Developmental Programming: Impact of Prenatal Testosterone Excess on Insulin Sensitivity, Adiposity, and Free Fatty Acid Profile in Postpubertal Female Sheep

Veiga-López, Almudena; Moeller, Jacob; Patel, Disha; Ye, W.; Pease, Anthony P.; Kinns, Jennifer; Padmanabhan, Vasantha

doi:10.1210/en.2012-2145

Cited by 61 publications

(32 citation statements)

References 74 publications

(108 reference statements)

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“…Importantly, the window of susceptibility for developing insulin resistance was found to be confined to a shorter programming window, namely 60–90 days of gestation [41]. Interestingly, at postpubertal time points (~16 mo of age), insulin sensitivity is increased, visceral adiposity and adipocyte size are reduced, and circulating palmitic acid is increased in prenatal T females [112]. Relative to earlier observations of reduced insulin sensitivity during early life and adulthood, these findings of increased insulin sensitivity and reduced adiposity postpubertally are suggestive of a period of developmental adaptation.…”

Section: Metabolic Dysfunctionsmentioning

confidence: 99%

Steroidogenic versus Metabolic Programming of Reproductive Neuroendocrine, Ovarian and Metabolic Dysfunctions

2015

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The susceptibility of the reproductive system to early exposure to steroid hormones has become a major concern in our modern societies. Human fetuses are at risk of abnormal programming via exposure to endocrine disrupting chemicals, inadvertent use of contraceptive pills during pregnancy, as well as from excess exposure to steroids due to disease states. Animal models provide an unparalleled resource to understand the developmental origin of diseases. In female sheep, prenatal exposure to testosterone excess results in an array of adult reproductive disorders that recapitulate those seen in women with polycystic ovary syndrome (PCOS), including disrupted neuroendocrine feedback mechanisms, increased pituitary sensitivity to gonadotropin-releasing hormone, luteinizing hormone excess, functional hyperandrogenism, and multifollicular ovarian morphology culminating in early reproductive failure. Prenatal testosterone treatment also leads to fetal growth retardation, insulin resistance, and hypertension. Mounting evidence suggests that developmental exposure to an improper steroidal/metabolic environment may mediate the programming of adult disorders in prenatal testosterone-treated females, and these defects are maintained or amplified by the postnatal sex steroid and metabolic milieu. This review addresses the steroidal and metabolic contributions to the development and maintenance of the PCOS phenotype in the prenatal testosterone-treated sheep model, including the effects of prenatal and postnatal treatment with an androgen antagonist or insulin sensitizer as potential strategies to prevent/ameliorate these dysfunctions. Insights obtained from these intervention strategies on the mechanisms underlying these defects are likely to have translational relevance to human PCOS.

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Section: Metabolic Dysfunctionsmentioning

confidence: 99%

Steroidogenic versus Metabolic Programming of Reproductive Neuroendocrine, Ovarian and Metabolic Dysfunctions

2015

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“…Interestingly, the impact of postnatal T-treatment on fat deposition in rats appears to be a function of the strain used with some showing an effect and others not [68, 71]. Visceral adiposity does not appear to be a feature of prenatal T-treated sheep during their postpubertal life [72]; in contrast these females manifest reduced visceral adiposity similar to that of lean women with PCOS [73]. An imbalance in the plasma lipid profile is evident in prenatal and postnatal T-treated rat models reflected as an increase in triglycerides and cholesterol [68, 70].…”

Section: Adult Metabolic Phenotype Of Pcos Modelsmentioning

confidence: 99%

“…An imbalance in the plasma lipid profile is evident in prenatal and postnatal T-treated rat models reflected as an increase in triglycerides and cholesterol [68, 70]. An imbalance in free fatty acid is also found in monkeys [74] and sheep [72]. No metabolic disruptions have been reported in the letrozole-treated rat model [30].…”

Section: Adult Metabolic Phenotype Of Pcos Modelsmentioning

confidence: 99%

Animal models of the polycystic ovary syndrome phenotype

2013

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The etiology of the polycystic ovary syndrome (PCOS) remains unclear, despite its high prevalence among infertility disorders in women of reproductive age. Although there is evidence for a genetic component of the disorder, other causes, such as prenatal insults are considered among the potential factors that may contribute to the development of the syndrome. Over the past few decades, several animal models have been developed in an attempt to understand the potential contribution of exposure to excess steroids on the development of this syndrome. The current review summarizes the phenotypes of current animal models exposed to excess steroid during the prenatal and early postnatal period and how they compare with the phenotype seen in women with PCOS.

