Inhibition of luteinizing hormone secretion by testosterone in men requires aromatization for its pituitary but not its hypothalamic effects: evidence from the tandem study of normal and gonadotropin-releasing hormone-deficient men.
BACKGROUND
Studies on the regulation of LH secretion by sex steroids in men are conflicting.


OBJECTIVE
Our aims were to determine the relative contributions of testosterone (T) and estradiol (E2) to LH regulation and localize their sites of negative feedback.


METHODS
This was a prospective study with three arms.


METHODS
The study was conducted at a General Clinical Research Center.


METHODS
Twenty-two normal (NL) men and 11 men with GnRH deficiency due to idiopathic hypogonadotropic hypogonadism (IHH) participated.


METHODS
Medical castration and inhibition of aromatase were achieved using high-dose ketoconazole (KC) for 7 d with 1) no sex steroid add-back; 2) T enanthate 125 mg im starting on d 4; or 3) E2 patch 37.5 microg/d starting on d 4. Blood sampling was performed every 10 min for 12 h at baseline, overnight on d 3-4 and d 6-7.


METHODS
Mean LH levels, LH pulse amplitude, and GnRH pulse frequency were assessed at baseline, d 3-4, and d 6-7.


RESULTS
In NL men, KC caused a 3-fold increase in mean LH on d 3-4, which was stable on d 6-7 with no add-back. Addition of T reduced LH levels (34.6+/-3.9 to 17.4+/-3.6 IU/liter, P<0.05) by slowing GnRH pulse frequency (13.3+/-0.4 to 6.7+/-1.0 pulses/12 h, P<0.005). LH amplitude increased (6.9+/-1.0 to 12.1+/-1.4 IU/liter, P<0.005). E2 add-back suppressed LH levels (36.4+/-5.6 to 19.0+/-2.4 IU/liter, P<0.005), by slowing GnRH pulse frequency (11.4+/-0.2 to 8.6+/-0.4 pulses/12 h, P<0.05) and had no impact on LH pulse amplitude. In IHH men, restoring normal T levels caused no suppression of mean LH levels or LH amplitude. E2 add-back normalized mean LH levels and decreased LH amplitude from 14.7+/-1.7 to 12+/-1.5 IU/liter (P<0.05).


CONCLUSIONS
1) T and E2 have independent effects on LH. 2) Inhibition of LH by T requires aromatization for its pituitary, but not hypothalamic effects. 3) E2 negative feedback on LH occurs at the hypothalamus.
Pitteloud
Nelly
N
Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA.
Dwyer
Andrew A
AA
DeCruz
Suzzunne
S
Lee
Hang
H
Boepple
Paul A
PA
Crowley
William F
WF
Hayes
Frances J
FJ
D000328:Adult; D047072:Aromatase Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D025461:Feedback, Physiological; D007987:Gonadotropin-Releasing Hormone / Q000172:deficiency*; D006801:Humans; D007006:Hypogonadism / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects*; D007654:Ketoconazole / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D010902:Pituitary Gland / Q000187:drug effects*; D011446:Prospective Studies; D013739:Testosterone / Q000378:metabolism / Q000494:pharmacology*
D047072:Aromatase Inhibitors; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D004958:Estradiol; D007986:Luteinizing Hormone; D007654:Ketoconazole