The NK3 Receptor Antagonist ESN364 Interrupts Pulsatile LH Secretion and Moderates Levels of Ovarian Hormones Throughout the Menstrual Cycle

Fraser GL, Graeme L Fraser, Hamid R Hoveyda, Hoveyda HR, Clarke IJ, Iain J Clarke, Ramaswamy S, Suresh Ramaswamy, Plant TM, Tony M Plant, Claudia Rose, Rose C, Robert P. Millar
Endocrinology · 2015 · doi:10.1210/en.2015-1409 · PMID:26305889
other OA: bronze public-domain-us
📄 Open PDF View on PubMed View at publisher
⚙ AI-generated summary by gemini-2.5-flash-lite, 2026-07-31 ⓘ

ESN364, an NK3 receptor antagonist, interrupts pulsatile LH secretion and dose-dependently reduces ovarian hormone levels by inhibiting ovulation, without causing menopausal levels of estradiol.

One-sentence paraphrase of the abstract; not a substitute for reading it. No clinical advice. How this works

Abstract

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.

My notes (saved in your browser only)

Condition tags

endometriosis

MeSH descriptors

Estradiol Luteinizing Hormone Menstrual Cycle Progesterone Receptors, Neurokinin-3 Animals Castration Estradiol Female Follicle Stimulating Hormone Follicle Stimulating Hormone Luteinizing Hormone Macaca fascicularis Male Menstrual Cycle Menstrual Cycle Progesterone Receptors, Neurokinin-3 Sheep

Citation neighborhood (sparse)

Too few in-corpus citations on either side for a chart; here are the lists.

Cites (4)

References (52)

Source provenance

crossref
last seen: 2026-05-16T01:00:23.683965+00:00
europepmc
last seen: 2026-08-28T06:11:01.063540+00:00
pubmed
last seen: 2026-05-13T22:17:46.044120+00:00
unpaywall
last seen: 2026-05-14T19:30:52.867331+00:00
License: public-domain-us · commercial use OK · attribution required
Courtesy of the U.S. National Library of Medicine