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Journal of Endocrinological Investigation

Published in:

01-05-2015 | Original Article

The impact of prenatal exposure to a single dose of testosterone on insulin resistance, glucose tolerance and lipid profile of female rat’s offspring in adulthood

Authors: M. Noroozzadeh, F. Ramezani Tehrani, K. Sedaghat, A. Godini, F. Azizi

Published in: Journal of Endocrinological Investigation | Issue 5/2015

Abstract

Purpose

In our previous study, we introduced a rat model of polycystic ovary syndrome (PCOS) induced by prenatal exposure to a single dose of testosterone on embryonic day 20. In the current study, we aimed to investigate whether prenatal exposure to a single dose of testosterone could also induce metabolic disturbances, especially insulin resistance in adulthood (100–110 days of age) and also to make it as an appropriate rat model of PCOS (exhibiting both reproductive and metabolic disturbances with minimum morphological disorders in reproductive system) for further studies in PCOS.

Methods

Pregnant rats in the experimental group were subcutaneously injected with 5 mg free testosterone on the gestational day 20, while controls received only the solvent. Female offspring of both groups, prenatally androgenized (PNA) rats (PCOS models of rats) and controls were examined.

Results

Body weight measures showed significant increase in the PNA rats compared to controls on days 30, 45, 60 of age and in adulthood (P < 0.05). PNA rats showed insulin resistance compared to controls. Impaired glucose tolerance was not observed in the PNA rats compared to controls. There were no significant differences in lipid profile between the PNA and control rats (P > 0.05).

Conclusion

Our study suggests that metabolic disturbances in PCOS and their severity during adult life probably depend on the particular time and levels of prenatal androgen exposure.

Setji TL, Brown AJ (2007) Polycystic ovary syndrome: diagnosis and treatment. Am J Med 120:128–132. doi:10.1016/j.amjmed.2006.06.029 CrossRefPubMed

Walters KA, Allan CM, Handelsman DJ (2012) Rodent models for human polycystic ovary syndrome. Biol Reprod 86(149):1–12. doi:10.1095/biolreprod.111.097808

Pasquali R, Stener-Victorin E, Yildiz BO, Duleba AJ, Hoeger K, Mason H, Homburg R, Hickey T, Franks S, Tapanainen JS, Balen A, Abbott DH, Diamanti-Kandarakis E, Legro RS (2011) PCOS forum: research in polycystic ovary syndrome today and tomorrow. Clin Endocrinol (Oxf) 74:424–433. doi:10.1111/j.1365-2265.2010.03956.x CrossRef

Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R (2011) Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol 7:219–231. doi:10.1038/nrendo.2010.217 CrossRefPubMed

Lobo RA, Carmina E (2000) The importance of diagnosing the polycystic ovary syndrome. Ann Intern Med 132:989–993. doi:10.7326/0003-4819-132-12-200006200-00010 CrossRefPubMed

Franks S (1995) Polycystic ovary syndrome. N Engl J Med 333:853–861. doi:10.1056/NEJM199509283331307 CrossRefPubMed

Xita N, Tsatsoulis A (2006) Review: fetal programming of polycystic ovary syndrome by androgen excess: evidence from experimental, clinical, and genetic association studies. J Clin Endocrinol Metab 91:1660–1666. doi:10.1210/jc.2005-2757 CrossRefPubMed

Foecking EM, McDevitt MA, Acosta-Martinez M, Horton TH, Levine JE (2008) Neuroendocrine consequences of androgen excess in female rodents. Horm Behav 53:673–692. doi:10.1016/j.yhbeh.2007.12.013 CrossRefPubMedCentralPubMed

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–E268. doi:10.1152/ajpendo.90208.2008 CrossRefPubMedCentralPubMed

10.

Abbott DH, Barnett DK, Bruns CM, Dumesic DA (2005) Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome? Hum Reprod Update 11:357–374. doi:10.1093/humupd/dmi013 CrossRefPubMed

11.

Manikkam M, Steckler TL, Welch KB, Inskeep EK, Padmanabhan V (2006) Fetal programming: prenatal testosterone treatment leads to follicular persistence/luteal defects; partial restoration of ovarian function by cyclic progesterone treatment. Endocrinology 147:1997–2007. doi:10.1210/en.2005-1338 CrossRefPubMed

12.

