1. Norman, R. J., Dewailly, D., Legro, R. S. & Hickey, T. E. Polycystic ovary syndrome. Lancet 370, 685–697 (2007).

2. Goodarzi, M. O., Dumesic, D. A., Chazenbalk, G. & Azziz, R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat. Rev. Endocrinol. 7, 219–231 (2011).

3. Jayasena, C. N. & Franks, S. The management of patients with polycystic ovary syndrome. Nat. Rev. Endocrinol. 10, 624–636 (2014).

4. March, W. A. et al. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum. Reprod. 25, 544–551 (2010).

5. Wild, R. A. et al. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J. Clin. Endocrinol. Metab. 95, 2038–2049 (2010).

6. Dumesic, D. A. & Lobo, R. A. Cancer risk and PCOS. Steroids 78, 782–785 (2013).

7. Cook, C. L., Siow, Y., Brenner, A. G. & Fallat, M. E. Relationship between serum Müllerian-inhibiting substance and other reproductive hormones in untreated women with polycystic ovary syndrome and normal women. Fertil. Steril. 77, 141–146 (2002).

8. Pigny, P., Jonard, S., Robert, Y. & Dewailly, D. Serum anti-Mullerian hormone as a surrogate for antral follicle count for definition of the polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 91, 941–945 (2006).

9. Pellatt, L. et al. Granulosa cell production of anti-Müllerian hormone is increased in polycystic ovaries. J. Clin. Endocrinol. Metab. 92, 240–245 (2007).

10. Pigny, P. et al. Elevated serum level of anti-Mullerian hormone in patients with polycystic ovary syndrome: relationship to the ovarian follicle excess and to the follicular arrest. J. Clin. Endocrinol. Metab. 88, 5957–5962 (2003).

11. Cimino, I. et al. Novel role for anti-Müllerian hormone in the regulation of GnRH neuron excitability and hormone secretion. Nat. Commun. 7, 10055 (2016).

12. Chang, R. J. The reproductive phenotype in polycystic ovary syndrome. Nat. Clin. Pract. Endocrinol. Metab. 3, 688–695 (2007).

13. McAllister, J. M., Legro, R. S., Modi, B. P. & Strauss, J. F. III Functional genomics of PCOS: from GWAS to molecular mechanisms. Trends Endocrinol. Metab. 26, 118–124 (2015).

14. Sir-Petermann, T. et al. Early metabolic derangements in daughters of women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 92, 4637–4642 (2007).

15. Köninger, A. et al. Anti-Mullerian-hormone levels during pregnancy and postpartum. Reprod. Biol. Endocrinol. 11, 60 (2013).

16. La Marca, A., Giulini, S., Orvieto, R., De Leo, V. & Volpe, A. Anti-Müllerian hormone concentrations in maternal serum during pregnancy. Hum. Reprod. 20, 1569–1572 (2005).

17. Sullivan, S. D. & Moenter, S. M. Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: implications for a common fertility disorder. Proc. Natl. Acad. Sci. USA 101, 7129–7134 (2004).

18. Moore, A. M., Prescott, M. & Campbell, R. E. Estradiol negative and positive feedback in a prenatal androgen-induced mouse model of polycystic ovarian syndrome. Endocrinology 154, 796–806 (2013).

19. Moore, A. M., Prescott, M., Marshall, C. J., Yip, S. H. & Campbell, R. E. Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome. Proc. Natl. Acad. Sci. USA 112, 596–601 (2015).

20. Orvis, G. D. & Behringer, R. R. Cellular mechanisms of Müllerian duct formation in the mouse. Dev. Biol. 306, 493–504 (2007).

21. Pinski, J. et al. Chronic administration of the luteinizing hormone-releasing hormone (LHRH) antagonist cetrorelix decreases gonadotrope responsiveness and pituitary LHRH receptor messenger ribonucleic acid levels in rats. Endocrinology 137, 3430–3436 (1996).

22. Halmos, G., Schally, A. V., Pinski, J., Vadillo-Buenfil, M. & Groot, K. Down-regulation of pituitary receptors for luteinizing hormone-releasing hormone (LH-RH) in rats by LH-RH antagonist cetrorelix. Proc. Natl. Acad. Sci. USA 93, 2398–2402 (1996).

23. Duijkers, I. J. et al. Single and multiple dose pharmacokinetics and pharmacodynamics of the gonadotrophin-releasing hormone antagonist cetrorelix in healthy female volunteers. Hum. Reprod. 13, 2392–2398 (1998).

24. Novembri, R. et al. Placenta expresses anti-Müllerian hormone and its receptor: sex-related difference in fetal membranes. Placenta 36, 731–737 (2015).

