STIMULATORY EFFECTS OF INTERLEUKIN-INDUCED ACTIVATION OF THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS ON GONADOTROPIN-SECRETION IN OVARIECTOMIZEDMONKEYS REPLACED WITH ESTRADIOL
En. Xiao et al., STIMULATORY EFFECTS OF INTERLEUKIN-INDUCED ACTIVATION OF THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS ON GONADOTROPIN-SECRETION IN OVARIECTOMIZEDMONKEYS REPLACED WITH ESTRADIOL, Endocrinology, 135(5), 1994, pp. 2093-2098
In a previous report, we have shown that acute activation of the hypot
halamo-pituitary-adrenal (HPA) axis by the cytokine interleukin-1 alph
a (IL-1 alpha) in the ovariectomized (OVX) rhesus monkey results in an
inhibition of LH secretion. Here, we study whether estradiol (E) repl
acement therapy, at a level that reproduces E concentrations typical o
f the late follicular phase, modifies the gonadotropin and cortisol re
sponses to IL-1 alpha administration. For E replacement, two Silastic
capsules containing E were implanted sc 5 days before the experiment.
The serum E concentration increased from less than 5 in OVX to 103.0 /- 5.2 pg/ml in OVX and E-replaced monkeys. The experimental protocols
were carried out 24 h or more after the LH surge that had been induce
d by E. In Exp 1, the effects of an intracerebroventricular (icv) infu
sion of physiological saline (group 1) or IL-1 alpha (2.1 or 4.2 mu g/
30 min; group 2) on LH, FSH, and cortisol were compared. IL-1 alpha ad
ministration resulted in a progressive release of LH (to 159.0 +/- 8.3
% of baseline at 5 h; P < 0.05, 3-5 h vs. saline). Cortisol decreased
in group 1 (84.5 +/- 1.3% by 5 h), but increased after IL-1 alpha (147
.3 +/- 12.6%; P < 0.05 vs, saline). In Exp 2, we determined whether th
e stimulatory effects of IL-1 alpha on LH result from the central acti
vation of CRH release (group 3). Infusion of the CRH antagonist, D-Phe
(12),Nle(21,38),C(a)Me,Leu(37)-CRF-(12-41) (240 or 360 mu g/2 h) preve
nted the increase in LH seen after IL-1 alpha treatment (67.3 +/- 12.5
% at 5 h, NS vs. saline). The CRH antagonist also prevented the increa
se in cortisol and progesterone induced by IL-1 alpha. In Exp 3, we te
sted whether the stimulatory effect of IL-1 alpha on LH secretion can
be simulated by ACTH infusion (group 4). ACTH-(1-24) (10-mu g bolus pl
us 50 mu g/5 h, iv) induced a progressive increase in LH secretion (to
221.5 +/- 27.8% of baseline by 5 h; P < 0.05, 3-5 h vs. saline). ACTH
also stimulated cortisol secretion (to 203.3 +/- 30.7% by 5 h). In Ex
p 4, we investigated the role of adrenal progesterone in the LH respon
se observed in groups 2 and 4. This increase in LH did not occur after
pretreatment with RU486, a progesterone antagonist (5 mg Mifepristone
77 +/- 24.2% by 5 h; P = NS vs. saline), although the increases in co
rtisol and progesterone were not prevented. The data demonstrate that
E modulates the response of the hypothalamo-pituitary-gonadal axis to
HPA axis activation by IL-1 alpha in the primate. In the presence of E
concentrations representative of the late follicular phase, LH secret
ion in response to IL-1 alpha is stimulated rather than inhibited. Thi
s effect is presumably related to an increased release of progesterone
from the adrenals in response to HPA axis activation. It is postulate
d that progesterone, in turn, facilitates the E positive feedback on L
H secretion.