Women's health disorders such as uterine fibroids and endometriosis are 
currently treated by GnRH modulators that effectively suppress the 
hypothalamic-pituitary-gonadal axis. The neurokinin-3 receptor (NK3R) is an 
alternative target with an important role in the modulation of this axis. In 
this report, we demonstrate that systemic administration of an NK3R antagonist 
(ESN364) prolongs the LH interpulse interval in ovarectomized ewes and 
significantly lowers plasma LH and FSH concentrations in castrated nonhuman 
primates (Macaca fascicularis). Moreover, daily oral dosing of ESN364 throughout 
the menstrual cycle in M fascicularis lowered plasma estradiol levels in a 
dose-dependent manner, although nadir levels of estradiol were maintained well 
above menopausal levels. Nevertheless, estradiol levels during the follicular 
phase were sufficiently inhibited at all doses to preclude the triggering of 
ovulation as evidenced by the absence of the LH surge and failure of a 
subsequent luteal phase rise in plasma progesterone concentrations, consistent 
with the absence of normal cycle changes in the uterus. Apart from the point at 
surge, FSH levels were not altered over the course of the menstrual cycle. These 
effects of ESN364 were reversible upon cessation of drug treatment. Together 
these data support the proposed role of neurokinin B-NK3R signaling in the 
control of pulsatile GnRH secretion. Furthermore, in contrast to GnRH 
antagonists, NK3R antagonists induce a partial suppression of estradiol and 
thereby offer a viable therapeutic approach to the treatment of ovarian sex 
hormone disorders with a mitigated risk of menopausal-like adverse events in 
response to long-term drug exposure.