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Anogenital distance in newborn daughters of women with polycystic ovary syndrome indicates fetal testosterone exposure

Part of: Liggins Institute, New Zealand and the Japanese DOHaD Society

Published online by Cambridge University Press:  09 January 2018

E. S. Barrett Open the ORCID record for E. S. Barrett [Opens in a new window] ,
K. M. Hoeger ,
S. Sathyanarayana ,
D. H. Abbott ,
J. B. Redmon ,
R. H. N. Nguyen  and
S. H. Swan
E. S. Barrett*
Affiliation:
Department of Epidemiology, Rutgers School of Public Health, Division of Epidemiology and Biostatistics, Environmental and Occupational Health Sciences Institute, Piscataway, NJ, USA Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
K. M. Hoeger
Affiliation:
Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
S. Sathyanarayana
Affiliation:
Departments of Pediatrics, Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA Seattle Children’s Research Institute, Seattle, WA, USA
D. H. Abbott
Affiliation:
Departments of Obstetrics and Gynecology and Neuroscience, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, USA
J. B. Redmon
Affiliation:
Department of Medicine, University of Minnesota, Minneapolis, MN, USA
R. H. N. Nguyen
Affiliation:
Department of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA
S. H. Swan
Affiliation:
Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
*
Address for correspondence: E. S. Barrett, Environmental and Occupational Health Sciences Institute, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA. E-mail Emily.barrett@eohsi.rutgers.edu
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Abstract

Polycystic ovary syndrome (PCOS) affects ~7% of reproductive age women. Although its etiology is unknown, in animals, excess prenatal testosterone (T) exposure induces PCOS-like phenotypes. While measuring fetal T in humans is infeasible, demonstrating in utero androgen exposure using a reliable newborn biomarker, anogenital distance (AGD), would provide evidence for a fetal origin of PCOS and potentially identify girls at risk. Using data from a pregnancy cohort (The Infant Development and Environment Study), we tested the novel hypothesis that infant girls born to women with PCOS have longer AGD, suggesting higher fetal T exposure, than girls born to women without PCOS. During pregnancy, women reported whether they ever had a PCOS diagnosis. After birth, infant girls underwent two AGD measurements: anofourchette distance (AGD-AF) and anoclitoral distance (AGD-AC). We fit adjusted linear regression models to examine the association between maternal PCOS and girls’ AGD. In total, 300 mother–daughter dyads had complete data and 23 mothers reported PCOS. AGD was longer in the daughters of women with a PCOS diagnosis compared with daughters of women with no diagnosis (AGD-AF: β=1.21, P=0.05; AGD-AC: β=1.05, P=0.18). Results were stronger in analyses limited to term births (AGD-AF: β=1.65, P=0.02; AGD-AC: β=1.43, P=0.09). Our study is the first to examine AGD in offspring of women with PCOS. Our results are consistent with findings that women with PCOS have longer AGD and suggest that during PCOS pregnancies, daughters may experience elevated T exposure. Identifying the underlying causes of PCOS may facilitate early identification and intervention for those at risk.

