50 Hart R, Hickey M, Franks S. Definitions, prevalence and symptoms of polycystic ovaries and polycystic ovary syndrome. *Best Pract Res Clin Obstet Gynaecol.* 2004;18(5):671-683.

51 Azziz R, Carmina E, Dewailly D, et al. Criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. *J Clin Endocrinol Metab.* 2006;91(11):4237-4245.

52 West S, Lashen H, Bloigu A, et al. Irregular menstruation and hyperandrogenaemia in adolescence are associated with polycystic ovary syndrome and infertility in later life: Northern Finland Birth Cohort 1986 study. *Hum Reprod.* 2014;29(10):2339-2351.

53 Villarroel C, López P, Merino PM, Iñiguez G, Sir-Petermann T, Codner E. Hirsutism and oligomenorrhea are appropriate screening criteria for polycystic ovary syndrome in adolescents. *Gynecol Endocrinol.* 2015;31(8):625-629.

54 Irving-Rodgers HF, Hummitzsch K, Murdiyarso LS, et al. Dynamics of extracellular matrix in ovarian follicles and corpora lutea of mice. *Cell Tissue Res.* 2010;339(3):613-624.

55 Cimino I, Casoni F, Liu X, et al. Novel role for anti-Müllerian hormone in the regulation of GnRH neuron excitability and hormone secretion. *Nat Commun.* 2016;7:10055.

56 Crisosto N, Ladrón de Guevara A, Echiburu B, et al. Higher luteinizing hormone levels associated with antimüllerian hormone in postmenarchal daughters of women with polycystic ovary syndrome. *Fertil Steril.* 2019;111(2):381-388.

57 Piltonen TT, Giacobini P, Edvinsson A, et al. Circulating antimüllerian hormone and steroid hormone levels remain high in pregnant women with polycystic ovary syndrome at term. *Fertil Steril.* 2019;111(3):588-596.e1.

58 Silva MSB, Giacobini P. New insights into anti-Müllerian hormone role in the hypothalamic-pituitary-gonadal axis and neuroendocrine development. *Cell Mol Life Sci.* 2021;78(1):1-16.

59 Webber LJ, Stubbs S, Stark J, et al. Formation and early development of follicles in the polycystic ovary. *Lancet.* 2003;362(9389):1017-1021.

60 Jonard S, Dewailly D. The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest. *Hum Reprod Update.* 2004;10:107-117.

61 Franks S, Stark J, Hardy K. Follicle dynamics and anovulation in polycystic ovary syndrome. *Hum Reprod Update.* 2008;14(4):367-378.

62 Dewailly D, Robin G, Peigne M, Decanter C, Pigny P, Catteau-Jonard S. Interactions between androgens, FSH, anti-Mullerian hormone and estradiol during folliculogenesis in the human normal and polycystic ovary. *Hum Reprod Update.* 2016;22(6):709-724.

63 Peigné M, Simon V, Pigny P, et al. Changes in circulating forms of anti-Müllerian hormone and androgens in women with and without PCOS: a systematic longitudinal study throughout pregnancy. *Hum Reprod.* 2023;38(5):938-950.

64 Mimouni NEH, Paiva I, Barbotin AL, et al. Polycystic ovary syndrome is transmitted via a transgenerational epigenetic process. *Cell Metab.* 2021;33(3):513-530.e8.

65 Pigny P, Jonard S, Robert Y, Dewailly D. Serum anti-Müllerian hormone as a surrogate for antral follicle count for definition of the polycystic ovary syndrome. *J Clin Endocrinol Metab.* 2006;91(3):941-945.

66 Halmos G, Sghally AV, 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 U S A.* 1996;93(6):2398-2402.

67 Halmos G, Schally AV. Changes in subcellular distribution of pituitary receptors for luteinizing hormone-releasing hormone (LH-RH) after treatment with the LH-RH antagonist cetrorelix. *Proc Natl Acad Sci U S A.* 2002;99(2):961-965.

68 Daniels TL, Berga SL. Resistance of gonadotropin releasing hormone drive to sex steroid-induced suppression in hyperandrogenic anovulation. *J Clin Endocrinol Metab.* 1997;82(12):4179-4183.

