Pioglitazone improves insulin action and normalizes menstrual cycles in a majority of prenatally androgenized female rhesus monkeys

Zhou, Rao; Bruns, Cristin M.; Bird, Ian M.; Kemnitz, Joseph W.; Goodfriend, Theodore L.; Dumesic, Daniel A.; Abbott, David H.

doi:10.1016/j.reprotox.2006.12.009

Cited by 44 publications

(50 citation statements)

References 78 publications

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“…Pioglitazone treatment not only diminishes insulin resistance and reduces circulating insulin levels, but also normalizes menstrual cyclicity and diminishes ovarian hyperandrogenism in most prenatally androgenized female monkeys (27), similar to its effects in PCOS women (38,39).…”

Section: Insulin Is Associated With Adrenal Androgen Excess In Prenatmentioning

confidence: 86%

“…Such experimentally induced androgen excess generates PCOS-like phenotypes when prenatally androgenized females reach adulthood (22). Early gestation exposed prenatally androgenized female monkeys show irregular or absent ovulatory menstrual cycles, ovarian hyperandrogenism, enlarged polyfollicular ovaries and luteinizing hormone (LH) hypersecretion, in addition to insulin resistance, diminished insulin secretion, increased incidence of type 2 diabetes, visceral adiposity and hyperlipidemia (22,(24)(25)(26)(27). Female monkeys similarly exposed to androgen excess during late gestation also exhibit an adult PCOS-like phenotype, but without obvious abnormalities in LH and insulin secretion, or in insulin action (22).…”

Section: Prenatally Androgenized Female Rhesus Monkeys As Models Of Amentioning

confidence: 99%

“…For example, 24 hours after an intramuscular injection of 200 IU of recombinant human chorionic gonadotropin (rhCG), both early and late gestation exposed prenatally androgenized female monkey groups exhibit elevated circulating testosterone levels compared to controls (22). Early gestation exposed prenatally androgenized monkeys also show an elevated ovarian 17-hydroxyprogesterone response to rhCG (28) together with elevated basal testosterone levels (29,27). These females with more obvious signs of fetal programming of adult hyperandrogenism were thus studied to determine whether they had adrenal androgen excess comparable to that found in PCOS women.…”

Section: Prenatally Androgenized Female Rhesus Monkeys As Models Of Amentioning

confidence: 99%

“…Modified from (31). Associations between serum values of (a) 17-hydroxyprogesterone at 60 minutes following an intravenous injection of 50μg ACTH and basal insulin, (b) DHEAS at 60 minutes following an intravenous injection of 50μg ACTH and basal insulin, and (c) DHEAS and 17-hydroxyprogesterone at 0 minutes following an intravenous injection of 50μg ACTH in control (open triangle: receiving placebo treatment (27), solid triangle: receiving pioglitazone treatment; 27) and PA (open square: placebo, solid square: pioglitazone) female monkeys. Data are expressed as log 10 transformed serum values only in (a) and (c).…”

Section: Conclusion and Therapeutic Considerationsmentioning

confidence: 99%

“…Differences in mean±SEM circulating adrenal steroid values between 0 and 60 minutes following an intravenous injection of 50μg ACTH in the combined group of control and prenatally androgenized female rhesus monkeys receiving placebo or pioglitazone treatment (27). …”

mentioning

confidence: 99%

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Fetal Programming of Adrenal Androgen Excess: Lessons from a Nonhuman Primate Model of Polycystic Ovary Syndrome