Keywords

AGDfetal programmingPCOSpregnancytestosterone
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 9 , Issue 3: Themed Issue: NZ-Japan , June 2018 , pp. 307 - 314
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Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2018 

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References

1. American Congress of Obstetricians and Gynecologists. Polycystic ovary syndrome. Obstet Gynecol. 2009; 114, 936–949.CrossRefGoogle Scholar
2. Sirmans, SM, Pate, KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin Epidemiol. 2013; 6, 1–13.CrossRefGoogle ScholarPubMed
3. Hart, R, Doherty, DA. The potential implications of a PCOS diagnosis on a woman’s long-term health using data linkage. J Clin Endocrinol Metab. 2015; 100, 911–919.CrossRefGoogle ScholarPubMed
4. Joham, AE, Ranasinha, S, Zoungas, S, Moran, L, Teede, HJ. Gestational diabetes and type 2 diabetes in reproductive-aged women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2014; 99, E447–E452.CrossRefGoogle ScholarPubMed
5. Nader, S. Infertility and pregnancy in women with polycystic ovary syndrome. Minerva Endocrinol. 2010; 35, 211–225.Google ScholarPubMed
6. Group TREA-sPCW. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004; 19, 41–47.CrossRefGoogle Scholar
7. Azziz, R, Carmina, E, Dewailly, D, et al. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril. 2009; 91, 456–488.CrossRefGoogle ScholarPubMed
8. Abbott, DH, Dumesic, DA, Franks, S. Developmental origin of polycystic ovary syndrome – a hypothesis. J Endocrinol. 2002; 174, 1–5.CrossRefGoogle ScholarPubMed
9. Abbott, DH, Nicol, LE, Levine, JE, Xu, N, Goodarzi, MO, Dumesic, DA. Nonhuman primate models of polycystic ovary syndrome. Mol Cell Endocrinol. 2013; 373, 21–28.CrossRefGoogle ScholarPubMed
10. Padmanabhan, V, Veiga-Lopez, A. Animal models of the polycystic ovary syndrome phenotype. Steroids. 2013; 78, 734–740.CrossRefGoogle ScholarPubMed
11. van Houten, EL, Kramer, P, McLuskey, A, Karels, B, Themmen, AP, Visser, JA. Reproductive and metabolic phenotype of a mouse model of PCOS. Endocrinology. 2012; 153, 2861–2869.CrossRefGoogle ScholarPubMed
12. Comim, FV, Hardy, K, Robinson, J, Franks, S. Disorders of follicle development and steroidogenesis in ovaries of androgenised foetal sheep. J Endocrinol. 2015; 225, 39–46.CrossRefGoogle ScholarPubMed
13. Barnes, RB, Rosenfield, RL, Ehrmann, DA, et al. Ovarian hyperandrogynism as a result of congenital adrenal virilizing disorders: evidence for perinatal masculinization of neuroendocrine function in women. J Clin Endocrinol Metab. 1994; 79, 1328–1333.Google ScholarPubMed
14. Hague, WM, Adams, J, Rodda, C, et al. The prevalence of polycystic ovaries in patients with congenital adrenal hyperplasia and their close relatives. Clin Endocrinol (Oxf). 1990; 33, 501–510.CrossRefGoogle ScholarPubMed
15. Morishima, A, Grumbach, MM, Simpson, ER, Fisher, C, Qin, K. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab. 1995; 80, 3689–3698.Google ScholarPubMed
16. Rosenfield, RL. The diagnosis of polycystic ovary syndrome in dolescents. Pediatrics. 2015; 136, 1154–1165.CrossRefGoogle Scholar
17. Kamangar, F, Okhovat, JP, Schmidt, T, et al. Polycystic ovary syndrome: special diagnostic and therapeutic considerations for children. Pediatr Dermatol. 2015; 32, 571–578.CrossRefGoogle ScholarPubMed
