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Review

Hyperandrogenic origins of polycystic ovary syndrome – implications for pathophysiology and therapy

ORCID Icon, ORCID Icon & ORCID Icon
Pages 131-143 | Received 17 Nov 2018, Accepted 28 Jan 2019, Published online: 15 Feb 2019

References

  • Dumesic DA, Oberfield SE, Stener-Victorin E, et al. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr Rev. 2015;36(5):487–525.
  • Azziz R, Marin C, Hoq L, et al. Health care-related economic burden of the polycystic ovary syndrome during the reproductive life span. J Clin Endocrinol Metab. 2005;90(8):4650–4658.
  • Azziz R. Polycystic ovary syndrome. Obstet Gynecol. 2018;132(2):321–336.
  • Brakta S, Lizneva D, Mykhalchenko K, et al. Perspectives on polycystic ovary syndrome: is polycystic ovary syndrome research underfunded? J Clin Endocrinol Metab. 2017;102(12):4421–4427.
  • Dokras A, Saini S, Gibson-Helm M, et al. Gaps in knowledge among physicians regarding diagnostic criteria and management of polycystic ovary syndrome. Fertil Steril. 2017;107(6):1380–1386.e1.
  • International PCOS Network. Teede HJ, Misso ML, Costello MF, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018;110(3):364–379.
  • Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81(1):19–25.
  • Nelson VL, Qin KN, Rosenfield RL, et al. The biochemical basis for increased testosterone production in theca cells propagated from patients with polycystic ovary syndrome. J Clin Endocrinol Metab. 2001;86(12):5925–5933.
  • Rosenfield RL, Ehrmann DA. The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev. 2016;37(5):467–520.
  • Ibáñez L, Oberfield SE, Witchel S, et al. An international consortium update: pathophysiology, diagnosis, and treatment of polycystic ovarian syndrome in adolescence. Horm Res Paediatr. 2017;88(6):371–395.
  • Witchel SF, Oberfield S, Rosenfield RL, et al. The diagnosis of polycystic ovary syndrome during adolescence. Horm Res Paediatr. 2015;83:376–389.
  • Abbott DH, Rayome BH, Dumesic DA, et al. Clustering of PCOS-like traits in naturally hyperandrogenic female rhesus monkeys. Hum Reprod. 2017;32:923-936.
  • Norman RJ, Dewailly D, Legro RS, et al. Polycystic ovary syndrome. Lancet. 2007;370(9588):685–697.
  • Wild RA, Carmina E, Diamanti-Kandarakis E, 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. 2010;95(5):2038–2049.
  • Azziz R, Black V, Hines GA, et al. Adrenal androgen excess in the polycystic ovary syndrome: sensitivity and responsivity of the hypothalamic-pituitary-adrenal axis. J Clin Endocrinol Metab. 1998;83(7):2317–2323.
  • O’Reilly MW, Kempegowda P, Walsh M, et al. AKR1C3-mediated adipose androgen generation drives lipotoxicity in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2017;102(9):3327–3339.
  • Kraynak M, Flowers MT, Shapiro RA, et al. Extraovarian gonadotropin negative feedback revealed by aromatase inhibition in female marmoset monkeys. Am J Physiol Endocrinol Metab. 2017;313(5):E507–E514.
  • O’Reilly MW, Kempegowda P, Jenkinson C, et al. 11-oxygenated C19 steroids are the predominant androgens in polycystic ovary syndrome. J Clin Endocrinol Metab. 2017;102(3):840–848.
  • Bobe J, Guiguen Y, Fostier A. Diversity and biological significance of sex hormone-binding globulin in fish, an evolutionary perspective. Mol Cell Endocrinol. 2010;316(1):66–78.
  • Handelsman DJ, Teede HJ, Desai R, et al. Performance of mass spectrometry steroid profiling for diagnosis of polycystic ovary syndrome. Hum Reprod. 2017;32(2):418–422.
  • McAllister JM, Legro RS, Modi BP, et al. Functional genomics of PCOS: from GWAS to molecular mechanisms. Trends Endocrinol Metab. 2015;26(3):118–124.
  • Dunaif A. Perspectives in polycystic ovary syndrome: from hair to eternity. J Clin Endocrinol Metab. 2016;101(3):759–768.
  • Gorsic LK, Kosova G, Werstein B, et al. Pathogenic Anti-Müllerian hormone variants in polycystic ovary syndrome. J Clin Endocrinol Metab. 2017;102(8):2862–2872.
  • Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol. 2018;14(5):270–284.
