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Am J Physiol Endocrinol Metab (February 27, 2007). doi:10.1152/ajpendo.00668.2006
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Submitted on December 7, 2006
Accepted on February 21, 2007

Hypertension caused by prenatal testosterone excess in female sheep

Andrew J King1*, N Bari Olivier2, Puliyur S. MohanKumar3, James S Lee4, Vasantha Padmanabhan4, and Gregory D. Fink5

1 Pharmacology and Toxicology, Michigan State University, East Lansing , Michigan, United States
2 Small Animal Clinical Sciences, Michigan State University, East Lansing , Michigan, United States
3 Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan, United States
4 Department of Pediatrics, Unversity of Michigan, Ann Arbor,, Michigan, United States
5 Department of Pharmacology and Toxicolo, Michigan State University, East Lansing, Michigan, United States

* To whom correspondence should be addressed. E-mail: kingand{at}msu.edu.

Polycystic ovary syndrome (PCOS), a leading cause of infertility, affects ~10% of women of reproductive age. The etiology and pathophysiology of PCOS are poorly understood. PCOS is multi-facetted and includes reproductive abnormalities and components of the metabolic syndrome, such as insulin resistance, obesity, dyslipidemia and hypertension. Exposure to excess testosterone (T) during the prenatal period may predispose individuals to PCOS phenotype. The goal of this study was to determine if hypertension and dyslipidemia occur in a well-characterized model of PCOS produced by prenatal treatment of sheep with T. Radiotelemetry was used to measure blood pressure over a 24-hour period in conscious, undisturbed animals. To normalize circulating estradiol levels across treatment, control (n=4) and prenatal T-treated (100 mg T propionate IM twice weekly from days 30 to 90 of fetal life; n=4) 2-year-old females were ovariectomized, instrumented with a radiotelemetry transmitter and clamped with early follicular phase levels of estrogen using an implant. Six days later a 24-hour recording period commenced. Prenatal T-treated sheep were hypertensive compared to control sheep and heart rate tended to be higher. T-treated sheep had hyperglycemia, insulin resistance, hypernatremia, hyperchloremia and both total and LDL cholesterol tended to be higher. Plasma aldosterone and epinephrine were significantly lower in T-treated sheep, whereas norepinephrine was unchanged. This first-ever use of radiotelemetric blood pressure recordings in sheep demonstrates that mild hypertension, a risk factor reported in some women with PCOS, is also a feature of the sheep model of PCOS produced by prenatal T-treatment.




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