Differential regulation of gonadotropin secretion by testosterone in the human male: Absence of a negative feedback effect of testosterone on follicle-stimulating hormone secretion
Fj. Hayes et al., Differential regulation of gonadotropin secretion by testosterone in the human male: Absence of a negative feedback effect of testosterone on follicle-stimulating hormone secretion, J CLIN END, 86(1), 2001, pp. 53-58
Studies of sex steroid regulation of gonadotropin secretion in the human ma
le have focused primarily on the respective site(s) of negative feedback of
testosterone (T) and estradiol (E-2). The use of pharmacological doses of
sex steroids in these studies has precluded conclusions about the relative
roles of T and E-2 in gonadotropin feedback. Thus, the aims of the present
study were to 1) determine the relative contributions of T vs. E-2 to the s
ex steroid component of gonadotropin regulation, and 2) distinguish the fee
dback effects of T that that are direct (i.e. mediated by the androgen rece
ptor) vs. indirect (mediated by aromatization to E-2).
Two experimental interventions were used: 1) inhibition of aromatization by
a selective aromatase inhibitor to examine the impact of selective E-2 wit
hdrawal; and 2) acute medical castration to examine the effect of ablating
both T and E-2. Sixteen normal (NL) men (mean age, 30.5 +/- 2.2 yr) were st
udied. Nine NL subjects were treated with the aromatase inhibitor, anastroz
ole (10 mg, orally, daily, for 5 days). Twelve NL men underwent medical cas
tration with ketoconazole (1-g loading dose followed by 400 mg, orally, fou
r times a day for 5 days). Ketoconazole-treated subjects received concomita
nt treatment with dexamethasone (0.5 mg twice daily) to prevent the develop
ment of adrenal insufficiency. Single blood samples were drawn daily betwee
n 0800-1000 h. To ensure that dexamethasone was not altering the gonadotrop
in response to sex steroid ablation by a direct pituitary effect, live GnRH
-deficient men (mean age, 37.6 +/- 3.9 yr) underwent GnRH dose-response stu
dies at baseline and after treatment with dexamethasone (0.5 mg twice daily
).
Aromatase blockade caused significant lowering of E-2 (33 +/- 3 to 14 +/- 1
pg/mL; P < 0.0005) with a corresponding increase in T levels (563 +/- 42 t
o 817 +/- 81 ng/dL; P < 0.05). Treatment with ketoconazole resulted in equi
valent suppression of E-2 (41 +/- 4 to 14 +/- 1 pg/mL; P < 0.0005), but als
o induced castrate levels of T (491 +/- 28 to 40 +/- 3 ng/dL; P < 0.0005).
Both treatment regimens were associated with a significant increase in gona
dotropin levels. For LH, the percent increase in serum levels after castrat
ion was almost 3-fold greater than that seen after selective E-2 withdrawal
(275 +/- 23% with ketoconazole us. 95.6 +/- 21% with anastrozole; P < 0.00
5). Despite the divergent changes in T levels with these two maneuvers (a m
arked decrease after ketoconazole and a significant increase with anastrozo
le), the percent rise in FSH levels was similar in the two protocols (91 +/
- 6% vs. 71 +/- 7%, respectively; P = NS). Inhibin B levels were unchanged
after selective E-2 withdrawal (156 +/- 23 vs. 176 +/- 19 pg/mL), but decre
ased slightly with ketoconazole (156 +/- 15 to 131 +/- 11 pg/mL; P < 0.05).
In contrast to the effects of glucocorticoid administration on gonadotropi
n secretion in women, no significant changes were observed in the GnRH-defi
cient men treated with dexamethasone in terms of mean LH levels (19.8 +/- 3
.2 vs. 23.3 +/- 5.4 IU/L), mean LH pulse amplitude after GnRH (16.0 +/- 2.5
vs. 19.0 +/- 5.1 IU/L), or mean FSH levels (8.0 +/- 1.9 vs. 9.2 +/- 2.4 IU
/L, pre vs. post).
These studies provide evidence of differential regulation of gonadotropin s
ecretion by T in the human male. T exerts both direct and indirect feedback
on LH secretion, whereas its effects on FSH appear to be mediated largely
by aromatization to E-2. From these data we conclude that in terms of sex s
teroid feedback, E-2 is the predominant regulator of FSH secretion in the h
uman male.