18. Harden, KA, Cowan, PA, Velasquez-Mieyer, P, Patton, SB. Effects of lifestyle intervention and metformin on weight management and markers of metabolic syndrome in obese adolescents. J Am Acad Nurse Pract. 2007; 19, 368–377.CrossRefGoogle ScholarPubMed
19. Harris-Glocker, M, Davidson, K, Kochman, L, Guzick, D, Hoeger, K. Improvement in quality-of-life questionnaire measures in obese adolescent females with polycystic ovary syndrome treated with lifestyle changes and oral contraceptives, with or without metformin. Fertil Steril. 2010; 93, 1016–1019.CrossRefGoogle ScholarPubMed
20. Hoeger, K, Davidson, K, Kochman, L, Cherry, T, Kopin, L, Guzick, DS. The impact of metformin, oral contraceptives, and lifestyle modification on polycystic ovary syndrome in obese adolescent women in two randomized, placebo-controlled clinical trials. J Clin Endocrinol Metab. 2008; 93, 4299–4306.CrossRefGoogle ScholarPubMed
21. Lass, N, Kleber, M, Winkel, K, Wunsch, R, Reinehr, T. Effect of lifestyle intervention on features of polycystic ovarian syndrome, metabolic syndrome, and intima-media thickness in obese adolescent girls. J Clin Endocrinol Metab. 2011; 96, 3533–3540.CrossRefGoogle ScholarPubMed
22. Barrett, ES, Parlett, LE, Redmon, JB, Swan, SH. Evidence for sexually dimorphic associations between maternal characteristics and anogenital distance, a marker of reproductive development. Am J Epidemiol. 2014; 179, 57–66.CrossRefGoogle ScholarPubMed
23. Salazar-Martinez, E, Romano-Riquer, P, Yanez-Marquez, E, Longnecker, MP, Hernandez-Avila, M. Anogenital distance in human male and female newborns: a descriptive, cross-sectional study. Environ Health. 2004; 3, 8.CrossRefGoogle ScholarPubMed
24. Banszegi, O, Altbacker, V, Bilko, A. Intrauterine position influences anatomy and behavior in domestic rabbits. Physiol Behav. 2009; 98, 258–262.CrossRefGoogle ScholarPubMed
25. Fouqueray, TD, Blumstein, DT, Monclus, R, Martin, JG. Maternal effects on anogenital distance in a wild marmot population. PloS One. 2014; 9, e92718.CrossRefGoogle Scholar
26. Hotchkiss, AK, Lambright, CS, Ostby, JS, Parks-Saldutti, L, Vandenbergh, JG, Gray, LE Jr. Prenatal testosterone exposure permanently masculinizes anogenital distance, nipple development, and reproductive tract morphology in female Sprague-Dawley rats. Toxicol Sci. 2007; 96, 335–345.CrossRefGoogle ScholarPubMed
27. Banszegi, O, Altbacker, V, Ducs, A, Bilko, A. Testosterone treatment of pregnant rabbits affects sexual development of their daughters. Physiol Behav. 2010; 101, 422–427.CrossRefGoogle ScholarPubMed
28. 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 Metabol. 2005; 289, E801–E806.CrossRefGoogle ScholarPubMed
29. Manikkam, M, Crespi, EJ, Doop, DD, et al. Fetal programming: prenatal testosterone excess leads to fetal growth retardation and postnatal catch-up growth in sheep. Endocrinology. 2004; 145, 790–798.CrossRefGoogle ScholarPubMed
30. Abbott, AD, Colman, RJ, Tiefenthaler, R, Dumesic, DA, Abbott, DH. Early-to-mid gestation fetal testosterone increases right hand 2D:4D finger length ratio in polycystic ovary syndrome-like monkeys. PloS One. 2012; 7, e42372.CrossRefGoogle Scholar
31. Sanchez-Ferrer, ML, Mendiola, J, Hernandez-Penalver, AI, et al. Presence of polycystic ovary syndrome is associated with longer anogenital distance in adult Mediterranean women. Hum Reprod. 2017; 32, 2315–2323.CrossRefGoogle ScholarPubMed