25. Simerly, R. B. Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain. Annu. Rev. Neurosci. 25, 507–536 (2002).

26. McCarthy, M. M., Arnold, A. P., Ball, G. F., Blaustein, J. D. & De Vries, G. J. Sex differences in the brain: the not so inconvenient truth. J. Neurosci. 32, 2241–2247 (2012).

27. Corbier, P., Edwards, D. A. & Roffi, J. The neonatal testosterone surge: a comparative study. Arch. Int. Physiol. Biochim. Biophys. 100, 127–131 (1992).

28. Clarkson, J. & Herbison, A. E. Hypothalamic control of the male neonatal testosterone surge. Phil. Trans. R. Soc. Lond. B 371, 20150115 (2016).

29. Herbison, A. E. Control of puberty onset and fertility by gonadotropin-releasing hormone neurons. Nat. Rev. Endocrinol. 12, 452–466 (2016).

30. Simerly, R. B. Hormonal control of the development and regulation of tyrosine hydroxylase expression within a sexually dimorphic population of dopaminergic cells in the hypothalamus. Brain Res. Mol. Brain Res. 6, 297–310 (1989).

31. Clarkson, J. & Herbison, A. E. Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology 147, 5817–5825 (2006).

32. De Vries, G. J. & Panzica, G. C. Sexual differentiation of central vasopressin and vasotocin systems in vertebrates: different mechanisms, similar endpoints. Neuroscience 138, 947–955 (2006).

33. Herbison, A. E. & Moenter, S. M. Depolarising and hyperpolarising actions of GABA(A) receptor activation on gonadotrophin-releasing hormone neurones: towards an emerging consensus. J. Neuroendocrinol. 23, 557–569 (2011).

34. Piltonen, T. et al. Serum anti-Müllerian hormone levels remain high until late reproductive age and decrease during metformin therapy in women with polycystic ovary syndrome. Hum. Reprod. 20, 1820–1826 (2005).

35. Sir-Petermann, T. et al. Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenization. Hum. Reprod. 17, 2573–2579 (2002).

36. Schaeffer, M. et al. Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons. Proc. Natl. Acad. Sci. USA 110, 1512–1517 (2013).

37. Prevot, V. et al. The versatile tanycyte: a hypothalamic integrator of reproduction and energy metabolism. Endocr. Rev. https://doi.org/10.1210/er.2017-00235 (2018).

38. Herde, M. K., Geist, K., Campbell, R. E. & Herbison, A. E. Gonadotropin-releasing hormone neurons extend complex highly branched dendritic trees outside the blood-brain barrier. Endocrinology 152, 3832–3841 (2011).

39. Ragin, R. C., Donahoe, P. K., Kenneally, M. K., Ahmad, M. F. & MacLaughlin, D. T. Human müllerian inhibiting substance: enhanced purification imparts biochemical stability and restores antiproliferative effects. Protein Expr. Purif. 3, 236–245 (1992).

40. Pankhurst, M. W. & McLennan, I. S. Human blood contains both the uncleaved precursor of anti-Mullerian hormone and a complex of the NH2- and COOH-terminal peptides. Am. J. Physiol. Endocrinol. Metab. 305, E1241–E1247 (2013).

41. Pankhurst, M. W., Chong, Y. H. & McLennan, I. S. Relative levels of the proprotein and cleavage-activated form of circulating human anti-Müllerian hormone are sexually dimorphic and variable during the life cycle. Physiol. Rep. 4, e12783 (2016).

42. Roland, A. V. & Moenter, S. M. Reproductive neuroendocrine dysfunction in polycystic ovary syndrome: insight from animal models. Front. Neuroendocrinol. 35, 494–511 (2014).

43. Moore, A. M. & Campbell, R. E. Polycystic ovary syndrome: Understanding the role of the brain. Front. Neuroendocrinol. 46, 1–14 (2017).

44. Abbott, D. H. et al. Nonhuman primate models of polycystic ovary syndrome. Mol. Cell. Endocrinol. 373, 21–28 (2013).

45. Abbott, D. H. et al. Clustering of PCOS-like traits in naturally hyperandrogenic female rhesus monkeys. Hum. Reprod. 32, 923–936 (2017).

46. Maliqueo, M. et al. Placental steroidogenesis in pregnant women with polycystic ovary syndrome. Eur. J. Obstet. Gynecol. Reprod. Biol. 166, 151–155 (2013).

47. Katulski, K., Czyzyk, A., Podfigurna-Stopa, A., Genazzani, A. R. & Meczekalski, B. Pregnancy complications in polycystic ovary syndrome patients. Gynecol. Endocrinol. 31, 87–91 (2015).

48. Maliqueo, M. et al. Placental STAT3 signaling is activated in women with polycystic ovary syndrome. Hum. Reprod. 30, 692–700 (2015).

