Neuroendocrine control of Reproduction in the Human

The aims of the U54 Harvard Reproductive Endocrine Sciences Center are to: i) provide infrastructure to support interdisciplinary translational research investigating the genes that control puberty and reproduction in the human, ii) Discover novel genes regulating puberty and reproduction in the human, iii) Define the full genotype-phenotype spectrum of idiopathic hypogonadotropic hypogonadism, iv) Study mutants in vitro, and v) Elucidate biologic pathways in the control of reproduction.  Additionally, the aim of my RO1 is to elucidate the role of the prokineticin pathway in the regulation of human reproduction and its impact on metabolism and circadian functions.  

In reproduction, all environmental and endogenous cues ultimately converge upon the single common neuroendocrine pathway of gonadotropin-releasing hormone (GnRH) from the hypothalamus and its stimulation of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary.  GnRH has traditionally been thought of as the first step in the reproductive cascade; its commanding role in this biological hierarchy allows it to control pulsatile gonadotropin secretion, modulate gonadal steroid feedback, and ultimately determine the initiation of pubertal development and fertility.  In 2003, we reported that, in both the human and the mouse, mutations in GPR54 cause a failure of the normal patterns of pulsatile GnRH release and hypogonadotropic hypogonadism. The ligand of GPR54 is kisspeptin--the impact of kisspeptin/GPR54 on GnRH secretion is well conserved across mammalian species; it is a genetic determinant and indisputable gatekeeper of normal reproductive function.  Since that time we have identified FGFR1 pathway as a key player in human reproduction and more recently the prokineticin system and another contributing developmental pathway.  Delineating these biologic pathways has provided deeper insights into the connection between metabolism and reproduction in the human.

The Harvard Reproductive Endocrine Sciences Center has been at the forefront in gene discovery related to the control of human reproduction.  The center has identified and helped to elucidate 3 of the major developmental pathways regulating puberty and human reproduction: GPR54-KISS system, FGF pathway, and the prokineticin system.  We have amassed the worlds largest cohort of patients (nearly 1,000 probands and approximately 18,000 family members) with the rare condition of idiopathic hypogonadotropic hypogonadism.  This unique disease model has been a fruitful model to identify novel genes and when combined with physiologic studies using pulsatile GnRH therapy creates genotype-phenotype correlations which contribute to our understanding of the pathophysiology of IHH and the genes and physiology of normal reproduction in the human.  Further, these genetic investigations have identified several interfaces linking reproduction and metabolism.

Using modern investigative techniques including physiologic investigation with unique biologic probes (i.e. pulsatile GnRH therapy), a human disease model, human genetics, in vitro studies, X-ray crystallography, and bioinformatics, the long-term goal of this proposal is to identify and characterize the full complement of genes controlling human reproduction and better understand how these genes impact metabolism by elucidating the complex non-reproductive phenotypes in patients with a variety of reproductive disorders including polycystic ovarian syndrome, hypothalamic amenorrhea, and hypogonadotropic hypogonadism..

References

1. Pitteloud N, Meysing A, Quinton R, Acierno JS Jr, Dwyer AA, Plummer L, Fliers E, Boepple P, Hayes F, Seminara S, Hughes VA, Ma J, Bouloux P, Mohammadi M, Crowley WF Jr. Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Molecular & Cellular Endo 254-255:60-9, 2006.
   
   
2. Pitteloud N, Acierno JS Jr, Meysing A, Eliseenkova AV, Ma J, Ibrahimi OA, Metzger DL, Hayes FJ, Dwyer AA, Hughes VA, Yialamas M, Hall JE, Grant E, Mohammadi M, Crowley WF Jr. Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. PNAS (USA) 103(16):6281-6, 2006.
   
   
3. Pitteloud N, Quinton R, Pearce S, Acierno J, Dwyer A, Plummer L, Hughes V, Seminara S, Cheng Y, Li W, MacColl G, Eliseenkova AV, Olsen SK, Ibrahimi OA, Hayes FJ, Boepple P, Hall J, Bouloux P, Mohammadi M, Crowley WF Jr.  Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. JCI. 2007;117:457-463.
   
   
4. Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, Hughes VA, Cole LW, Pearce SH, Lee H, Boepple P, Crowley WF Jr, Pitteloud N. Sustained reversal of congenital hypogonadotropic hypogonadism after discontinuation of therapy. New Engl J Medicine 2007; 357:863-932.
   
   
5. Pitteloud N, Zhang C, Pignatelli D, Li JD, Raivio T, Cole L, Plummer L, Jacobson-Dickman EE, Mellon P, Zhou QY, Crowley WF Jr.  Loss-of-function mutation in the prokineticin 2 gene cause Kallmann Syndrome and normosmic Idiopathic Hypogonadotropic Hypogonadism.  PNAS. 2007;104:1744-17452.
   
   
6. Cole LW, Sidis Y, Zhang C, Quinton R, Plumer L, Pignatelli D, Hughes VA, Dwyer AA, Raivio T, Hayes FJ, Seminara SB, Huot C, Alos N, Speiser P, Takeshita A, Van Vliet G, Pearce S, Crowley WF Jr, Zhou QY, Pitteloud N.  Mutations in prokineticin 2 (PROK2) and PROK2 receptor (PROKR2) in human gonadotrophin-releasing hormone deficiency: Molecular genetics and clinical spectrum.  J. Clin Endocrinol Metab. 2008; 93: 3551-9.