Elevated concentrations of the β-subunit of human chorionic gonadotropin and testosterone in the amniotic fluid of gestations of diabetic mothers

Barbieri, Robert L.; Saltzman, Daniel H.; Torday, John S.; Randall, Rebecca W.; Frigoletto, Fredric D.; Ryan, Kenneth J.

doi:10.1016/0002-9378(86)90746-5

Cited by 33 publications

(9 citation statements)

References 17 publications

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“…This hypothesis agrees with previous reports in diabetic women of elevated amniotic fluid testosterone levels 43 , along with findings of hirsutism, ovarian theca-lutein cysts and thecal cell hyperplasia in their female stillbirth offspring 44,45 .…”

Section: Ontogeny Of the Human Fetal Ovarysupporting

confidence: 93%

“…If metabolic disorders of pregnancy, such as PCOS, obesity and diabetes mellitus, induce androgen overproduction by the midgestational human fetal ovary, then advanced fetal surveillance technologies and postnatal assessment of intrauterine androgen exposure will be required to understand whether adult PCOS can be reprogramed in susceptible female offspring. Equally important, abnormal placentation may simultaneously affect fetal adaptation to maternal nutrient availability, with altered placental DNA methylation 87 or other epigenetic and metabolic abnormalities influencing fetal growth, infant birth weight and long-term physiology of the offspring 43,88,89 . As the number of robust susceptibility loci for PCOS emerges from ongoing GWAS data, additional studies will be needed to interrogate the possible role of these genes in fetal reprogramming of PCOS.…”

Section: Future Directionsmentioning

confidence: 99%

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Intrauterine Environment and Polycystic Ovary Syndrome

et al. 2014

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The maternal-fetal environment plays an important role in developmental programming of adult disease. Metabolic and hormonal dysfunction during human fetal development accompanies gestational diabetes as a common occurrence in polycystic ovary syndrome (PCOS) mothers, while human fetal androgen excess from congenital adrenal hyperplasia or virilizing tumors precedes PCOS-like symptoms after birth. To date, clinical studies of infant blood levels at term have yet to confirm that human fetal androgen excess promotes PCOS development after birth. Earlier in development, however, circulating androgen levels in the second trimester female human fetus can normally rise into the male range. Furthermore, midgestational amniotic testosterone levels are elevated in female fetuses of PCOS compared to normal mothers and might influence fetal development, since experimentally-induced fetal androgen excess in animals produces a PCOS-like phenotype with reproductive and metabolic dysfunction. Such alterations in the maternal-fetal environment likely program adult PCOS by epigenetic modifications of genetic susceptibility of the fetus to PCOS after birth. Understanding this phenomenon requires advanced fetal surveillance technologies and postnatal assessment of midgestational androgen exposure for new clinical strategies to improve reproduction in PCOS women, optimize long-term health of their offspring, and minimize susceptibility to acquiring PCOS in future generations.

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Section: Ontogeny Of the Human Fetal Ovarysupporting

confidence: 93%

Section: Future Directionsmentioning

confidence: 99%

Intrauterine Environment and Polycystic Ovary Syndrome

et al. 2014

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“…Consistent with this hypothesis, genes for receptors to insulin, IGF-I and IGF-II and protein for P450 c17 enzyme exist in second trimester human fetal ovaries [156,157]. In addition, female stillbirth offspring of diabetic mothers have increased birth weight and pancreatic beta cell hyperplasia with hirsutism, ovarian theca-lutein cysts and thecal cell hyperplasia [158,159], while elevated amniotic fluid levels of the β-hCG and T occur in pregnant diabetic mothers receiving insulin [160].…”

