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Cited by 184Ovarian function and disordersBirth, Development, and HealthSexual Differentiation and Disorders

Prenatal androgen exposure programs metabolic dysfunction in female mice

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Roland, Alison V, Nunemaker, Craig S, Keller, Susanna R, Moenter, Suzanne M·2010·Journal of Endocrinology
DOI 10.1677/joe-10-0217PMC PMC3612271
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Abstract

Polycystic ovary syndrome (PCOS) is a common fertility disorder with metabolic sequelae. Our laboratory previously characterized reproductive phenotypes in a prenatally androgenized (PNA) mouse model for PCOS. PNA mice exhibited elevated testosterone and LH levels, irregular estrous cycles, and neuroendocrine abnormalities suggesting increased central drive to the reproductive system. In this study, we examined metabolic characteristics of female PNA mice. PNA mice exhibited increased fasting glucose and impaired glucose tolerance (IGT) that were independent of age and were not associated with changes in body composition or peripheral insulin sensitivity. IGT was associated with defects in pancreatic islet function leading to an impaired response to high glucose, consistent with impaired insulin secretion. Exposure of isolated pancreatic islets to androgen in vitro demonstrated an impaired response to glucose stimulation similar to that in PNA mice, suggesting androgens may have activational in addition to organizational effects on pancreatic islet function. PNA mice also exhibited increased size of visceral adipocytes, suggesting androgen-programed differences in adipocyte differentiation and/or function. These studies demonstrate that in addition to causing reproductive axis abnormalities, in utero androgen exposure can induce long-term metabolic alterations in female mice.

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  • Prenatal androgen treatment induces HPG changes as well as metabolic alterations including insulin resistance, obesity, and enlarged adipocytes in female rhesus monkeys and mice.

    “Prenatal androgen treatment induces HPG changes as well as metabolic alterations including insulin resistance, obesity, and enlarged adipocytes in female rhesus monkeys and mice (Abbott et al., 2009; Roland et al., 2010).”

    From Endometriosis and polycystic ovary syndrome are diametric disorders (2021) · cites this paper as Roland et al., 2010

    The Abstract and Discussion report reproductive-axis abnormalities, metabolic changes, and enlarged visceral adipocytes in prenatally androgenized female mice. But the Discussion explicitly says these mice did not develop increased adiposity or peripheral insulin resistance. This verdict concerns Roland et al.’s mouse findings, not the separately cited rhesus-monkey work. (LLM, conf=0.91)

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Research works printed but not linked: 57