69 Dapas M, Lin FTJ, Nadkarni GN, et al. Distinct subtypes of polycystic ovary syndrome with novel genetic associations: an unsupervised, phenotypic clustering analysis. *PLoS Med.* 2020;17(6):e1003132.

70 Wray S, Hoffman G. A developmental study of the quantitative distribution of LHRH neurons within the central nervous system of postnatal male and female rats. *J Comp Neurol.* 1986;252(4):522-531.

71 Campos P, Herbison AE. Optogenetic activation of GnRH neurons reveals minimal requirements for pulsatile luteinizing hormone secretion. *Proc Natl Acad Sci U S A.* 2014;111(51):18387-18392.

72 Pastor CL, Griffin-Korf ML, Aloi JA, Evans WS, Marshall JC. Polycystic ovary syndrome: evidence for reduced sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. *J Clin Endocrinol Metab.* 1998;83(2):582-590.

73 Silva MSB, Campbell RE. Polycystic ovary syndrome and the neuroendocrine consequences of androgen excess. *Compr Physiol.* 2022;12(2):3347-3369.

74 Moore AM, Prescott M, Marshall CJ, Yip SH, Campbell RE. Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome. *Proc Natl Acad Sci U S A.* 2015;112(2):596-601.

75 Moore AM, Lohr DB, Coolen LM, Lehman MN. Prenatal androgen exposure alters KNDy neurons and their afferent network in a model of polycystic ovarian syndrome. *Endocrinology.* 2021;162(11):bqab158.

76 Pielecka J, Quaynor SD, Moenter SM. Androgens increase gonadotropin-releasing hormone neuron firing activity in females and interfere with progesterone negative feedback. *Endocrinology.* 2006;147(3):1474-1479.

77 Herbison AE, Skinner DC, Robinson JE, King IS. Androgen receptor-immunoreactive cells in ram hypothalamus: distribution and co-localization patterns with gonadotropin-releasing hormone, somatostatin and tyrosine hydroxylase. *Neuroendocrinology.* 1996;63(2):120-131.

78 Wintermantel TM, Campbell RE, Porteous R, et al. Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin-releasing hormone neurons and fertility. *Neuron.* 2006;52(2):271-280.

79 Skinner DC, Caraty A, Allingham R. Unmasking the progesterone receptor in the preoptic area and hypothalamus of the ewe: no colocalization with gonadotropin-releasing neurons. *Endocrinology.* 2001;142(2):573-579.

80 Caldwell ASL, Eid S, Kay CR, et al. Haplosufficient genomic androgen receptor signaling is adequate to protect female mice from induction of polycystic ovary syndrome features by prenatal hyperandrogenization. *Endocrinology.* 2015;156(4):1441-1452.

81 Caldwell ASL, Edwards MC, Desai R, et al. Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome. *Proc Natl Acad Sci U S A.* 2017;114(16):E3334-E3343.

82 Ho EV, Shi C, Cassin J, et al. Reproductive deficits induced by prenatal antimüllerian hormone exposure require androgen receptor in kisspeptin cells. *Endocrinology.* 2021;162(12):bqab197.

83 Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, Steiner RA. Regulation of gonadotropin-releasing hormone secretion by Kisspeptin/Dynorphin/Neurokinin B neurons in the arcuate nucleus of the mouse. *J Neurosci.* 2009;29(38):11859-11866.

84 Goodman RL, Maltby MJ, Millar RP, et al. Evidence that dopamine acts via kisspeptin to hold GnRH pulse frequency in check in anestrous ewes. *Endocrinology.* 2012;153(12):5918-5927.

85 Goodman RL, Hileman SM, Nestor CC, et al. Kisspeptin, neurokinin B, and dynorphin act in the arcuate nucleus to control activity of the GnRH pulse generator in ewes. *Endocrinology.* 2013;154(11):4259-4269.

86 Mittelman-Smith MA, Williams H, Krajewski-Hall SJ, et al. Arcuate kisspeptin/neurokinin B/dynorphin (KNDy) neurons mediate the estrogen suppression of gonadotropin secretion and body weight. *Endocrinology.* 2012;153(6):2800-2812.