Section: Alternate Mechanisms Of Developmental Programmingmentioning

confidence: 85%

Polycystic ovary syndrome and its developmental origins

Dumesic

Abbott

Padmanabhan

2007

Rev Endocr Metab Disord

255

168

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The prenatal testosterone (T)-treated adult female rhesus monkey is one animal model of polycystic ovary syndrome (PCOS) in women, with early prenatal T excess programming a permanent PCOS-like phenotype characterized by luteinizing hormone (LH) hypersecretion from reduced hypothalamic sensitivity to steroid negative feedback and relative insulin excess from increased abdominal adiposity. These combined reproductive and metabolic abnormalities are associated with ovarian hyperandrogenism and follicular arrest in adulthood, as well as premature follicle differentiation and impaired embryo development during gonadotropin therapy for in vitro fertilization (IVF). A second animal model for PCOS, the prenatal T-treated sheep also is characterized by LH hypersecretion from reduced hypothalamic sensitivity to steroid negative feedback, persistent follicles and insulin resistance, but also is associated with intrauterine growth retardation and compensatory growth after birth. The ability of prenatal T excess in both species to alter the developmental trajectory of multiple organ systems in utero provides evidence that the hormonal environment of intrauterine life programs target tissue differentiation, raising the possibility that T excess in human fetal development promotes PCOS in adulthood. Such a hypothesis must include data from clinical studies of PCOS women to clarify the homology between these PCOS-like animal models and PCOS per se in reproductive and metabolic function. Future studies should develop new clinical strategies that improve pregnancy outcome and minimize pregnancy loss in women with disorders of insulin action, including PCOS, obesity and diabetes mellitus as well as minimize transgenerational susceptibility to adult PCOS and its metabolic derangements in male close relatives.

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“…For instance, serum T levels in 40% of female fetuses at mid gestation were found to be in the male range (Beck-Peccoz et al 1991). Amniotic fluid T levels were found to be also elevated in diabetic pregnancies (Barbieri et al 1986). Furthermore, female stillbirth offspring of diabetic mothers have hirsutism, ovarian theca-lutein cysts and thecal cell hyperplasia (Driscoll et al 1960) indicative of excess androgen exposure.…”

Section: Introductionmentioning

confidence: 99%

Developmental programming: prenatal androgen excess disrupts ovarian steroid receptor balance

Ortega¹,

Salvetti²,

Padmanabhan³

2009

Reproduction

121

115

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Steroid hormones play an important role in reproduction and the receptors through which they signal change in a developmental time, follicle stage, and cell-specific manner. Disruption in steroid receptor expression affects follicle formation and differentiation. In this study, using prenatal testosterone (T) and dihydrotestosterone (DHT)-treated female sheep as model systems we tested the hypothesis that prenatal androgen excess disrupts the developmental ontogeny of ovarian steroid receptor protein expression. Pregnant Suffolk ewes were injected twice weekly with T propionate or DHT propionate (a non-aromatizable androgen) in cottonseed oil from day 30 to 90 of gestation. Changes in ovarian estrogen receptors (ERα, ERβ), androgen receptor (AR) and progesterone receptor (PR) proteins were determined at fetal (day 90 and 140), postpubertal (10 months) and adult (21 months; only prenatal T-treated sheep studied) ages by immunohistochemistry. Prenatal T and DHT treatment induced selective increase in AR but not ER or PR expression in the stroma and granulosa cells of fetal day 90 and 140 ovaries. An increase in ERα and decrease in ERβ immunostaining coupled with increased AR expression were evident in granulosa cells of antral follicles of 10 and 21-month old prenatal T but not DHT-treated females (analyzed only at 10 months). These findings provide evidence that an early increase in ovarian AR is the first step in the altered ovarian developmental trajectory of prenatal T-treated females and manifestation of postnatal ovarian dysfunction are likely facilitated via altered equilibrium of antral follicular granulosa cell ER / AR protein expression.

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Elevated concentrations of the β-subunit of human chorionic gonadotropin and testosterone in the amniotic fluid of gestations of diabetic mothers

Cited by 33 publications

References 17 publications

Intrauterine Environment and Polycystic Ovary Syndrome

Intrauterine Environment and Polycystic Ovary Syndrome

Polycystic ovary syndrome and its developmental origins

Developmental programming: prenatal androgen excess disrupts ovarian steroid receptor balance

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