Developmental origins of adult disease (DoHAD) refers to critical gestational ages during human fetal development and beyond when the endocrine metabolic status of the mother can permanently program the physiology and/or morphology of the fetus, modifying its susceptibility to disease after birth. The aim of this review is to address how DoHAD plays an important role in the phenotypic expression of polycystic ovary syndrome (PCOS), the most common endocrinopathy of women characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology. Clinical studies of PCOS women are integrated with findings from relevant animal models to show how intergenerational transmission of these central components of PCOS are programmed through an altered maternal endocrine-metabolic environment that adversely affects the female fetus and long-term offspring health. Prenatal testosterone treatment in monkeys and sheep have been particularly crucial in our understanding of developmental programming of PCOS because organ system differentiation in these species, as in humans, occurs during fetal life. These animal models, along with altricial rodents, produce permanent PCOS-like phenotypes variably characterized by LH hypersecretion from reduced steroid-negative feedback, hyperandrogenism, ovulatory dysfunction, increased adiposity, impaired glucose-insulin homeostasis and other metabolic abnormalities. The review concludes that DoHAD underlies the phenotypic expression of PCOS through an altered maternal endocrine-metabolic environment that can induce epigenetic modifications of fetal genetic susceptibility to PCOS after birth. It calls for improved maternal endocrine-metabolic health of PCOS women to lower their risks of pregnancy-related complications and to potentially reduce intergenerational susceptibility to PCOS and its metabolic derangements in offspring.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects up to 6.8% of reproductive age women. Experimental research and clinical observations suggest that PCOS may originate in the very early stages of development, possibly even during intrauterine life. This suggests that PCOS is either genetically-transmitted or is due to epigenetic alterations that develop in the intrauterine microenvironment. Although familial cases support the role of genetic factors, no specific genetic pattern has been defined in PCOS. Several candidate genes have been implicated in its pathogenesis, but none can specifically be implicated in PCOS development. Hypotheses based on the impact of the intrauterine environment on PCOS development can be grouped into two categories. The first is the "thrifty" phenotype hypothesis, which states that intrauterine nutritional restriction in fetuses causes decreased insulin secretion and, as a compensatory mechanism, insulin resistance. Additionally, an impaired nutritional environment can affect the methylation of some specific genes, which can also trigger PCOS. The second hypothesis postulates that fetal exposure to excess androgen can induce changes in differentiating tissues, causing the PCOS phenotype to develop in adult life. This review aimed to examine the role of fetal programming in development of PCOS.

Exposure of pregnant mothers to elevated concentrations of circulating testosterone levels is associated with fetal growth restriction and delivery of small-for-gestational-age babies. We examined whether maternal testosterone crosses the placenta to directly suppress fetal growth or if it modifies placental function to reduce the capacity for transport of nutrients to the fetus.

Pregnant rats were exposed to testosterone propionate (TP; 0.5 mg/kg) by daily subcutaneous injection from gestational days (GD) 15-19. Maternal and fetal testosterone levels, placental nutrient transport activity and expression of transporters and birth weight of pups and their anogenital distances were determined.

This dose of TP doubled maternal testosterone levels but had no effect on fetal testosterone levels. Maternal daily weight gain was significantly lower only on GD 19 in TP treated dams compared to controls. Placental weight and birth weight of pups were significantly reduced, but the anogenital distance of pups were unaffected by TP treatment. Maternal plasma amino acids concentrations were altered following testosterone exposure, with decreases in glutamine, glycine, tyrosine, serine, proline, and hydroxyproline and increases in asparagine, isoleucine, leucine, lysine, histidine and arginine. In the TP dams, placental system A amino acid transport activity was significantly reduced while placental glucose transport capacity was unaffected. Decreased expression of mRNA and protein levels of slc38a2/Snat2, an amino acid transporter, suggests that reduced transporter proteins may be responsible for the decrease in amino acid transport activity.

