PROJECT II (Kl: SEMINARA) Over the last five years, Project II has explored the physiology of kisspeptin as a powerful stimulus of GnRH secretion. The focus of Project II in the current grant cycle is the integration of kisspeptin with another neuropeptide that has recently been implicated in the genetics of GnRH deficiency, neurokinin B. Patients with mutations in the neurokinin pathway have high rates of reversal of their hypogonadotropism with restoration of endogenous GnRH-induced LH pulses. The first specific aim explores the subphenotype of reversible GnRH deficiency in patients with mutations in the kisspeptin and neurokinin B pathways, and in particular, the relationship between reversal and sex steroid exposure. The second specific aim explores the physiologic interplay between kisspeptin and neurokinin B in stimulating GnRH secretion in normal volunteers and patients carrying mutations in each of these signaling pathways. These tools will include continuous kisspeptin administration via infusion-(acting as a surrogate kisspeptin receptor antagonist), and a neurokinin B receptor antagonist. The third specific aim extends the physiologic tools used in the human into the mouse, as well as incorporating phenotyping of mice with targeted deletions within the neurokinin B pathway, and developing a mouse model of reversible hypogonadotropism.

Public Health Relevance

These studies have direct implications for reproductive medicine. Kisspeptin and neurokinin B (or analogous compounds) may provide another avenue treating patients reproductive disorders ranging form abnormalities of pubertal timing, to reproductive cancers, to endometriosis, and infertility.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Crowley, William F; Balasubramanian, Ravi (2017) MicroRNA-7a2 suppression causes hypogonadotropism and uncovers signaling pathways in gonadotropes. J Clin Invest 127:796-797
Maguire, Caroline A; Song, Yong Bhum; Wu, Min et al. (2017) Tac1 Signaling Is Required for Sexual Maturation and Responsiveness of GnRH Neurons to Kisspeptin in the Male Mouse. Endocrinology 158:2319-2329
Abreu, Ana Paula; Kaiser, Ursula B (2016) Pubertal development and regulation. Lancet Diabetes Endocrinol 4:254-264
Simavli, Serap; Abreu, Ana Paula; Kwaan, Mary R et al. (2016) Candidate gene analysis in a case of congenital absence of the endometrium. Fertil Res Pract 2:3
Stamou, M I; Cox, K H; Crowley Jr, William F (2016) Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the ""-Omics"" Era. Endocr Rev 2016:4-22
Cox, Kimberly H (2016) A Bisphenol by Any Other Name... Endocrinology 157:449-51
Min, Le; Nie, Min; Zhang, Anna et al. (2016) Computational Analysis of Missense Variants of G Protein-Coupled Receptors Involved in the Neuroendocrine Regulation of Reproduction. Neuroendocrinology 103:230-9
Min, Le; Leon, Silvia; Li, Huan et al. (2015) RF9 Acts as a KISS1R Agonist In Vivo and In Vitro. Endocrinology 156:4639-48
Stamou, M I; Cox, K H; Crowley Jr, William F (2015) Discovering Genes Essential to the Hypothalamic Regulation of Human Reproduction Using a Human Disease Model: Adjusting to Life in the ""-Omics"" Era. Endocr Rev 36:603-21
Abreu, Ana Paula; Macedo, Delanie B; Brito, Vinicius N et al. (2015) A new pathway in the control of the initiation of puberty: the MKRN3 gene. J Mol Endocrinol 54:R131-9

Showing the most recent 10 out of 141 publications