Birch RA, Padmanabhan V, Foster DL, Unsworth WP, Robinson JE (2003) Prenatal programming of reproductive neuroendocrine function: fetal androgen exposure produces progressive disruption of reproductive cycles in sheep. Endocrinology 144:1426–1434. doi:10.1210/en.2002-220965 CrossRefPubMed

13.

Abbott DH, Dumesic DA, Eisner JR, Colman RJ, Kemnitz JW (1998) Insights into the development of polycystic ovary syndrome (PCOS) from studies of prenatally androgenized female rhesus monkeys. Trends Endocrinol Metab 9:62–67CrossRefPubMed

14.

Recabarren SE, Padmanabhan V, Codner E, Lobos A, Duran 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–E806. doi:10.1152/ajpendo.00107.2005 CrossRefPubMed

15.

van Houten EL, Kramer P, McLuskey A, Karels B, Themmen AP, Visser JA (2012) Reproductive and metabolic phenotype of a mouse model of PCOS. Endocrinology 153:2861–2869. doi:10.1210/en.2011-1754 CrossRefPubMed

16.

Yan X, Dai X, Wang J, Zhao N, Cui Y, Liu J (2013) Prenatal androgen excess programs metabolic derangements in pubertal female rats. J Endocrinol 217:119–129. doi:10.1530/JOE-12-0577 CrossRefPubMed

17.

Ramezani Tehrani F, Noroozzadeh M, Zahediasl S, Piryaei A, Azizi F (2014) Introducing a rat model of prenatally androgen-induced polycystic ovary syndrome in adulthood. Exp Physiol. doi:10.1113/expphysiol.2014.078055

18.

Marcondes FK, Bianchi FJ, Tanno AP (2002) Determination of the estrous cycle phases of rats: some helpful considerations. Braz J Biol 62:609–614. doi:10.1590/S1519-69842002000400008 CrossRefPubMed

19.

Sloop KW, Willard FS, Brenner MB, Ficorilli J, Valasek K, Showalter AD, Farb TB, Cao JX, Cox AL, Michael MD, Gutierrez Sanfeliciano SM, Tebbe MJ, Coghlan MJ (2010) Novel small molecule glucagon-like peptide-1 receptor agonist stimulates insulin secretion in rodents and from human islets. Diabetes 59:3099–3107. doi:10.2337/db10-0689 CrossRefPubMedCentralPubMed

20.

Padmanabhan V, Veiga-Lopez A, Abbott DH, Recabarren SE, Herkimer C (2010) Developmental programming: impact of prenatal testosterone excess and postnatal weight gain on insulin sensitivity index and transfer of traits to offspring of overweight females. Endocrinology 151:595–605. doi:10.1210/en.2009-1015 CrossRefPubMedCentralPubMed

21.

DeUgarte CM, Bartolucci AA, Azziz R (2005) Prevalence of insulin resistance in the polycystic ovary syndrome using the homeostasis model assessment. Fertil Steril 83:1454–1460. doi:10.1016/j.fertnstert.2004.11.070 CrossRefPubMed

22.

Carmina E, Lobo RA (2004) Use of fasting blood to assess the prevalence of insulin resistance in women with polycystic ovary syndrome. Fertil Steril 82:661–665. doi:10.1016/j.fertnstert.2004.01.041 CrossRefPubMed

23.

Bremer AA (2010) Polycystic ovary syndrome in the pediatric population. Metab Syndr Relat Disord 8:375–394. doi:10.1089/met.2010.0039 CrossRefPubMedCentralPubMed

24.

Corbould A, Zhao H, Mirzoeva S, Aird F, Dunaif A (2006) Enhanced mitogenic signaling in skeletal muscle of women with polycystic ovary syndrome. Diabetes 55:751–759. doi:10.2337/diabetes.55.03.06.db05-0453 CrossRefPubMed

25.

Dunaif A, Wu X, Lee A, Diamanti-Kandarakis E (2001) Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). Am J Physiol Endocrinol Metab 281:E392–E399PubMed

26.