87 Yan X, Yuan C, Zhao N, Cui Y, Liu J. Prenatal androgen excess enhances stimulation of the GNRH pulse in pubertal female rats. *J Endocrinol.* 2014;222(1):73-85.

88 Osuka S, Iwase A, Nakahara T, et al. Kisspeptin in the hypothalamus of 2 rat models of polycystic ovary syndrome. *Endocrinology.* 2017;158(2):367-377.

89 Sucquart IE, Nagarkar R, Edwards MC, et al. Neurokinin 3 receptor antagonism ameliorates key metabolic features in a hyperandrogenic PCOS mouse model. *Endocrinology.* 2021;162(5):bqab020.

90 McCarthy EA, Dischino D, Maguire C, et al. Inhibiting Kiss1 neurons with kappa opioid receptor agonists to treat polycystic ovary syndrome and vasomotor symptoms. *J Clin Endocrinol Metab.* 2022;107(1):e328-e347.

91 Skorupskaitė K, George JT, Veldhuis JD, Millar RP, Anderson RA. Kisspeptin and neurokinin B interactions in modulating
gonadotropin secretion in women with polycystic ovary syndrome. *Hum Reprod.* 2020;35(6):1421-1431.

92 Abbara A, Dhillo WS. Targeting elevated GnRH pulsatility to treat polycystic ovary syndrome. *J Clin Endocrinol Metab.* 2021;106:E4275-E4277.

93 Romero-Ruiz A, Skorupskaitė K, Gaytan F, et al. Kisspeptin treatment induces gonadotropic responses and rescues ovulation in a subset of preclinical models and women with polycystic ovary syndrome. *Hum Reprod.* 2019;34(12):2495-2512.

94 Pérez-López FR, Ornat L, López-Baena MT, Santabárbara J, Savirón-Cornudella R, Pérez-Roncero GR. Circulating kisspeptin and anti-Müllerian hormone levels, and insulin resistance in women with polycystic ovary syndrome: a systematic review, meta-analysis, and meta-regression. *Eur J Obstet Gynecol Reprod Biol.* 2021;260:85-98.

95 Dumesic DA, Richards JS. Ontogeny of the ovary in polycystic ovary syndrome. Elsevier *Fertil Steril*. 2013;100:23-38.

96 Pradeep PK, Li X, Peegel H, Menon KMJ. Dihydrotestosterone inhibits granulosa cell proliferation by decreasing the cyclin D2 mRNA expression and cell cycle arrest at G1 phase. *Endocrinology*. 2002;143(8):2930-2935.

97 Tesarik J, Mendoza C. Direct non-genomic effects of follicular steroids on maturing human oocytes: oestrogen versus androgen antagonism. *Hum Reprod Update*. 1997;3(2):95-100.

98 Piltonen TT, Komsi E, Morin-Papunen LC, et al. AMH as part of the diagnostic PCOS workup in large epidemiological studies. *Eur J Endocrinol.* 2023;188(6):547-554.

99 Mortimer RH, Lev-Gur M, Freeman R, Fleischer N. Pituitary response to bolus and continuous intravenous infusion of luteinizing hormone-releasing factor in normal women and women with polycystic ovarian syndrome. *Am J Obstet Gynecol.* 1978;130(6):630-634.

100 Tarlatzis BC, Grimbizis G, Pournaropoulos F, et al. The prognostic value of basal luteinizing hormone:follicle-stimulating hormone ratio in the treatment of patients with polycystic ovarian syndrome by assisted reproduction techniques. *Hum Reprod.* 1995;10(10):2545-2549.

101 Thompson IR, Kaiser UB. GnRH pulse frequency-dependent differential regulation of LH and FSH gene expression. *Mol Cell Endocrinol.* 2014;385:28-35.

102 Chang HM, Klausen C, Leung PCK. Antimüllerian hormone inhibits follicle-stimulating hormone-induced adenylyl cyclase activation, aromatase expression, and estradiol production in human granulosa-lutein cells. *Fertil Steril.* 2013;100(2):585-592.e1.