32. Wu, Y, Zhong, G, Chen, S, Zheng, C, Liao, D, Xie, M. Polycystic ovary syndrome is associated with anogenital distance, a marker of prenatal androgen exposure. Hum Reprod. 2017; 32, 937–943.Google ScholarPubMed
33. Mendiola, J, Roca, M, Minguez-Alarcon, L, et al. Anogenital distance is related to ovarian follicular number in young Spanish women: a cross-sectional study. Environ Health. 2012; 11, 90.CrossRefGoogle ScholarPubMed
34. Mira-Escolano, MP, Mendiola, J, Minguez-Alarcon, L, et al. Longer anogenital distance is associated with higher testosterone levels in women: a cross-sectional study. BJOG. 2014; 121, 1359–1364.CrossRefGoogle ScholarPubMed
35. Wainstock, T, Shoham-Vardi, I, Sheiner, E, Walfisch, A. Fertility and anogenital distance in women. Reprod Toxicol. 2017; 73, 345–349. https://doi.org/10.1016/j.reprotox.2017.07.009.CrossRefGoogle ScholarPubMed
36. Callegari, C, Everett, S, Ross, M, Brasel, JA. Anogenital ratio: measure of fetal virilization in premature and full-term newborn infants. J Pediatr. 1987; 111, 240–243.CrossRefGoogle ScholarPubMed
37. 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.CrossRefGoogle ScholarPubMed
38. Barrett, ES, Sathyanarayana, S, Janssen, S, et al. Environmental health attitudes and behaviors: findings from a large pregnancy cohort study. Eur J Obstet Gynecol Reprod Biol. 2014; 176, 119–125.CrossRefGoogle ScholarPubMed
39. Swan SH, Sathyanarayana S, Barrett ES, et al. First-trimester phthalate exposure is linked to shorter anogenital distance in newborn boys. Human Reprod. 2015; 30, 963–972.Google Scholar
40. Taponen, S, Ahonkallio, S, Martikainen, H, et al. Prevalence of polycystic ovaries in women with self-reported symptoms of oligomenorrhoea and/or hirsutism: Northern Finland Birth Cohort 1966 Study. Hum Reprod. 2004; 19, 1083–1088.CrossRefGoogle ScholarPubMed
41. 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. 2013; 21, 1526–1532.CrossRefGoogle ScholarPubMed
42. 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, 2339–2351.CrossRefGoogle ScholarPubMed
43. Day, FR, Hinds, DA, Tung, JY, et al. Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Nat Commun. 2015; 6, 8464.CrossRefGoogle ScholarPubMed
44. Dunaif, A. Perspectives in polycystic ovary syndrome: from hair to eternity. J Clin Endocrinol Metab. 2016; 101, 759–768.CrossRefGoogle ScholarPubMed
45. Sathyanarayana S, Grady R, Redmon JB, et al. Anogenital distance and penile width measurements in The Infant Development and the Environment Study (TIDES): methods and predictors. J Pediatr Urol. 2015; 11, 76.e1–6.Google Scholar
46. Swan, SH. Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans. Environ Res. 2008; 108, 177–184.CrossRefGoogle ScholarPubMed
47. Barrett, E, Hoeger, K, Sathyanarayana, S, Redmon, JB, Nguyen, RH, Swan, SH. Anogenital distance, a biomarker of prenatal androgen exposure, is longer among newborn daughters of women with polycystic ovary syndrome (PCOS), 2016. Endocrine Society (ENDO): Boston, MA.Google Scholar
48. Barrett ES, Parlett LE, Sathyanarayana S, Redmon JB, Nguyen RH, Swan SH. Prenatal Stress as a Modifier of Associations between Phthalate Exposure and Reproductive Development: results from a Multicentre Pregnancy Cohort Study. Paediatr Perinat Epidemiol. 2016; 30, 105–114.Google Scholar
49. Sir-Petermann, T, Maliqueo, M, Angel, B, Lara, HE, Perez-Bravo, F, Recabarren, SE. Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenization. Hum Reprod. 2002; 17, 2573–2579.CrossRefGoogle ScholarPubMed