  1. Amiel SA Sherwin RS Simonson DC Lauritano AA Tamborlane WV 1986 Impaired insulin action in puberty. A contributing factor to poor glycemic control in adolescents with diabetes N Engl J Med 315 215 219 3523245
  2. Arnold AP Breedlove SM 1985 Organizational and activational effects of sex steroids on brain and behavior: a reanalysis Horm Behav 19 469 498 3910535
  3. Blouin K Veilleux A Luu-The V Tchernof A 2009 Androgen metabolism in adipose tissue: recent advances Mol Cell Endocrinol 301 97 103 19022338
  4. Bock G Chittilapilly E Basu R Toffolo G Cobelli C Chandramouli V Landau BR Rizza R 2007 Contribution of hepatic and extrahepatic insulin resistance to the pathogenesis of impaired fasting glucose: role of increased rates of gluconeogenesis Diabetes 56 1703 1711 17384334
  5. Brill DS Moenter SM 2009 Androgen Receptor Antagonism and an Insulin Sensitizer Block the Advancement of Vaginal Opening by High-Fat Diet in Mice Biol Reprod In press PMC2802232 19605781
  6. Brissova M Powers A 2008 Chapter 1. Architecture of Pancreatic Islets Pancreatic Beta Cell in Health and Disease 3 11
  7. Bruns CM Baum ST Colman RJ Eisner JR Kemnitz JW Weindruch R Abbott DH 2004 Insulin resistance and impaired insulin secretion in prenatally androgenized male rhesus monkeys J Clin Endocrinol Metab 89 6218 6223 15579780
  8. Cacho J Sevillano J de Castro J Herrera E Ramos MP 2008 Validation of simple indexes to assess insulin sensitivity during pregnancy in Wistar and Sprague-Dawley rats Am J Physiol Endocrinol Metab 295 E2169 2176 18796548
  9. Carlsen SM Jacobsen G Romundstad P 2006 Maternal testosterone levels during pregnancy are associated with offspring size at birth Eur J Endocrinol 155 365 370 16868152
  10. Carter JD Dula SB Corbin KL Wu R Nunemaker CS 2009 A Practical Guide to Rodent Islet Isolation and Assessment Biol Proced Online in press PMC3056052 19957062
  11. Chen J Ahn K Gee N Ahmed M Duleba A Zhao L Gee S Hammock B Lasley B 2008 Triclocarban enhances testosterone action: a new type of endocrine disruptor? Endocrinology 149 1173 1179 18048496 PMC2275366
  12. Deering TG Ogihara T Trace AP Maier B Mirmira RG 2009 Methyltransferase Set7/9 maintains transcription and euchromatin structure at islet-enriched genes Diabetes 58 185 193 18984737 PMC2606870
  13. Demissie M Lazic M Foecking EM Aird F Dunaif A Levine JE 2008 Transient prenatal androgen exposure produces metabolic syndrome in adult female rats Am J Physiol Endocrinol Metab 295 E262 268 18544644 PMC2519755
  14. Díaz-Sánchez V Morimoto S Morales A Robles-Díaz G Cerbón M 1995 Androgen receptor in the rat pancreas: genetic expression and steroid regulation Pancreas 11 241 245 8577677
  15. Dumesic DA Abbott DH Padmanabhan V 2007 Polycystic ovary syndrome and its developmental origins Rev Endocr Metab Disord 8 127 141 17659447 PMC2935197
  16. Dunaif A 1997 Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis Endocrine Reviews 18 774 800 9408743
  17. Dunaif A Finegood DT 1996 Beta-cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome Journal of Clinical Endocrinology & Metabolism 81 942 947 8772555
  18. Evans-Molina C Robbins RD Kono T Tersey SA Vestermark GL Nunemaker CS Garmey JC Deering TG Keller SR Maier B Mirmira RG 2009 Peroxisome proliferator-activated receptor gamma activation restores islet function in diabetic mice through reduction of endoplasmic reticulum stress and maintenance of euchromatin structure Mol Cell Biol 29 2053 2067 19237535 PMC2663298
  19. Gore AC Roberts JL Gibson MJ 1999 Mechanisms for the regulation of gonadotropin-releasing hormone gene expression in the developing mouse Endocrinology 140 2280 2287 10218981
  20. Gray LE Wilson VS Stoker T Lambright C Furr J Noriega N Howdeshell K Ankley GT Guillette L 2006 Adverse effects of environmental antiandrogens and androgens on reproductive development in mammals Int J Androl 29 96 104 16466529
  21. Guest PC Rhodes CJ Hutton JC 1989 Regulation of the biosynthesis of insulin-secretory-granule proteins. Co-ordinate translational control is exerted on some, but not all, granule matrix constituents Biochem J 257 431 437 2649074 PMC1135598
  22. Henquin JC Nenquin M Stiernet P Ahren B 2006 In vivo and in vitro glucose-induced biphasic insulin secretion in the mouse: pattern and role of cytoplasmic Ca2+ and amplification signals in beta-cells Diabetes 55 441 451 16443779
  23. Hotchkiss AK Furr J Makynen EA Ankley GT Gray LE 2007 In utero exposure to the environmental androgen trenbolone masculinizes female Sprague-Dawley rats Toxicol Lett 174 31 41 17931805
  24. Jackson LM Timmer KM Foster DL 2008 Sexual differentiation of the external genitalia and the timing of puberty in the presence of an antiandrogen in sheep Endocrinology 149 4200 4208 18450972 PMC2488226
  25. Jackson LM Timmer KM Foster DL 2009 Organizational actions of postnatal estradiol in female sheep treated prenatally with testosterone: programming of prepubertal neuroendocrine function and the onset of puberty Endocrinology 150 2317 2324 19131574 PMC2671902
  26. Jahanshahi P Wu R Carter JD Nunemaker CS 2009 Evidence of diminished glucose stimulation and endoplasmic reticulum function in nonoscillatory pancreatic islets Endocrinology 150 607 615 18818288 PMC2646533
  27. Kahn SE 2001 Clinical review 135: The importance of beta-cell failure in the development and progression of type 2 diabetes J Clin Endocrinol Metab 86 4047 4058 11549624
  28. Kahn SE Hull RL Utzschneider KM 2006 Mechanisms linking obesity to insulin resistance and type 2 diabetes Nature 444 840 846 17167471