103 Devillers M, Petit F, Cluzet V, et al. FSH inhibits AMH to support ovarian estradiol synthesis in infantile mice. *J Endocrinol.* 2018;240:215-228.

104 Manfredi-Lozano M, Leysen V, Adamo M, et al. GnRH replacement rescues cognition in Down syndrome. *Science.* 2022;377(6610):eabq4515.

105 Dokras A, Stener-Victorin E, Yildiz BO, et al. Androgen Excess-Polycystic Ovary Syndrome Society: position statement on depression, anxiety, quality of life, and eating disorders in polycystic ovary syndrome. *Fertil Steril.* 2018;109(5):888-899.
gonadotropin secretion in women with polycystic ovary syndrome. *Hum Reprod.* 2020;35(6):1421-1431.

92 Abbara A, Dhillo WS. Targeting elevated GnRH pulsatility to treat polycystic ovary syndrome. *J Clin Endocrinol Metab.* 2021;106:E4275-E4277.

93 Romero-Ruiz A, Skorupskaitė K, Gaytan F, et al. Kisspeptin treatment induces gonadotropic responses and rescues ovulation in a subset of preclinical models and women with polycystic ovary syndrome. *Hum Reprod.* 2019;34(12):2495-2512.

94 Pérez-López FR, Ornat L, López-Baena MT, Santabárbara J, Savirón-Cornudella R, Pérez-Roncero GR. Circulating kisspeptin and anti-Müllerian hormone levels, and insulin resistance in women with polycystic ovary syndrome: a systematic review, meta-analysis, and meta-regression. *Eur J Obstet Gynecol Reprod Biol.* 2021;260:85-98.

95 Dumesic DA, Richards JS. Ontogeny of the ovary in polycystic ovary syndrome. Elsevier *Fertil Steril*. 2013;100:23-38.

96 Pradeep PK, Li X, Peegel H, Menon KMJ. Dihydrotestosterone inhibits granulosa cell proliferation by decreasing the cyclin D2 mRNA expression and cell cycle arrest at G1 phase. *Endocrinology*. 2002;143(8):2930-2935.

97 Tesarik J, Mendoza C. Direct non-genomic effects of follicular steroids on maturing human oocytes: oestrogen versus androgen antagonism. *Hum Reprod Update*. 1997;3(2):95-100.

98 Piltonen TT, Komsi E, Morin-Papunen LC, et al. AMH as part of the diagnostic PCOS workup in large epidemiological studies. *Eur J Endocrinol.* 2023;188(6):547-554.

99 Mortimer RH, Lev-Gur M, Freeman R, Fleischer N. Pituitary response to bolus and continuous intravenous infusion of luteinizing hormone-releasing factor in normal women and women with polycystic ovarian syndrome. *Am J Obstet Gynecol.* 1978;130(6):630-634.

100 Tarlatzis BC, Grimbizis G, Pournaropoulos F, et al. The prognostic value of basal luteinizing hormone:follicle-stimulating hormone ratio in the treatment of patients with polycystic ovarian syndrome by assisted reproduction techniques. *Hum Reprod.* 1995;10(10):2545-2549.

101 Thompson IR, Kaiser UB. GnRH pulse frequency-dependent differential regulation of LH and FSH gene expression. *Mol Cell Endocrinol.* 2014;385:28-35.

102 Chang HM, Klausen C, Leung PCK. Antimüllerian hormone inhibits follicle-stimulating hormone-induced adenylyl cyclase activation, aromatase expression, and estradiol production in human granulosa-lutein cells. *Fertil Steril.* 2013;100(2):585-592.e1.

103 Devillers M, Petit F, Cluzet V, et al. FSH inhibits AMH to support ovarian estradiol synthesis in infantile mice. *J Endocrinol.* 2018;240:215-228.

104 Manfredi-Lozano M, Leysen V, Adamo M, et al. GnRH replacement rescues cognition in Down syndrome. *Science.* 2022;377(6610):eabq4515.

105 Dokras A, Stener-Victorin E, Yildiz BO, et al. Androgen Excess-Polycystic Ovary Syndrome Society: position statement on depression, anxiety, quality of life, and eating disorders in polycystic ovary syndrome. *Fertil Steril.* 2018;109(5):888-899.