Developmental Programming: Impact of Excess Prenatal Testosterone on Intrauterine Fetal Endocrine Milieu and Growth in Sheep1

Veiga-López, Almudena; Steckler, Teresa L.; Abbott, David H.; Welch, Kathleen B.; MohanKumar, P.S.; Phillips, David J.; Refsal, Kent R.; Padmanabhan, Vasantha

doi:10.1095/biolreprod.110.086686

Cited by 107 publications

(107 citation statements)

References 77 publications

(112 reference statements)

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“…Administration of testosterone during pregnancy in rats or sheep does not affect the food intake or weight gain of the dam or the maternal levels of insulin, estrogen, progesterone, glucose, or lipids (36,47). These findings indicate that the effects of prenatal androgenization on the placenta, fetus, and female offspring are not caused by changes in maternal metabolism.…”

mentioning

confidence: 80%

“…Testosterone is a lipophilic hormone and can diffuse from the amniotic fluid into the fetal circulation and across the placenta (16,28,44). However, previous studies have reported that a significant increase in maternal testosterone level in rats is not associated with a significant increase in testosterone in the fetus (35,50), whereas in both sheep and monkeys it has been shown that elevated maternal testosterone levels also elevate fetal testosterone levels in female offspring (2,47). Also, a recent preliminary report indicates altered enzymatic regulation in PCOS placentas, as demonstrated by higher 3␤-HSD1 placental expression and lower P450 aromatase activities compared with controls (11).…”

Section: Effect Of Prenatal Testosterone Exposure On the Placenta Andmentioning

confidence: 99%

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Maternal androgen excess reduces placental and fetal weights, increases placental steroidogenesis, and leads to long-term health effects in their female offspring

Sun

Maliqueo

Benrick

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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-Victorin E. Maternal androgen excess reduces placental and fetal weights, increases placental steroidogenesis, and leads to long-term health effects in their female offspring. Am J Physiol Endocrinol Metab 303: E1373-E1385, 2012. First published October 9, 2012 doi:10.1152/ajpendo.00421.2012.-Here, we tested the hypothesis that excess maternal androgen in late pregnancy reduces placental and fetal growth, increases placental steroidogenesis, and adversely affects glucose and lipid metabolism in adult female offspring. Pregnant Wistar rats were randomly assigned to treatment with testosterone (daily injections of 5 mg of free testosterone from gestational days 16 to 19) or vehicle alone. In experiment 1, fetal and placental weights, circulating maternal testosterone, estradiol, and corticosterone levels, and placental protein expression and distribution of estrogen receptor-␣ and -␤, androgen receptor, and 17␤-hydroxysteroid dehydrogenase 2 were determined. In experiment 2, birth weights, postnatal growth rates, circulating testosterone, estradiol, and corticosterone levels, insulin sensitivity, adipocyte size, lipid profiles, and the presence of nonalcoholic fatty liver were assessed in female adult offspring. Treatment with testosterone reduced placental and fetal weights and increased placental expression of all four proteins. The offspring of testosterone-treated dams were born with intrauterine growth restriction; however, at 6 wk of age there was no difference in body weight between the offspring of testosterone-and control-treated rats. At 10 -11 wk of age, the offspring of the testosterone-treated dams had less fat mass and smaller adipocyte size than those born to control rats and had no difference in insulin sensitivity. Circulating triglyceride levels were higher in the offspring of testosterone-treated dams, and they developed nonalcoholic fatty liver as adults. We demonstrate for the first time that prenatal testosterone exposure alters placental steroidogenesis and leads to dysregulation of lipid metabolism in their adult female offspring. testosterone; prenatal; maternal; placenta; polycystic ovary syndrome; insulin sensitivity; steroidogenesis; estrogen receptor; androgen receptor THE MATERNAL ENVIRONMENT may influence epigenetic processes during placental and fetal development that have long-lasting effects and lead to diseases such as hypertension, obesity, type 2 diabetes, and endocrine and reproductive dysfunction in adult offspring (6,24). Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and is associated with hyperandrogenism, oligo/anovulation (infertility), and polycystic ovaries (5, 26). PCOS is also associated with metabolic disturbances such as hyperinsulinemia and type 2 diabetes and dysfunctional lipid profile, symptoms that are aggravated by obesity (5). Women with PCOS are at a higher risk of delivering prematurely, developing gestational diabetes and preeclampsia (33), and having both small-for-gestational-age (40) and large-for-...