  29. Legro RS Driscoll D Strauss JF 3rd Fox J Dunaif A 1998 Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome Proceedings of the National Academy of Sciences of the United States of America 95 14956 14960 9843997 PMC24557
  30. Li RJ Qiu SD Wang HX Tian H Wang LR Huo YW 2008 Androgen receptor: a new player associated with apoptosis and proliferation of pancreatic beta-cell in type 1 diabetes mellitus Apoptosis 13 959 971 18543106
  31. Liu SCH Wang Q Lienhard GE Keller SR 1999 Insulin receptor substrate 3 is not essential for growth or glucose homeostasis J Biol Chem 275 18093 18099 10364263
  32. Lundgren M Svensson M Lindmark S Rensrom F Ruge T Eriksson JW 2007 Fat cell enlargement is an independent marker of insulin resistance and ‘hyperleptinaemia’ Diabetologia 50 625 633 17216279
  33. MacLusky NJ Naftolin F 1981 Sexual differentiation of the central nervous system Science 211 1294 1302 6163211
  34. Mather K 2009 Surrogate measures of insulin resistance: of rats, mice, and men Am J Physiol Endocrinol Metab 296 E398 399 19171846
  35. McAbee MD Doncarlos LL 1999 Estrogen, but not androgens, regulates androgen receptor messenger ribonucleic acid expression in the developing male rat forebrain Endocrinology 140 3674 3681 10433226
  36. McCartney CR Prendergast KA Chhabra S Eagleson CA Yoo R Chang RJ Foster CM Marshall JC 2006 The association of obesity and hyperandrogenemia during the pubertal transition in girls: obesity as a potential factor in the genesis of postpubertal hyperandrogenism J Clin Endocrinol Metab 91 1714 1722 16492701
  37. McCormick CM Furey BF Child M Sawyer MJ Donohue SM 1998 Neonatal sex hormones have ‘organizational’ effects on the hypothalamic-pituitary-adrenal axis of male rats Brain Res Dev Brain Res 105 295 307 9541747
  38. Miyawaki J Sakayama K Kato H Yamamoto H Masuno H 2007 Perinatal and postnatal exposure to bisphenol a increases adipose tissue mass and serum cholesterol level in mice J Atheroscler Thromb 14 245 252 17938543
  39. Morimoto S Fernandez-Mejia C Romero-Navarro G Morales-Peza N Díaz-Sánchez V 2001 Testosterone effect on insulin content, messenger ribonucleic acid levels, promoter activity, and secretion in the rat Endocrinology 142 1442 1447 11250923
  40. Moschos S Chan JL Mantzoros CS 2002 Leptin and reproduction: a review Fertil Steril 77 433 444 11872190
  41. Newbold RR Padilla-Banks E Jefferson WN 2009 Environmental estrogens and obesity Mol Cell Endocrinol 304 84 89 19433252 PMC2682588
  42. Ogishima T Mitani F Suematsu M 2008 Cytochrome P-450(17alpha) in beta-cells of rat pancreas and its local steroidogenesis J Steroid Biochem Mol Biol 111 80 86 18556192
  43. Quigley CA 2002 Editorial: The postnatal gonadotropin and sex steroid surge-insights from the androgen insensitivity syndrome J Clin Endocrinol Metab 87 24 28 11788615
  44. Recabarren SE Padmanabhan V Codner E Lobos A Durán C Vidal M Foster DL Sir-Petermann T 2005 Postnatal developmental consequences of altered insulin sensitivity in female sheep treated prenatally with testosterone Am J Physiol Endocrinol Metab 289 E801 806 16215166
  45. Sam S Dunaif A 2003 Polycystic ovary syndrome: syndrome XX? Trends Endocrinol Metab 14 365 370 14516934
  46. Scherer PE Trujillo ME 2006 Adipose Tissue-Derived Factors: Impact on Health and Disease Endocr Rev 27 762 778 17056740
  47. Shao RLK Weijdegård B Egecioglu E Fernandez-Rodriguez J Zhang FP Thurin-Kjellberg A Bergh C Billig H 2007 Estrogen-induced upregulation of AR expression and enhancement of AR nuclear translocation in mouse fallopian tubes in vivo Am J Physiol Endocrinol Metab 292 E604 614 17047162
  48. Singh R Artaza J Taylor W Gonzalez-Cadavid N Bhasin S 2003 Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1/2 pluripotent cells through an androgen receptor-mediated pathway Endocrinology 144 5081 5088 12960001
  49. Sir-Petermann T Maliqueo M Angel B Lara HE Perez-Bravo F Recabarren SE 2002 Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenization Human Reproduction 17 2573 2579 12351531
  50. Skurk T Alberti-Huber C Herder C Hauner H 2007 Relationship between adipocyte size and adipokine expression and secretion J Clin Endocrinol Metab 92 1023 1033 17164304
  51. Steckler T Wang J Bartol FF Roy SK Padmanabhan V 2005 Fetal programming: prenatal testosterone treatment causes intrauterine growth retardation, reduces ovarian reserve and increases ovarian follicular recruitment Endocrinology 146 3185 3193 15802500
  52. Sullivan SD Moenter SM 2004 Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: implications for a common fertility disorder Proc Natl Acad Sci U S A 101 7129 7134 15096602 PMC406477
  53. Tapanainen J Kellokumpu-Lehtinen P Pelliniemi L Huhtaniemi I 1981 Age-related changes in endogenous steroids of human fetal testis during early and midpregnancy J Clin Endocrinol Metab 52 98 102 6450220
  54. Wickham EPr Cheang KI Clore JN Baillargeon JP Nestler JE 2010 Total and high-molecular weight adiponectin in women with polycystic ovary syndrome Metabolism in press PMC2946975 20359725
  55. Winborn WB Sheridan PJ McGill HCJ 1987 Sex steroid receptors in the stomach, liver, pancreas, and gastrointestinal tract of the baboon Gastroenterology 92 23 3781192
  56. Wood RI Ebling FJ I’Anson H Bucholtz DC Yellon SM Foster DL 1991 Prenatal androgens time neuroendocrine sexual maturation Endocrinology 128 2457 2468 2019261
  57. Yeh S Tsai MY Xu Q Mu XM Lardy H Huang KE Lin H Yeh SD Altuwaijri S Zhou X Xing L Boyce BF Hung MC Zhang S Gan L Chang C 2002 Generation and characterization of androgen receptor knockout (ARKO) mice: an in vivo model for the study of androgen functions in selective tissues Proc Natl Acad Sci U S A 99 13498 13503 12370412 PMC129702