  • Crespo RP, Bachega TASS, Mendonça BB, et al. An update of genetic basis of PCOS pathogenesis. Arch Endocrinol Metab. 2018;62(3):352–361.
  • Chen ZJ, Zhao H, He L, et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat Genet. 2011;43(1):55–59.
  • Liu H, Zhao H, Chen ZJ. Genome-wide association studies for polycystic ovary syndrome. Semin Reprod Med. 2016;34(4):224–229.
  • Jones MR, Chua AK, Mengesha EA, et al. Metabolic and cardiovascular genes in polycystic ovary syndrome: a candidate-wide association study (CWAS). Steroids. 2012;77(4):317–322.
  • Hayes MG, Urbanek M, Ehrmann DA, et al. Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun. 2015;6:7502.
  • Teede HJ, Joham AE, Paul E, et al. Longitudinal weight gain in women identified with polycystic ovary syndrome: results of an observational study in young women. Obesity (Silver Spring). 2013;21(8):1526–1532.
  • Pau CT, Mosbruger T, Saxena R, et al. Phenotype and tissue expression as a function of genetic risk in polycystic ovary syndrome. PLoS One. 2017;12(1):e0168870.
  • Legro RS, Driscoll D, Strauss JF 3rd, et al. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci U S A. 1998;95(25):14956–14960.
  • Vink JM, Sadrzadeh S, Lambalk CB, et al. Heritability of polycystic ovary syndrome in a Dutch twin-family study. J Clin Endocrinol Metab. 2006;91(6):2100–2104.
  • Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev. 2012;33(6):981–1030.
  • Strauss JF 3rd. Some new thoughts on the pathophysiology and genetics of polycystic ovary syndrome. Ann N Y Acad Sci. 2003;997:42–48.
  • Sir-Petermann T, Angel B, Maliqueo M, et al. Prevalence of Type II diabetes mellitus and insulin resistance in parents of women with polycystic ovary syndrome. Diabetologia. 2002;45(7):959–964.
  • Mahajan A, Taliun D, Thurner M, et al. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nat Genet. 2018;50(11):1505-1513.
  • Meigs JB, Cupples LA, Wilson PW. Parental transmission of T2D: the framingham offspring study. Diabetes. 2000;49(12):2201–2207.
  • Dabelea D, Hanson RL, Lindsay RS, et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes. 2000;49(12):2208–2211.
  • Barker DJ, Fall CH. Fetal and infant origins of cardiovascular disease. Arch Dis Child. 1993;68(6):797–799.
  • Sommese L, Benincasa G, Lanza M, et al. Novel epigenetic-sensitive clinical challenges both in type 1 and type 2 diabetes. J Diabetes Complications. 2018;32(11):1076–1084.
  • Ortiz-Flores AE, Luque-Ramírez M, Escobar-Morreale HF. Pharmacotherapeutic management of comorbid polycystic ovary syndrome and diabetes. Expert Opin Pharmacother. 2018;5:1–12.
  • Nugent BM, Bale TL. The omniscient placenta: metabolic and epigenetic regulation of fetal programming. Front Neuroendocrinol. 2015;39:28–37.
  • Corso-Díaz X, Jaeger C, Chaitankar V, et al. Epigenetic control of gene regulation during development and disease: A view from the retina. Prog Retin Eye Res. 2018;65:1–27.
  • Moore GE, Abu-Amero SN, Bell G, et al. Evidence that insulin is imprinted in the human yolk sac. Diabetes. 2001;50(1):199–203.
  • Li S, Zhu D, Duan H, et al. The epigenomics of polycystic ovarian syndrome: from pathogenesis to clinical manifestations. Gynecol Endocrinol. 2016;32(12):942–946.
  • Lambertini L, Saul SR, Copperman AB, et al. Intrauterine reprogramming of the polycystic ovary syndrome: evidence from a pilot study of cord blood global methylation analysis. Front Endocrinol (Lausanne). 2017;8:352.
  • Wang P, Zhao H, Li T, et al. Hypomethylation of the LH/choriogonadotropin receptor promoter region is a potential mechanism underlying susceptibility to polycystic ovary syndrome. Endocrinology. 2014;155(4):1445–1452.
  • Jones MR, Brower MA, Xu N, et al. Systems genetics reveals the functional context of PCOS loci and identifies genetic and molecular mechanisms of disease heterogeneity. PLoS Genet. 2015;11(8):e1005455.
  • Song J, Luo S, Li SW. miRNA-592 is downregulated and may target LHCGR in polycystic ovary syndrome patients. Reprod Biol. 2015;15(4):229–237.