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confidence: 80%

Section: Effect Of Prenatal Testosterone Exposure On the Placenta Andmentioning

confidence: 99%

Maternal androgen excess reduces placental and fetal weights, increases placental steroidogenesis, and leads to long-term health effects in their female offspring

Sun

Maliqueo

Benrick

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…In support of this premise, placentas from PCOS mothers were found to have lower aromatase and higher 3b-HSD1 activities, which could lead to increased androgen levels during pregnancy (Maliqueo et al 2013). The studies of Veiga-Lopez et al (2011) in sheep have found male and female sheep fetuses whose mothers were administered testosterone to have elevated plasma testosterone levels compared with their control counterparts.…”

Section: Effect Of Prenatal Testosterone Excess On Gonadal Testosteromentioning

confidence: 93%

Pituitary and testis responsiveness of young male sheep exposed to testosterone excess during fetal development

Recabarren¹,

Rojas-García²,

Einspanier³

et al. 2013

Reproduction

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Prenatal exposure to excess testosterone induces reproductive disturbances in both female and male sheep. In females, it alters the hypothalamus-pituitary-ovarian axis. In males, prenatal testosterone excess reduces sperm count and motility. Focusing on males, this study tested whether pituitary LH responsiveness to GNRH is increased in prenatal testosterone-exposed males and whether testicular function is compromised in the testosterone-exposed males. Control males (nZ6) and males born to ewes exposed to twice weekly injections of 30 mg testosterone propionate from days 30 to 90 and of 40 mg testosterone propionate from days 90 to 120 of gestation (nZ6) were studied at 20 and 30 weeks of age. Pituitary and testicular responsiveness was tested by administering a GNRH analog (leuprolide acetate). To complement the analyses, the mRNA expression of LH receptor (LHR) and that of steroidogenic enzymes were determined in testicular tissue. Basal LH and testosterone concentrations were higher in the testosterone-exposed-males. While LH response to the GNRH analog was higher in the testosterone-exposed males than in the control males, testosterone responses did not differ between the treatment groups. The testosterone:LH ratio was higher in the control males than in the testosterone-exposed males of 30 weeks of age, suggestive of reduced Leydig cell sensitivity to LH in the testosterone-exposed males. The expression of LHR mRNA was lower in the testosterone-exposed males, but the mRNA expression of steroidogenic enzymes did not differ between the groups. These findings indicate that prenatal testosterone excess has opposing effects at the pituitary and testicular levels, namely increased pituitary sensitivity to GNRH at the level of pituitary and decreased sensitivity of the testes to LH.

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“…3,27 In sheep, abnormalities of the reproductive, metabolic, and growth axes can be induced by exposure to abnormal steroid concentrations or environmental endocrine disrupters during vulnerable stages of in utero development. 11,18,19,21,23,34 Prenatal exposure to excess androgens between days 30 and 90 of gestation has a virilizing effect on the external genitalia of female lambs, and affected animals have a penis and a scrotal sac without testes. 4,14 The ovaries are in the correct anatomical position but have gross abnormalities soon after birth.…”

Section: 26mentioning

confidence: 99%

Masculinization of the Distal Tubular and External Genitalia in Female Sheep With Prenatal Androgen Exposure

et al. 2011

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Prenatal exposure to endogenous or exogenous androgens alters the development of the female reproductive tract. Although lesions in ovaries and external genitalia of androgenized female sheep have been reported, lesions of the tubular genitalia have not. Testosterone propionate (TP) or dihydrotestosterone (DHT) was administered by intramuscular injection twice weekly to 32 ewes from 30 to 90 days of pregnancy. The ewes lambed normally. The reproductive tracts from 24 treated and 13 control postpubertal female offspring were examined at 10 months of age. The ovaries, oviducts, and uteri were grossly and histologically normal in both TP-and DHT-exposed sheep. However, in the DHT-treated sheep, the uterus connected to a misshapen, saccular vagina that opened into the urethra; in the TP-treated sheep, it ended in a blind sac. In both TP-and DHT-treated sheep, the urethra was approximately 5 times longer than that of control sheep, and it resembled a male urethra with bilateral male accessory genital glands. The urethra terminated in a fully developed penis in both TP-and DHT-treated sheep, and a scrotal sac was present (without testes). These results show that prenatal exposure of female sheep to exogenous androgens results in masculinization of the tubular and external genitalia.

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Developmental Programming: Impact of Excess Prenatal Testosterone on Intrauterine Fetal Endocrine Milieu and Growth in Sheep1

Cited by 107 publications

References 77 publications

Maternal androgen excess reduces placental and fetal weights, increases placental steroidogenesis, and leads to long-term health effects in their female offspring

Maternal androgen excess reduces placental and fetal weights, increases placental steroidogenesis, and leads to long-term health effects in their female offspring

Pituitary and testis responsiveness of young male sheep exposed to testosterone excess during fetal development

Masculinization of the Distal Tubular and External Genitalia in Female Sheep With Prenatal Androgen Exposure

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