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“…Increased maternal T produces at least two major potential effects: direct actions of T on the fetus and indirect actions on the maternal-fetal unit, which result in intrauterine growth retardation and chronic conditions in adult life, such as hypertension, dyslipidemia, and diabetes mellitus. 1-6 Numerous studies have demonstrated that T directly causes fetal damage. 7-11 On the other hand, the adverse effects of T on fetal growth could be from indirect action of T on the maternal-fetal unit and the uteroplacental circulation.…”

Section: Introductionmentioning

confidence: 99%

Elevated Testosterone Levels During Rat Pregnancy Cause Hypersensitivity to Angiotensin II and Attenuation of Endothelium-Dependent Vasodilation in Uterine Arteries

et al. 2014

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Elevated testosterone levels increase maternal blood pressure and decrease uterine blood flow in pregnancy, resulting in abnormal perinatal outcomes. We tested whether elevated testosterone alters uterine artery adaptations during pregnancy, and if these alterations depend upon endothelium-derived factors such as nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and prostacyclin, or endothelium-independent mechanisms such as angiotensin II. Pregnant Sprague-Dawley rats were injected with vehicle (n=20) or testosterone propionate (0.5mg/Kg/day from gestation-day 15-19;n=20). Plasma testosterone levels increased 2-fold in testosterone-injected rats compared to controls. Elevated testosterone significantly decreased placental and pup weights compared to controls. In endothelium-intact uterine arteries, contractile responses to thromboxane, phenylephrine and angiotensin II were greater in testosterone-treated rats compared to controls. In endothelium-denuded arteries, contractile responses to angiotensin II (pD2=9.1±0.04 vs. 8.7±0.04 in controls,p<0.05) but not thromboxane and phenylephrine were greater in testosterone-treated rats. Angiotensin II type-1b receptor expression was increased while angiotensin II type-2 receptor was decreased in testosterone-exposed arteries. In endothelium-denuded arteries, relaxations to sodium nitroprusside were unaffected. Endothelium-dependent relaxation to acetylcholine was significantly lower in arteries from testosterone-treated dams (Emax=51.80%±6.9% vs. 91.98%±1.4% in controls,p<0.05). Assessment of endothelial factors showed NO-, EDHF- and prostacyclin-mediated relaxations were blunted in testosterone-treated dams. Endothelial NO-synthase, small conductance calcium-activated potassium channel-3 and prostacyclin receptor expressions were significantly decreased in arteries from testosterone-treated dams. Hypoxia-inducible factor-1α, Ankrd37 and Egln were significantly increased in testosterone-exposed placentae. These results suggest that elevated maternal testosterone impairs uterine vascular function, which may lead to an increased vascular resistance and a decrease in uterine blood flow.

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Developmental Programming: Impact of Prenatal Testosterone Excess on Insulin Sensitivity, Adiposity, and Free Fatty Acid Profile in Postpubertal Female Sheep

Cited by 61 publications

References 74 publications

Steroidogenic versus Metabolic Programming of Reproductive Neuroendocrine, Ovarian and Metabolic Dysfunctions

Steroidogenic versus Metabolic Programming of Reproductive Neuroendocrine, Ovarian and Metabolic Dysfunctions

Animal models of the polycystic ovary syndrome phenotype

Elevated Testosterone Levels During Rat Pregnancy Cause Hypersensitivity to Angiotensin II and Attenuation of Endothelium-Dependent Vasodilation in Uterine Arteries

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