50. 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.CrossRefGoogle ScholarPubMed
51. Adams, J, Franks, S, Polson, DW, et al. Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotropin releasing hormone. Lancet. 1985; 2, 1375–1379.CrossRefGoogle ScholarPubMed
52. Padmanabhan, V, Veiga-Lopez, A. Reproduction symposium: developmental programming of reproductive and metabolic health. J Anim Sci. 2014; 92, 3199–3210.CrossRefGoogle ScholarPubMed
53. Abbott, DH, Dumesic, DA, Lewis, KC, et al. Naturally occurring hyperandrogenism and intermittent menstrual cycles in female rhesus monkeys. Endocr Rev. 2012; 33(Suppl), MON-16.Google Scholar
54. Bornehag, CG, Carlstedt, F, Jonsson, BA, et al. Prenatal phthalate exposures and anogenital distance in Swedish boys. Environ Health Perspect. 2014; 123, 101–107.CrossRefGoogle ScholarPubMed
55. Suzuki, Y, Yoshinaga, J, Mizumoto, Y, Serizawa, S, Shiraishi, H. Foetal exposure to phthalate esters and anogenital distance in male newborns. Int J Androl. 2012; 35, 236–244.CrossRefGoogle ScholarPubMed
56. Baron-Cohen, S, Auyeung, B, Norgaard-Pedersen, B, et al. Elevated fetal steroidogenic activity in autism. Mol Psychiatry. 2015; 20, 369–376.CrossRefGoogle ScholarPubMed
57. Baron-Cohen, S, Knickmeyer, RC, Belmonte, MK. Sex differences in the brain: implications for explaining autism. Science. 2005; 310, 819–823.CrossRefGoogle ScholarPubMed
58. Kosidou, K, Dalman, C, Widman, L, et al. Maternal polycystic ovary syndrome and the risk of autism spectrum disorders in the offspring: a population-based nationwide study in Sweden. Mol Psychiatry. 2015; 21, 1441–1448.CrossRefGoogle ScholarPubMed
59. 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. 2012; 77, 898–904.CrossRefGoogle ScholarPubMed
60. Baron-Cohen, S. The essential difference: the truth about the male and female brain. 2003. Basic Books: New York.Google Scholar
61. Goy, RW, Bercovitch, FB, McBrair, MC. Behavioral masculinization is independent of genital masculinization in prenatally androgenized female rhesus macaques. Horm Behav. 1988; 22, 552–571.CrossRefGoogle ScholarPubMed
62. Thornton, J, Goy, RW. Female-typical sexual behavior of rhesus and defeminization by androgens given prenatally. Horm Behav. 1986; 20, 129–147.CrossRefGoogle ScholarPubMed
63. Dokras, A, Clifton, S, Futterweit, W, Wild, R. Increased prevalence of anxiety symptoms in women with polycystic ovary syndrome: systematic review and meta-analysis. Fertil Steril. 2012; 97, 225–230.e222.CrossRefGoogle ScholarPubMed
64. Hu, M, Richard, JE, Maliqueo, M, et al. Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring. Proc Natl Acad Sci U S A. 2015; 112, 14348–14353.CrossRefGoogle ScholarPubMed
65. Pasterski, V, Acerini, CL, Dunger, DB, et al. Postnatal penile growth concurrent with mini-puberty predicts later sex-typed play behavior: evidence for neurobehavioral effects of the postnatal androgen surge in typically developing boys. Horm Behav. 2015; 69, 98–105.CrossRefGoogle ScholarPubMed
66. Kanova, N, Bicikova, M. Hyperandrogenic states in pregnancy. Physiol Res. 2011; 60, 243–252.CrossRefGoogle ScholarPubMed
67. Xita, N, Tsatsoulis, A. Genetic variants of sex hormone-binding globulin and their biological consequences. Mol Cell Endocrinol. 2010; 316, 60–65.CrossRefGoogle ScholarPubMed
68. Maliqueo, M, Lara, HE, Sanchez, F, Echiburu, B, Crisosto, N, Sir-Petermann, T. Placental steroidogenesis in pregnant women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2013; 166, 151–155.CrossRefGoogle ScholarPubMed