  • Comim FV, Teerds K, Hardy K, et al. Increased protein expression of LHCG receptor and 17α-hydroxylase/17–20-lyase in human polycystic ovaries. Hum Reprod. 2013;28(11):3086–3092.
  • Hirshfeld-Cytron J, Barnes RB, Ehrmann DA, et al. Characterization of functionally typical and atypical types of polycystic ovary syndrome. J Clin Endocrinol Metab. 2009;94(5):1587–1594.
  • Wang XX, Wei JZ, Jiao J, et al. Genome-wide DNA methylation and gene expression patterns provide insight into polycystic ovary syndrome development. Oncotarget. 2014;5(16):6603–6610.
  • Yu YY, Sun CX, Liu YK, et al. Genome-wide screen of ovary-specific DNA methylation in polycystic ovary syndrome. Fertil Steril. 2015;104(1):145–153.e6.
  • Jiang SW, Xu S, Chen H, et al. Pathologic significance of SET/I2PP2A-mediated PP2A and non-PP2A pathways in Polycystic Ovary Syndrome (PCOS). Clin Chim Acta. 2017;464:155-159.
  • Xu B, Gao L, Cui Y, et al. SET protein up-regulated testosterone production in the cultured preantral follicles. Reprod Biol Endocrinol. 2013;11:9.
  • Murri M, Insenser M, Fernández-Durán E, et al. Non-targeted profiling of circulating microRNAs in women with polycystic ovary syndrome (PCOS): effects of obesity and sex hormones. Metabolism. 2018;86:49.
  • Beck-Peccoz P, Padmanabhan V, Baggiani AM, et al. Maturation of hypothalamic-pituitary-gonadal function in normal human fetuses: circulating levels of gonadotropins, their common alpha-subunit and free testosterone, and discrepancy between immunological and biological activities of circulating follicle-stimulating hormone. J Clin Endocrinol Metab. 1991;73(3):525–532.
  • Palomba S, Marotta R, Di Cello A, et al. Pervasive developmental disorders in children of hyperandrogenic women with polycystic ovary syndrome: a longitudinal case-control study. Clin Endocrinol (Oxf). 2012;77(6):898–904.
  • Schindler AE. Hormones in human amniotic fluid. Monogr Endocrinol. 1982;21:1–158.
  • Goy RW, Bercovitch FB, McBrair MC. Behavioral masculinization is independent of genital masculinization in prenatally androgenized female rhesus macaques. Horm Behav. 1988;22(4):552–571.
  • Roselli CE, Estill CT, Stadelman HL, et al. Separate critical periods exist for testosterone-induced differentiation of the brain and genitals in sheep. Endocrinology. 2011;152(6):2409–2415.
  • Dean A, Sharpe RM. Clinical review: anogenital distance or digit length ratio as measures of fetal androgen exposure: relationship to male reproductive development and its disorders. J Clin Endocrinol Metab. 2013;98(6):2230–2238.
  • Abbott DH, Barnett DK, Levine JE, et al. Endocrine antecedents of polycystic ovary syndrome in fetal and infant prenatally androgenized female rhesus monkeys. Biol Reprod. 2008;79(1):154–163.
  • Veiga-Lopez A, Steckler TL, Abbott DH, et al. Developmental programming: impact of excess prenatal testosterone on intrauterine fetal endocrine milieu and growth in sheep. Biol Reprod. 2011;84(1):87–96.
  • Abbott DH, Levine JE, Dumesic DA. Translational insight into Polycystic Ovary Syndrome (PCOS) from female monkeys with PCOS-like traits. Curr Pharm Des. 2016;22(36):5625–5633.
  • Cesta CE, Månsson M, Palm C, et al. Polycystic ovary syndrome and psychiatric disorders: co-morbidity and heritability in a nationwide Swedish cohort. Psychoneuroendocrinology. 2016;73:196–203.
  • Sir-Petermann T, Maliqueo M, Angel B, et al. Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenization. Hum Reprod. 2002;17(10):2573–2579.
  • Weiss PAM, Scholz HS, Haas J, et al. Long-term follow-up of diabetes of mothers with type I diabetes. Evidence for hereditary and nonhereditary transmission of diabetes and precursors. Diabetes Care. 2000;23:905-911  .
  • Maliqueo M, Lara HE, Sánchez F, et al. Placental steroidogenesis in pregnant women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2013;166(2):151–155.
  • Fux-Otta C, Maliqueo M, Echiburú B, et al. Pregnancy outcomes in women with polycystic ovary syndrome in two Latin American populations. J Obstet Gynaecol. 2018;38(6):750–755.
