Ghrelin, the only known orexigenic gut hormone, is secreted mainly from the 
stomach, increases with fasting and before meal initiation in humans and rats, 
and increases food intake after central or peripheral administration. To 
investigate sex differences in the action of ghrelin, we assessed the effects of 
exogenous ghrelin in intact male and female rats, the effects of exogenous 
ghrelin in ovariectomized (OVX) and estradiol (E2)-treated female rats, as well 
as the effects of OVX on plasma ghrelin and hypothalamic orexigneic neuropeptide 
expression in rats and on food intake and weight gain in transgenic mice lacking 
the ghrelin receptor (Ghsr(-/-) mice). Male and OVX female rats were 
significantly more sensitive than intact female rats to the orexigenic effects 
of both centrally (intra-third ventricular, i3vt, 0.01, 0.1, and 1.0 nmol) and 
systemically (ip, 3, 6, and 9 nmol) administered ghrelin. This difference is 
likely to be estradiol dependent because E2 attenuated the orexigenic action of 
ghrelin in OVX female and male rats. Furthermore, OVX increased food intake and 
body weight in wild-type mice, but not in Ghsr(-/-) mice, suggesting that OVX 
increases food intake by releasing ghrelin from a tonic inhibitory effect of 
estradiol. In addition, following OVX, there was an increase in plasma ghrelin 
that was temporally associated with increased food intake, body weight, and 
hypothalamic neuropeptide Y and Agouti-related protein mRNA expression. 
Collectively, these data suggest that estradiol inhibits the orexigenic action 
of ghrelin in females, that weight gain associated with OVX is ghrelin mediated, 
and that this endocrine interaction may account for an important sex differences 
in food intake and the regulation of body weight.