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Authors
Roland, A. V., Nunemaker, C. S., Keller, S. R., & Moenter, S. M.
Affiliations
University of Virginia (US)
Corresponding author
Moenter, Suzanne M
ORCID
Venue
Journal of Endocrinology
Publisher
Bioscientifica
Published
2010-08-16
Volume
207
Issue
2
Pages
213-223
ISSN
  • 0022-0795 (ISSN-L)
  • 1479-6805
DOI
10.1677/joe-10-0217
PMC
PMC3612271
OpenAlex
W2157390106
Cited by
184
References
5
Citations by year
2026: 10 · 2025: 6 · 2024: 13 · 2023: 12 · 2022: 10 · 2021: 13 · 2020: 20 · 2019: 17 · 2018: 10 · 2017: 11 · 2016: 7 · 2015: 14 · 2014: 12 · 2013: 10 · 2012: 11
FWCI
11.05
Type
journal article
Language
en
Open access
Locations
  • Journal of Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5p30dk063609-05, U54-HD28-934, HD28934)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK-063609, P30-DK-063609)
  • National Institute of Neurological Disorders and Stroke (F31NS062646)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD028934, U54-HD-28934)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
Keywords
prenatal androgen exposure, polycystic ovary syndrome, metabolic dysfunction, impaired glucose tolerance, islet function, insulin secretion, visceral adipocytes, adipogenesis, insulin sensitivity
MeSH terms
Aging, Androgens, Animals, Body Composition, Calcium, Female, Insulin, Islets of Langerhans, Polycystic Ovary Syndrome, Pregnancy, Prenatal Exposure Delayed Effects, Dihydrotestosterone, Adipocytes, Glucose Intolerance, Mice

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