  • Palm CVB, Glintborg D, Kyhl HB, et al. Polycystic ovary syndrome and hyperglycaemia in pregnancy. A narrative review and results from a prospective Danish cohort study. Diabetes Res Clin Pract. 2018;145:167-177.
  • Bahri Khomami M, Boyle JA, Tay CT, et al. Polycystic ovary syndrome and adverse pregnancy outcomes: current state of knowledge, challenges and potential implications for practice. Clin Endocrinol (Oxf). 2018;88(6):761-769.
  • Tata B, Mimouni NEH, Barbotin AL, et al. Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood. Nat Med. 2018;24(6):834–846.
  • Homburg R, Gudi A, Shah A, et al. A novel method to demonstrate that pregnant women with polycystic ovary syndrome hyper-expose their fetus to androgens as a possible stepping stone for the developmental theory of PCOS. A pilot study. Reprod Biol Endocrinol. 2017;15:61.
  • Giacomoni PU, Mammone T, Teri M. Gender-linked differences in human skin. J Dermatol Sci. 2009;55:144–149.
  • Barrett ES, Hoeger KM, Sathyanarayana S, et al. Anogenital distance in newborn daughters of women with polycystic ovary syndrome indicates fetal testosterone exposure. J Dev Orig Health Dis. 2018 Jan;9:1–8.
  • Abbott AD, Colman RJ, Tiefenthaler R, et al. Early-to-mid gestation fetal testosterone increases right hand 2D:4D finger length ratio in polycystic ovary syndrome-like monkeys. PLoS One. 2012;7(8):e42372.
  • Sir-Petermann T, Codner E, Maliqueo M, et al. Increased anti-Müllerian hormone serum concentrations in prepubertal daughters of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91(8):3105–3109.
  • Sánchez-Ferrer ML, Mendiola J, Hernández-Peñalver AI, et al. Presence of polycystic ovary syndrome is associated with longer anogenital distance in adult Mediterranean women. Hum Reprod. 2017;32:2315-2323.
  • Wu Y, Zhong G, Chen S, et al. Polycystic ovary syndrome is associated with anogenital distance, a marker of prenatal androgen exposure. Hum Reprod. 2017;32:937-943.
  • Hernández-Peñalver AI, Sánchez-Ferrer ML, Mendiola J, et al. Assessment of anogenital distance as a diagnostic tool in polycystic ovary syndrome. Reprod Biomed Online. 2018;37(6):741-749.
  • Lujan ME, Bloski TG, Chizen DR, et al. Digit ratios do not serve as anatomical evidence of prenatal androgen exposure in clinical phenotypes of polycystic ovary syndrome. Hum Reprod. 2010;25:204-211.
  • Torchen LC, Idkowiak J, Fogel NR, et al. Evidence for increased 5α-reductase activity during early childhood in daughters of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2016;101:2069-2075.
  • Barry JA, Kay AR, Navaratnarajah R, et al. Umbilical vein testosterone in female infants born to mothers with polycystic ovary syndrome is elevated to male levels. J Obstet Gynaecol. 2010;30:444-446.
  • Daan NM, Koster MP, Steegers-Theunissen RP, et al. Endocrine and cardiometabolic cord blood characteristics of offspring born to mothers with and without polycystic ovary syndrome. Fertil Steril. 2017;107:261-268.e3.
  • Caanen MR, Kuijper EA, Hompes PG, et al. Mass spectrometry methods measured androgen and estrogen concentrations during pregnancy and in newborns of mothers with polycystic ovary syndrome. Eur J Endocrinol. 2016;174:25-32.
  • Anderson H, Fogel N, Grebe SK, et al. Infants of women with polycystic ovary syndrome have lower cord blood androstenedione and estradiol levels. J Clin Endocrinol Metab. 2010;95:2180-2186.
  • Hollier LP, Keelan JA, Hickey M, et al. Measurement of androgen and estrogen concentrations in cord blood: accuracy, biological interpretation, and applications to understanding human behavioral development. Front Endocrinol (Lausanne). 2014;5:64.
  • Abbott DH, Dumesic DA, Eisner JR, et al. Insights into the development of polycystic ovary syndrome (PCOS) from studies of prenatally androgenized female rhesus monkeys. Trends Endocrinol Metab. 1998;9(2):62-67.
  • Eisner JR, Dumesic DA, Kemnitz JW, et al. Timing of prenatal androgen excess determines differential impairment in insulin secretion and action in adult female rhesus monkeys. J Clin Endocrinol Metab. 2000;85(3):1206-1210.