49. Huang, X. & Harlan, R. E. Absence of androgen receptors in LHRH immunoreactive neurons. Brain Res. 624, 309–311 (1993).

50. DeFazio, R. A. & Moenter, S. M. Estradiol feedback alters potassium currents and firing properties of gonadotropin-releasing hormone neurons. Mol. Endocrinol. 16, 2255–2265 (2002).

51. Huang, C. C. et al. Symptom patterns and phenotypic subgrouping of women with polycystic ovary syndrome: association between endocrine characteristics and metabolic aberrations. Hum. Reprod. 30, 937–946 (2015).

52. Rebar, R. et al. Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome. J. Clin. Invest. 57, 1320–1329 (1976).

53. Chang, R. J., Mandel, F. P., Lu, J. K. & Judd, H. L. Enhanced disparity of gonadotropin secretion by estrone in women with polycystic ovarian disease. J. Clin. Endocrinol. Metab. 54, 490–494 (1982).

54. Roland, A. V., Nunemaker, C. S., Keller, S. R. & Moenter, S. M. Prenatal androgen exposure programs metabolic dysfunction in female mice. J. Endocrinol. 207, 213–223 (2010).

55. Azziz, R. Introduction: determinants of polycystic ovary syndrome. Fertil. Steril. 106, 4–5 (2016).

56. Lizneva, D. et al. Phenotypes and body mass in women with polycystic ovary syndrome identified in referral versus unselected populations: systematic review and meta-analysis. Fertil. Steril. 106, 1510–1520.e2 (2016).

57. Ezeh, U., Yildiz, B. O. & Azziz, R. Referral bias in defining the phenotype and prevalence of obesity in polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 98, E1088–E1096 (2013).

58. Dumesic, D. A. et al. Hyperandrogenism accompanies increased intra-abdominal fat storage in normal weight polycystic ovary syndrome women. J. Clin. Endocrinol. Metab. 101, 4178–4188 (2016).

59. McGee, E. A. & Hsueh, A. J. Initial and cyclic recruitment of ovarian follicles. Endocr. Rev. 21, 200–214 (2000).

60. Sokka, T. & Huhtaniemi, I. Ontogeny of gonadotrophin receptors and gonadotrophin-stimulated cyclic AMP production in the neonatal rat ovary. J. Endocrinol. 127, 297–303 (1990).

61. Granfors, M. et al. Thyroid testing and management of hypothyroidism during pregnancy: a population-based study. J. Clin. Endocrinol. Metab. 98, 2687–2692 (2013).

62. Spergel, D. J., Krüth, U., Hanley, D. F., Sprengel, R. & Seeburg, P. H. GABA- and glutamate-activated channels in green fluorescent protein-tagged gonadotropin-releasing hormone neurons in transgenic mice. J. Neurosci. 19, 2037–2050 (1999).

63. Caldwell, A. S. L. et al. Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome. Proc. Natl. Acad. Sci. USA 114, E3334–E3343 (2017).

64. Hrabovszky, E. et al. Sexual dimorphism of kisspeptin and neurokinin B immunoreactive neurons in the infundibular nucleus of aged men and women. Front. Endocrinol. (Lausanne) 2, 80 (2011).

65. Casoni, F. et al. Development of the neurons controlling fertility in humans: new insights from 3D imaging and transparent fetal brains. Development 143, 3969–3981 (2016).

66. Clarkson, J. et al. Sexual differentiation of the brain requires perinatal kisspeptin-GnRH neuron signaling. J. Neurosci. 34, 15297–15305 (2014).

67. Balland, E. et al. Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain. Cell Metab. 19, 293–301 (2014).

68. Xu, C. et al. KLB, encoding β-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism. EMBO Mol. Med. 9, 1379–1397 (2017).

69. Wang, H., Chung-Davidson, Y. W. & Li, W. Identification and quantification of sea lamprey gonadotropin-releasing hormones by electrospray ionization tandem mass spectrometry. J. Chromatogr. A 1345, 98–106 (2014).

70. Renier, N. et al. iDISCO: a simple, rapid method to immunolabel large tissue samples for volume imaging. Cell 159, 896–910 (2014).

71. Belle, M. et al. Tridimensional visualization and analysis of early human development. Cell 169, 161–173.e12 (2017).

72. Belle, M. et al. A simple method for 3D analysis of immunolabeled axonal tracts in a transparent nervous system. Cell Rep. 9, 1191–1201 (2014).

73. Steyn, F. J. et al. Development of a methodology for and assessment of pulsatile luteinizing hormone secretion in juvenile and adult male mice. Endocrinology 154, 4939–4945 (2013).