Taken together, these data suggest that increased maternal testosterone concentrations do not cross the placenta to directly suppress fetal growth but affects amino acid nutrient delivery to the fetus by downregulating specific amino acid transporter activity.

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.

To explore the hypothesis that maternal androgen levels are elevated before the onset of preeclampsia.

A case-control study in three university hospitals in Norway and Sweden included 29 women with mild preeclampsia and 142 controls. Maternal levels of dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone and sex hormone binding globulin (SHBG) were measured, and the free testosterone index (FTI) was calculated in weeks 17 and 33 of gestation.

Androstenedione, testosterone and FTI were elevated in gestational weeks 17 and 33 in women who eventually developed preeclampsia, while DHEAS was elevated at week 17 only. At week 17 elevated testosterone and FTI were seen in women bearing both male and female fetuses. At week 33 elevated levels of androstenedione, testosterone and FTI was seen in women with male fetuses only. Comparing the lower tertile with the upper tertile of FTI at week 17 of gestation gave an odds ratio (OR) for preeclampsia of 3.7 [95% confidence interval (CI) 1.3-10.4].

Maternal androgen levels are already elevated in the early second trimester among women who eventually develop preeclampsia. Thus hyperandrogenism may be considered as an early risk marker of preeclampsia and it might be involved in the pathogenesis of preeclampsia.

Dehydroepiandrosterone sulphate, progesterone, estradiol, estriol and human placental lactogen (hPL) were biochemically assayed in a group of 92 pregnancies in which intra-uterine growth retardation was suspected. The group was selected with ultrasound fetometry at 32 weeks of gestation, and maternal blood was sampled at 33, 35, 37 and 39 weeks of gestation. The IUGR group consisted of 30 pregnancies resulting in the birth of an infant with a birthweight of 2 standard deviations or more below the mean for gestational age in the Malmö population. Intra-uterine growth trends were defined by serial ultrasound fetometry performed every second week. Both serum hormone and hPL content were examined in relation to birth-weight, occurrence of imminent asphyxia at delivery, Apgar score, and pH in the umbilical vein. Neither dehydroepiandrosterone sulphate, nor progesterone nor estradiol values correlated to any of the outcome variables. To some extent estriol values distinguished IUGR from non-IUGR fetuses but not until the 39th gestational week, whereas hPL was effective in this respect in all weeks studied. An hPL value below 4 mg/l predicted IUGR with a sensitivity ranging from 52% to 74%, and a specificity ranging from 85% to 78%. HPL correlated well with the subsequent intra-uterine growth rate, but not with the outcome variables studied.

The response to an intravenous load of 50 mg of dehydroepiandrosterone sulfate given to women with a pregnancy prolonged to more than 42 weeks was compared to the response in control pregnant women at 40 weeks. The half-life of dehydroepiandrosterone sulfate was longer in the prolonged pregnancy group than in the control group (mean +/- SEM, 3.64 +/- 0.24 hour versus 2.78 +/- 1.08 hour, p less than 0.05), and the rises of serum free estrone and free estradiol 4 hours after infusion were less in the prolonged pregnancy group than in the control group. Maternal venous and umbilical venous estrone, estradiol, free estriol, and dehydroepiandrosterone sulfate levels were compared in samples from control, postmature, and postterm groups. Umbilical estriol concentrations were significantly less in the postmature group (67.8 +/- 9.5 ng/ml, mean +/- SEM) than in the control group (136 +/- 22.8 ng/ml, mean +/- SEM, p less than 0.01), but there were no significant differences between dehydroepiandrosterone sulfate, estrone, and estradiol levels. Maternal venous estriol levels were lower in the postmature group (13.3 +/- 2.1, p less than 0.05) than in the control group (25.0 +/- 4.9). A reduction in overall placental estrogen production was indicated by the results of the dehydroepiandrosterone sulfate loads in the patients with prolonged pregnancy, yet the normal umbilical venous estrone and estradiol levels do not fit this conclusion. There is no explanation for the discrepancy at this time.