  • Abbott DH, Tarantal AF, Dumesic DA. Fetal, infant, adolescent and adult phenotypes of polycystic ovary syndrome in prenatally androgenized female rhesus monkeys. Am J Primatol. 2009;71(9):776-784.
  • Herman RA, Jones B, Mann DR, et al. Timing of prenatal androgen exposure: anatomical and endocrine effects on juvenile male and female rhesus monkeys. Horm Behav. 2000;38(1):52-66.
  • Pepe GJ, Maniu A, Aberdeen G, et al. Insulin resistance elicited in postpubertal primate offspring deprived of estrogen in utero. Endocrine. 2016;54(3):788–797.
  • Pepe GJ, Lynch TJ, Albrecht ED. Regulation of baboon fetal ovarian development by placental estrogen: onset of puberty is delayed in offspring deprived ofestrogen in utero. Biol Reprod. 2013;89(6):132.
  • Kim SO, Aberdeen G, Lynch TJ, et al. Adipose and liver function in primate offspring with insulin resistance induced by estrogen deprivation in utero. Endocrinol Diabetes Metab J. 2017;1(3).
  • Pepe GJ, Maniu A, Aberdeen G, et al. Estrogen regulation of fetal adrenal cortical zone-specific development in the nonhuman primate impacts adrenal production of androgen and cortisol and response to ACTH in females in adulthood. Endocrinology. 2016;157(5):1905-1913.
  • Clarke IJ, Scaramuzzi RJ, Short RV. Ovulation in prenatally androgenized ewes. J Endocrinol. 1977;73(2):385-389.
  • Veiga-Lopez A, Moeller J, Patel D, et al. Developmental programming: impact of prenatal testosterone excess on insulin sensitivity, adiposity, and free fatty acid profile in postpubertal female sheep. Endocrinology. 2013;154(5):1731-1742.
  • Robinson JE, Forsdike RA, Taylor JA. In utero exposure of female lambs to testosterone reduces the sensitivity of the gonadotropin-releasing hormone neuronal network to inhibition by progesterone. Endocrinology. 1999;140(12):5797-5805.
  • Recabarren SE, Padmanabhan V, Codner E, et al. Postnatal developmental consequences of altered insulin sensitivity in female sheep treated prenatally with testosterone. Am J Physiol Endocrinol Metab. 2005;289(5):E801-E806.
  • Smith P, Steckler TL, Veiga-Lopez A, et al. Developmental programming: differential effects of prenatal testosterone and dihydrotestosterone on follicular recruitment, depletion of follicular reserve, and ovarian morphology in sheep. Biol Reprod. 2009;80(4):726-736.
  • Padmanabhan V, Veiga-Lopez A. Sheep models of polycystic ovary syndrome phenotype. Mol Cell Endocrinol. 2013;373(1–2):8-20.
  • Abi Salloum B, Herkimer C, Lee JS, et al. Developmental programming: prenatal and postnatal contribution of androgens and insulin in the reprogramming of estradiol positive feedback disruptions in prenatal testosterone-treated sheep. Endocrinology. 2012;153(6):2813-2822.
  • Veiga-Lopez A, Lee JS, Padmanabhan V. Developmental programming: insulin sensitizer treatment improves reproductive function in prenatal testosterone-treated female sheep. Endocrinology. 2010;151(8):4007-4017.
  • Abi Salloum B, Veiga-Lopez A, Abbott DH, et al. Developmental programming: exposure to testosterone excess disrupts steroidal and metabolic environment in pregnant sheep. Endocrinology. 2015 Jun;156(6):2323-2337.
  • Rae M, Grace C, Hogg K, et al. The pancreas is altered by in utero androgen exposure: implications for clinical conditions such as polycystic ovary syndrome (PCOS). PLoS One. 2013;8(2):e56263.
  • Hogg K, Wood C, McNeilly AS, et al. The in utero programming effect of increased maternal androgens and a direct fetal intervention on liver and metabolic function in adult sheep. PLoS One. 2011;6(9):e24877.
  • Ramaswamy S, Grace C, Mattei AA, et al. Developmental programming of polycystic ovary syndrome (PCOS): prenatal androgens establish pancreatic islet α/β cell ratio and subsequent insulin secretion. Sci Rep. 2016;6:27408.
  • Wu XY, Li ZL, Wu CY, et al. Endocrine traits of polycystic ovary syndrome in prenatally androgenized female Sprague-Dawley rats. Endocr J. 2010;57(3):201-209.