69. Palomba, S, Russo, T, Falbo, A, et al. Macroscopic and microscopic findings of the placenta in women with polycystic ovary syndrome. Hum Reprod. 2013; 28, 2838–2847.CrossRefGoogle ScholarPubMed
70. Palomba, S, Russo, T, Falbo, A, et al. Decidual endovascular trophoblast invasion in women with polycystic ovary syndrome: an experimental case-control study. J Clin Endocrinol Metab. 2012; 97, 2441–2449.CrossRefGoogle ScholarPubMed
71. Govind, A, Obhrai, MS, Clayton, RN. Polycystic ovaries are inherited as an autosomal dominant trait: analysis of 29 polycystic ovary syndrome and 10 control families. J Clin Endocrinol Metab. 1999; 84, 38–43.CrossRefGoogle ScholarPubMed
72. Hague, WM, Adams, J, Reeders, ST, Peto, TE, Jacobs, HS. Familial polycystic ovaries: a genetic disease? Clin Endocrinol (Oxf). 1988; 29, 593–605.CrossRefGoogle ScholarPubMed
73. Lunde, O, Magnus, P, Sandvik, L, Hoglo, S. Familial clustering in the polycystic ovarian syndrome. Gynecol Obstet Invest. 1989; 28, 23–30.CrossRefGoogle ScholarPubMed
74. Puttabyatappa, M, Cardoso, RC, Padmanabhan, V. Effect of maternal PCOS and PCOS-like phenotype on the offspring’s health. Mol Cell Endocrinol. 2015; 435, 29–39.CrossRefGoogle ScholarPubMed
75. 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, 5625–5633.CrossRefGoogle ScholarPubMed
76. Cole, B, Hensinger, K, Maciel, GA, Chang, RJ, Erickson, GF. Human fetal ovary development involves the spatiotemporal expression of p450c17 protein. J Clin Endocrinol Metab. 2006; 91, 3654–3661.CrossRefGoogle ScholarPubMed
77. Ellinwood, WE, McClellan, MC, Brenner, RM, Resko, JA. Estradiol synthesis by fetal monkey ovaries correlates with antral follicle formation. Biol Reprod. 1983; 28, 505–516.CrossRefGoogle ScholarPubMed
78. Fowler, PA, Anderson, RA, Saunders, PT, et al. Development of steroid signaling pathways during primordial follicle formation in the human fetal ovary. J Clin Endocrinol Metab. 2011; 96, 1754–1762.CrossRefGoogle ScholarPubMed
79. Crisosto, N, Echiburu, B, Maliqueo, M, et al. Improvement of hyperandrogenism and hyperinsulinemia during pregnancy in women with polycystic ovary syndrome: possible effect in the ovarian follicular mass of their daughters. Fertil Steril. 2012; 97, 218–224.CrossRefGoogle ScholarPubMed
80. Crisosto, N, Codner, E, Maliqueo, M, et al. Anti-Mullerian hormone levels in peripubertal daughters of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2007; 92, 2739–2743.CrossRefGoogle ScholarPubMed
81. Dumesic, DA, Abbott, DH, Eisner, JR, Goy, RW. Prenatal exposure of female rhesus monkeys to testosterone propionate increases serum luteinizing hormone levels in adulthood. Fertil Steril. 1997; 67, 155–163.CrossRefGoogle ScholarPubMed
82. Stadtmauer, LA, Wong, BC, Oehninger, S. Should patients with polycystic ovary syndrome be treated with metformin? Benefits of insulin sensitizing drugs in polycystic ovary syndrome – beyond ovulation induction. Hum Reprod. 2002; 17, 3016–3026.CrossRefGoogle ScholarPubMed
83. Carlsen, SM, Vanky, E. Metformin influence on hormone levels at birth, in PCOS mothers and their newborns. Hum Reprod. 2010; 25, 786–790.CrossRefGoogle ScholarPubMed
84. Vanky, E, Salvesen, KA, Heimstad, R, Fougner, KJ, Romundstad, P, Carlsen, SM. Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study. Hum Reprod. 2004; 19, 1734–1740.CrossRefGoogle ScholarPubMed