; D011446:Prospective Studies; D011944:Receptors, Androgen / Q000502:physiology*; D012738:Sex Hormone-Binding Globulin / Q000032:analysis; D013739:Testosterone / Q000097:blood; D014105:Tosyl Compounds / Q000097:blood / Q000494:pharmacology; D055815:Young Adult
D000726:Androgen Antagonists; D000813:Anilides; D009570:Nitriles; D011944:Receptors, Androgen; D012738:Sex Hormone-Binding Globulin; D014105:Tosyl Compounds; D013739:Testosterone; D004958:Estradiol; D005485:Flutamide; D007986:Luteinizing Hormone; C053541:bicalutamide