  • Slob AK, Den Hamer R, Woutersen PJ, et al. Prenatal testosterone propionate and postnatal ovarian activity in the rat. Acta Endocrinol (Copenh). 1983;103(3):420-427.
  • Demissie M, Lazic M, Foecking EM, et al. Transient prenatal androgen exposure produces metabolic syndrome in adult female rats. Am J Physiol Endocrinol Metab. 2008;295(2):E262-E268.
  • Foecking EM, McDevitt MA, Acosta-Martínez M, et al. Neuroendocrine consequences of androgen excess in female rodents. Horm Behav. 2008;53(5):673-692.
  • Fagman JB, Wilhelmson AS, Motta BM, et al. The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice. FASEB J. 2015;29(4):1540-1550.
  • Walters KA, Edwards MC, Tesic D, et al. The role of central androgen receptor actions in regulating the hypothalamic-pituitary-ovarian axis. Neuroendocrinology. 2018;106(4):389-400.
  • Van Sinderen M, Steinberg G, Jorgensen SB, et al. Sexual dimorphism in the glucose homeostasis phenotype of the aromatase knockout (ArKO) mice. J Steroid Biochem Mol Biol. 2017;170:39-48.
  • Schomberg DW, Couse JF, Mukherjee A, et al. Targeted disruption of the estrogen receptor-alpha gene in female mice: characterization of ovarian responses and phenotype in the adult. Endocrinology. 1999;140(6):2733-2744.
  • Park CJ, Zhao Z, Glidewell-Kenney C, et al. Genetic rescue of nonclassical ERα signaling normalizes energy balance in obese Erα-null mutant mice. J Clin Invest. 2011;121(2):604-612.
  • Risma KA, Clay CM, Nett TM, et al. Targeted overexpression of luteinizing hormone in transgenic mice leads to infertility, polycystic ovaries, and ovarian tumors. Proc Natl Acad Sci U S A. 1995;92(5):1322-1326.
  • Nilson JH, Abbud RA, Keri RA, et al. Chronic hypersecretion of luteinizing hormone in transgenic mice disrupts both ovarian and pituitary function, with some effects modified by the genetic background. Recent Prog Horm Res. 2000;55:69-89.
  • Kero JT, Savontaus E, Mikola M, et al. Obesity in transgenic female mice with constitutively elevated luteinizing hormone secretion. Am J Physiol Endocrinol Metab. 2003;285(4):E812-E818.
  • Abbott DH, Bruns CR, Barnett DK, et al. Experimentally induced gestational androgen excess disrupts glucoregulation in rhesus monkey dams and their female offspring. Am J Physiol Endocrinol Metab. 2010;299(5):E741-E751.
  • Sullivan EL, Rivera HM, True CA, et al. Maternal and postnatal high-fat diet consumption programs energy balance and hypothalamic melanocortin signaling in nonhuman primate offspring. Am J Physiol Regul Integr Comp Physiol. 2017;313:R169-R179.
  • Nicol LE, O’Brien TD, Dumesic DA, et al. Abnormal infant islet morphology precedes insulin resistance in PCOS-like monkeys. PLoS One. 2014;9:e106527.
  • Martin B, Sacks DA. The global burden of hyperglycemia in pregnancy – trends from studies in the last decade. Diabetes Res Clin Pract. 2018;145:17-19.
  • Goy RW, Robinson JA. Prenatal exposure of rhesus monkeys to patent androgens: morphological, behavioral and physiological consequences. In: Hunt VR, Smith MK, Worth D, editors. Banbury report II: environmental factors in human growth and development. Cold Spring Harbor: Cold Spring Harbor Laboratory; 1982. p. 355–378.
  • Zehr JL, Van Meter PE, Wallen K. Factors regulating the timing of puberty onset in female rhesus monkeys (Macaca mulatta): role of prenatal androgens, social rank, and adolescent body weight. Biol Reprod. 2005;72:1087-1094.
  • Abbott DH, Nicol LE, Levine JE, et al. Nonhuman primate models of polycystic ovary syndrome. Mol Cell Endocrinol. 2013;373(1–2):21-28.
  • Abbott DH, Dumesic DA, Eisner JR, et al. The prenatally androgenized female rhesus monkey as a model for polycystic ovarian syndrome. In: Azziz R, Nestler JE, Dewailly D, editors. Androgen excess disorders in women. Philadelphia: Lippencott-Raven Press; 1997. p. 369–382.