Abbott¹,

Zhou²,

Bird

et al. 2008

Disorders of the Human Adrenal Cortex

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Adrenal androgen excess is found in adult female rhesus monkeys previously exposed to androgen treatment during early gestation. In adulthood, such prenatally androgenized female monkeys exhibit elevated basal circulating levels of DHEAS, typical of PCOS women with adrenal androgen excess. Further androgen and glucocorticoid abnormalities in PA female monkeys are revealed by acute ACTH stimulation: DHEA, androstenedione and corticosterone responses are all elevated compared to responses in controls. Pioglitazone treatment, however, diminishes circulating DHEAS responses to ACTH in both prenatally androgenized and control female monkeys, while increasing the 17-hydroxyprogesterone response and reducing the DHEA to 17-hydroxyprogesterone ratio. Since 60-min post-ACTH serum values for 17-hydroxyprogesterone correlate negatively with basal serum insulin levels (all female monkeys on pioglitazone and placebo treatment combined), while similar DHEAS values correlate positively with basal serum insulin levels, circulating insulin levels may preferentially support adrenal androgen biosynthesis in both prenatally androgenized and control female rhesus monkeys. Overall, our findings suggest that differentiation of the monkey adrenal cortex in a hyperandrogenic fetal environment may permanently upregulate adult adrenal androgen biosynthesis through specific elevation of 17,20-lyase activity in the zona fasciculata-reticularis. As adult prenatally androgenized female rhesus monkeys closely emulate PCOS-like symptoms, excess fetal androgen programming may contribute to adult adrenal androgen excess in women with PCOS.

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Section: Insulin Is Associated With Adrenal Androgen Excess In Prenatmentioning

confidence: 86%

Section: Prenatally Androgenized Female Rhesus Monkeys As Models Of Amentioning

confidence: 99%

Section: Prenatally Androgenized Female Rhesus Monkeys As Models Of Amentioning

confidence: 99%

Section: Conclusion and Therapeutic Considerationsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Fetal Programming of Adrenal Androgen Excess: Lessons from a Nonhuman Primate Model of Polycystic Ovary Syndrome

Abbott¹,

Zhou²,

Bird

et al. 2008

Disorders of the Human Adrenal Cortex

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Fetal, infant, adolescent and adult phenotypes of polycystic ovary syndrome in prenatally androgenized female rhesus monkeys

Abbott

Tarantal

Dumesic³

2009

American J Primatol

145

114

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Old World monkeys provide naturally-occurring and experimentally-induced phenotypes closely resembling the highly prevalent polycystic ovary syndrome (PCOS) in women. In particular, experimentally-induced fetal androgen excess in female rhesus monkeys produces a comprehensive adult PCOS-like phenotype that includes both reproductive and metabolic dysfunction found in PCOS women. Such a reliable experimental approach enables the use of the prenatally androgenized (PA) female rhesus monkey model to (1) examine fetal, infant and adolescent antecedents of adult pathophysiology, gaining valuable insight into early phenotypic expression of PCOS, and (2) to understand adult pathophysiology from a mechanistic perspective. Elevated circulating luteinizing hormone (LH) levels are the earliest indication of reproductive dysfunction in late gestation nonhuman primate fetuses and infants exposed to androgen excess during early (late first to second trimester) gestation. Such early gestation-exposed PA infants also are hyperandrogenic, with both LH hypersecretion and hyperandrogenism persisting in early gestation-exposed PA adults. Similarly, subtle metabolic abnormalities appearing in young nonhuman primate infants and adolescents precede the abdominal adiposity, hyperliplidemia, and increased incidence of type 2 diabetes that characterize early gestated-exposed PA adults.These new insights into the developmental origins of PCOS, and progression of the pathophysiology from infancy to adulthood, provide opportunities for clinical intervention to ameliorate the PCOS phenotype thus providing a preventive health care approach to PCOS-related abnormalities. For example, PCOS-like traits in PA monkeys, as in PCOS women, can improve with better insulin-glucose homeostasis, suggesting that lifestyle interventions preventing increased adiposity in adolescent daughters of PCOS mothers also may reduce their risk of acquiring many PCOS-related metabolic abnormalities in adulthood.

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Uterine Origins and Evolution in Childhood

Tsatsoulis

Xita²

2009

Diagnosis and Management of Polycystic Ovary Syndrome

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Pioglitazone improves insulin action and normalizes menstrual cycles in a majority of prenatally androgenized female rhesus monkeys

Cited by 44 publications

References 78 publications

Fetal Programming of Adrenal Androgen Excess: Lessons from a Nonhuman Primate Model of Polycystic Ovary Syndrome

Fetal Programming of Adrenal Androgen Excess: Lessons from a Nonhuman Primate Model of Polycystic Ovary Syndrome

Fetal, infant, adolescent and adult phenotypes of polycystic ovary syndrome in prenatally androgenized female rhesus monkeys

Uterine Origins and Evolution in Childhood

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