Dunaif A, Xia J, Book CB, Schenker E, Tang Z (1995) Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest 96:801–810. doi:10.1172/JCI118126 CrossRefPubMedCentralPubMed

27.

Nada SE, Thompson RC, Padmanabhan V (2010) Developmental programming: differential effects of prenatal testosterone excess on insulin target tissues. Endocrinology 151:5165–5173. doi:10.1210/en.2010-0666 CrossRefPubMedCentralPubMed

28.

Roland AV, Nunemaker CS, Keller SR, Moenter SM (2010) Prenatal androgen exposure programs metabolic dysfunction in female mice. J Endocrinol 207:213–223. doi:10.1677/JOE-10-0217 CrossRefPubMedCentralPubMed

29.

Amalfi S, Velez LM, Heber MF, Vighi S, Ferreira SR, Orozco AV, Pignataro O, Motta AB (2012) Prenatal hyperandrogenization induces metabolic and endocrine alterations which depend on the levels of testosterone exposure. Plos One 7:e37658. doi:10.1371/journal.pone.0037658 CrossRefPubMedCentralPubMed

30.

Sir-Petermann T, Codner E, Pérez V, Echiburú B, Maliqueo M, Ladron de Guevara A, Preisler J, Crisosto N, Sánchez F, Cassorla F (2009) Metabolic and reproductive features before and during puberty in daughters of women with polycystic ovary syndrome. J Clin Endocrinol Metab 94:1923–1930. doi:10.1210/jc.2008-2836 CrossRefPubMedCentralPubMed

31.

Bridger T, MacDonald S, Baltzer F, Rodd C (2006) Randomized placebo-controlled trial of metformin for adolescents with polycystic ovary syndrome. Arch Pediatr Adolesc Med 160:241–246. doi:10.1001/archpedi.160.3.241 CrossRefPubMed

32.

Arslanian SA, Lewy VD, Danadian K (2001) Glucose intolerance in obese adolescents with polycystic ovary syndrome: roles of insulin resistance and beta-cell dysfunction and risk of cardiovascular disease. J Clin Endocrinol Metab 86:66–71. doi:10.1210/jcem.86.1.7123 PubMed

33.

Shi D, Dyck MK, Uwiera RRE, Russell JC, Proctor SD, Vine DF (2009) A unique rodent model of cardiometabolic risk associated with the metabolic syndrome and polycystic ovary syndrome. Endocrinology 150:4425–4436. doi:10.1210/en.2008-1612 CrossRefPubMed

34.

Shi D, Vine DF (2012) Animal models of polycystic ovary syndrome: a focused review of rodent models in relationship to clinical phenotypes and cardiometabolic risk. Fertil Steril 98:185–193. doi:10.1016/j.fertnstert.2012.04.006 CrossRefPubMed

35.

Mannerås L, Cajander S, Holmäng A, Seleskovic Z, Lystig T, Lönn M, Stener-Victorin E (2007) A new rat model exhibiting both ovarian and metabolic characteristics of polycystic ovary syndrome. Endocrinology 148:3781–3791. doi:10.1210/en.2007-0168 CrossRefPubMed

36.

Wang ET, Calderon-Margalit R, Cedars MI, Daviglus ML, Merkin SS, Schreiner PJ, Sternfeld B, Wellons M, Schwartz SM, Lewis CE, Williams OD, Siscovick DS, Bibbins-Domingo K (2011) Polycystic ovary syndrome and risk for long-term diabetes and dyslipidemia. Obstet Gynecol 117:6–13. doi:10.1097/AOG.0b013e31820209bb CrossRefPubMedCentralPubMed

Title: The impact of prenatal exposure to a single dose of testosterone on insulin resistance, glucose tolerance and lipid profile of female rat’s offspring in adulthood
Authors: M. Noroozzadeh
F. Ramezani Tehrani
K. Sedaghat
A. Godini
F. Azizi
Publication date: 01-05-2015
Publisher: Springer International Publishing
Published in: Journal of Endocrinological Investigation / Issue 5/2015
Electronic ISSN: 1720-8386
DOI: https://doi.org/10.1007/s40618-014-0198-y

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