  • Abbott DH, Vepraskas SH, Horton TH, et al. Accelerated episodic luteinizing hormone release accompanies blunted progesterone regulation in PCOS-like female rhesus monkeys (Macaca Mulatta) exposed to testosterone during early-to-mid gestation. Neuroendocrinology. 2018;107(2):133–146.
  • Daniels TL, Berga SL. Resistance of gonadotropin releasing hormone drive to sex steroid-induced suppression in hyperandrogenic anovulation. J Clin Endocrinol Metab. 1997;82;4179-4183.
  • Eagleson CA, Gingrich MB, Pastor CL, et al. Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. J Clin Endocrinol Metab. 2000;85:4047-4052.
  • Dumesic DA, Schramm RD, Peterson E, et al. Impaired developmental competence of oocytes in adult prenatally androgenized female rhesus monkeys undergoing gonadotropin stimulation for in vitro fertilization. J Clin Endocrinol Metab. 2002;87:1111-1119.
  • Broughton DE, Moley KH. Obesity and female infertility: potential mediators of obesity’s impact. Fertil Steril. 2017;107:840-847.
  • Dumesic DA, Patankar MS, Barnett DK, et al. Early prenatal androgenization results in diminished ovarian reserve in adult female rhesus monkeys. Hum Reprod. 2009;24:3188-3195.
  • Ahmad AK, Kao CN, Quinn M, et al. Differential rate in decline in ovarian reserve markers in women with polycystic ovary syndrome compared with control subjects: results of a longitudinal study. Fertil Steril. 2018;109:526-531.
  • Abbott DH, Barnett DK, Bruns CM, et al. Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome? Hum Reprod Update. 2005;11(4):357-374.
  • Lee S, Arslanian S. Body composition and cardiorespiratory fitness between metabolically healthy versus metabolically unhealthy obese black and white adolescents. J Adolesc Health. 2018 Oct 31;S1054–S139X(18): 30408–7. DOI:10.1016/j.jadohealth.2018.08.024. [Epub ahead of print].
  • Keller E, Chazenbalk GD, Aguilera P, et al. Impaired preadipocyte differentiation into adipocytes in subcutaneous abdominal adipose of PCOS-like female rhesus monkeys. Endocrinology. 2014;155:2696-2703.
  • Xu N, Kwon S, Abbott DH, et al. Epigenetic mechanism underlying the development of polycystic ovary syndrome(PCOS)-like phenotypes in prenatally androgenized rhesus monkeys. PLoS One. 2011;6:e27286.
  • Pervin S, Singh V, Tucker A, et al. Modulation of transforming growth factor-β/follistatin signaling and white adipose browning: therapeutic implications for obesity related disorders. Horm Mol Biol Clin Investig. 2017;31(2).
  • Sam S. Differential effect of subcutaneous abdominal and visceral adipose tissue on cardiometabolic risk. Horm Mol Biol Clin Investig. 2018;33(1).
  • Zhou R, Bruns CM, Bird IM, et al. Pioglitazone improves insulin action and normalizes menstrual cycles in a majority of prenatally androgenized female rhesus monkeys. Reprod Toxicol. 2007;23:438-448.
  • Padmanabhan V, Cardoso RC, Puttabyatappa M. Developmental programming, a pathway to disease. Endocrinology. 2016;157:1328-1340.
  • Moore AM, Campbell RE. Polycystic ovary syndrome: understanding the role of the brain. Front Neuroendocrinol. 2017;46:1-14.
  • Walters KA, Gilchrist RB, Ledger WL, et al. New perspectives on the pathogenesis of PCOS: neuroendocrine origins. Trends Endocrinol Metab. 2018;29(12):841-852.
  • Hogg K, Young JM, Oliver EM, et al. Enhanced thecal androgen production is prenatally programmed in an ovine model of polycystic ovary syndrome. Endocrinology. 2012;153:450-461.
  • Ortega HH, Salvetti NR, Padmanabhan V. Developmental programming: prenatal androgen excess disrupts ovarian steroid receptor balance. Reproduction. 2009;137:865-877.
  • Veiga-Lopez A, Moeller J, Abbott DH, et al. Developmental programming: rescuing disruptions in preovulatory follicle growth and steroidogenesis from prenatal testosterone disruption. J Ovarian Res. 2016;9(1):39.
  • Padmanabhan V, Veiga-Lopez A, Herkimer C, et al. Developmental programming: prenatal and postnatal androgen antagonist and insulin sensitizer interventions prevent advancement of puberty and improve LH surge dynamics in prenatal testosterone-treated sheep. Endocrinology. 2015;156(7):2678-2692.
  • Roland AV, Nunemaker CS, Keller SR, et al. Prenatal androgen exposure programs metabolic dysfunction in female mice. J Endocrinol. 2010;207(2):213-223.
  • De Leo V, Lanzetta D, D’Antona D, et al. Hormonal effects of flutamide in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1998;83;99-102.
  • Caldwell AS, 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.
  • 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:E3334-E3343.
  • Silva MS, Prescott M, Campbell RE. Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS. JCI Insight. 2018;3(7).
  • Moore AM, Prescott M, Marshall CJ, et al. 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;112:596-601.
  • Sullivan SD, Moenter SM. Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: implications for a common fertility disorder. Proc Natl Acad Sci U S A. 2004;101:7129-7134.
  • Dunaif A, Chang RJ, Franks S, et al. Polycystic ovary syndrome: current controversies, from the ovary to the pancreas. Totowa, NJ: Humana Press; 2008.  p. vii.
  • Tomaszycki ML, Gouzoules H, Wallen K. Sex differences in juvenile rhesus macaque (Macaca mulatta) agonistic screams: life history differences and effects of prenatal androgens. Dev Psychobiol. 2005;47(4):318–327.
  • Herman RA, Wallen K. Cognitive performance in rhesus monkeys varies by sex and prenatal androgen exposure. Horm Behav. 2007;51(4):496–507.
  • Wallen K. Hormonal influences on sexually differentiated behavior in nonhuman primates. Front Neuroendocrinol. 2005;26(1):7–26.
  • Cardoso RC, Burns A, Moeller J, et al. Developmental programming: insulin sensitizer prevents the GnRH-stimulated LH hypersecretion in a sheep model of PCOS. Endocrinology. 2016;157:4641-4653.
  • Holt RI, Lambert KD. The use of oral hypoglycaemic agents in pregnancy. Diabet Med. 2014;31(3):282–291.
  • Glueck CJ, Pranikoff J, Aregawi D, et al. Prevention of gestational diabetes by metformin plus diet in patients with polycystic ovary syndrome. Fertil Steril. 2008;89(3):625–634.
  • Hjorth-Hansen A, Salvesen Ø, Engen Hanem LG, et al. Fetal growth and birth anthropometrics in metformin-exposed offspring born to mothers with PCOS. J Clin Endocrinol Metab. 2018;103(2):740–747.
  • Hanem LGE, Stridsklev S, Júlíusson PB, et al. Metformin use in PCOS pregnancies increases the risk of offspring overweight at 4 years of age: follow-up of two RCTs. J Clin Endocrinol Metab. 2018;103(4):1612–1621.
  • Barbour LA, Scifres C, Valent AM, et al. A cautionary response to SMFM statement: pharmacological treatment of gestational diabetes. Am J Obstet Gynecol. 2018;219(4):367.e1–367.e7.
  • Løvvik TS, Carlsen SM, Steffensen B, et al. Metformin treatment of pregnant women with polycystic ovary syndrome - a randomized, nordic multi-center trial. OR33-4. Endocr Rev. 2018;38(2,Suppl):OR33–4.
  • Biondani G, Peyron JF. Metformin, an Anti-diabetic Drug to Target Leukemia. Front Endocrinol (Lausanne). 2018;9:446.
  • de Zegher F, Lopez-Bermejo A, Ibáñez L. Adipose tissue expandability and the early origins of PCOS. Trends Endocrinol Metab. 2009;20(9):418–423.
  • Dumesic DA, Akopians AL, Madrigal VK, et al. Hyperandrogenism accompanies increased intra-abdominal fat storage in normal weight polycystic ovary syndrome women. J Clin Endocrinol Metab. 2016;101(11):4178–4188.
  • Harnois-Leblanc S, Trottier A, Leblanc S, et al. Evolution of metabolic alterations 5 Years after early puberty in a cohort of girls predisposed to polycystic ovary syndrome. Reprod Biol Endocrinol. 2017;15(1):56.
  • Han SY, Clarkson J, Piet R, et al. Optical approaches for interrogating neural circuits controlling hormone secretion. Endocrinology. 2018;159(11):3822–3833.
  • Levine JE, Kraynak M, Willging MM, et al. Hypothalamic ERa gene silencing induces obesity in female Rhesus monkeys. Endocr Rev. 2018;39(2): Suppl: SUN-072.
  • Seita Y, Tsukiyama T, Iwatani C, et al. Generation of transgenic cynomolgus monkeys that express green fluorescent protein throughout the whole body. Sci Rep. 2016;6:24868.

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