Medical ProgressIntergenerational Influences between Maternal Polycystic Ovary Syndrome and Offspring: An Updated Overview
Section snippets
PCOS and Intrauterine Androgen Exposure
High fetal androgen exposure may be the result of a combined effect of high maternal androgen concentrations,2,11 placental injury,12 and fetal androgen production.13 The anogenital distance (the distance between the cranial edge of the anus and the base of the clitoris) is longer in daughters of women with PCOS,14 reflecting androgen exposure in utero. Congenital adrenal hyperplasia, a known example of intrauterine androgen excess of fetal origin, can lead to the development of the PCOS
Effects on the Reproductive System of Offspring
Daughters born to women with PCOS show features of PCOS during peripubertal period.33 During the onset of puberty, dehydroepiandrosterone sulfate concentrations are increased,34 and during puberty, increased testosterone levels and lower sex hormone-binding globulin have been described.35 These manifestations may reflect an early stage in the development of PCOS for these at-risk girls. Prenatally androgenized rats exhibit elevated serum androstenedione and testosterone concentrations in young
Metabolic Effects
Sir-Petermann et al found metabolic alterations in daughters of women with PCOS when compared with controls.35 Previous studies demonstrated that prenatal androgen excess disturbed insulin-glucose hemodynamics in adult female rhesus monkeys and induced IR in prenatally androgenized adult rats.59,60 Padmanabhan et al found that the programming of reduced insulin sensitivity in prenatal testosterone-treated ewes was thought to be caused by the androgenic action of testosterone.61 Furthermore,
Cardiovascular Effects
A recent meta-analysis reported the subtle signs of compromised cardiometabolic health in children of women with PCOS, especially for the female offspring.69 King et al found that prenatally androgenized female sheep had mild hypertension in adulthood, possibly related to activation of the sympathetic nervous system, lipid abnormalities, and other increased cardiovascular risk factors.70 Previous research further identified a novel androgen-mediated mechanism through transcriptional regulation
Neuropsychiatric Effects
One matched case-control study conducted in Sweden of 23 748 children with autism spectrum disorder and 208 796 controls found that maternal PCOS increased the odds of autism by 59% among the offspring after adjusting for confounding factors.74 Fetal testosterone levels in amniotic fluid are positively correlated with autistic traits.75,76 Brain structural differentiation is altered in patients with autism compared with control groups; the total number and numerical density of Purkinje cells in
Effects on Growth and Development
A recent large prospective cohort study found that greater maternal salivary testosterone/estradiol ratios were associated with a greater risk of small for gestational age offspring.90 High levels of androgens during pregnancy are associated with growth restriction in utero91 by influencing the nutrient transport and blood supply to the placenta,92 among other effects. Growth restriction in utero is associated with adverse perinatal outcomes and long-term complications. Smith et al described a
Effects on Intestinal Flora
The role of intestinal flora in the regulation of the brain–gut axis has received increasing attention. Adult prenatally androgenized rats exhibit intestinal microbial dysbiosis and an altered abundance of bacteria involved in the production of short-chain fatty acid metabolites, which may be related to increased risk for hypertension and cardiovascular disease.72 In addition, a positive correlation is found between the severity of autism and the severity of gastrointestinal dysfunction.95
Genetic Predisposition
In familial clustering and twin studies,96 genetic factors are involved in the etiology of PCOS. Genome-wide association studies (GWAS) have confirmed a range of candidate genes and loci for PCOS.97,98 Chen et al identified 11 risk loci associated with PCOS by analyzing genome-wide association data in Han Chinese women.98 The majority of the candidate genes at the associated loci are involved in insulin signaling, reproductive hormone function, and type 2 diabetes.98 Transmission disequilibrium
Pregnancy Complications
Women with PCOS are at significantly greater risk of developing gestational diabetes mellitus, pregnancy-induced hypertension, and preeclampsia.5 Pregnancy complications could have an impact on neonatal outcomes and the long-term health of offspring, independent of PCOS-related features. The association between maternal gestational diabetes and the risk of metabolic disease in the offspring has been well established.6 Glucose is transported through the placenta, causing fetal hyperglycemia and
Medication Use
Metformin is considered a first-line drug to treat type 2 diabetes and gestational diabetes, by increasing tissue insulin sensitivity, reducing insulin concentrations, and inhibiting hepatic glucose production. Although metformin can be transferred through the placenta, it is considered safe throughout pregnancy.122 However, Hjorth-Hansen et al described larger head sizes in the offspring of overweight women with PCOS, which was notable in utero.123 Data from another study suggested that
Maternal Metabolic Abnormalities
Previous studies have reported that maternal nutrition, hormones, and the metabolic environment affect the metabolism of the offspring.128 The disturbed metabolic environment in utero induced by maternal IR or hyperinsulinemia has been proven to impact an offspring's long-term health. Maternal IR is associated with birth weight and the incidence of large for gestational age infants, independent of maternal obesity and glucose levels.129 Similar to this finding, Isganaitis et al also found that
Other Factors
Other potentially relevant factors related to PCOS may be involved in affecting the health of offspring. Previous research showed that advanced glycation end-products may relate to the pathogenesis of PCOS, which can induce the generation of oxidative stress and proinflammatory cytokines through activating key intracellular signaling pathways.134 And prenatal exposure to endocrine-disrupting chemicals may induce fetal programming alterations.135,136 Recently, excess prenatal anti-Müllerian
Conclusions and Future Directions
The impact of maternal PCOS on the offspring is complex and multifactorial. As shown in the Figure, The effect of prenatal androgen hyperexposure on the development of offspring is multidimensional, traversing all stages of fetal development. We speculate that epigenetic alterations and placental changes may be the central roles of androgen. IR may interact with intrauterine androgen excess to affect the intrauterine environment and fetal programming. Hyperinsulinemia has been found to be
Data statement
Data sharing statement available at www.jpeds.com.
References (140)
- et al.
Increased antimüllerian hormone levels and other reproductive endocrine changes in adult male relatives of women with polycystic ovary syndrome
Fertil Steril
(2016) - et al.
Placental steroidogenesis in pregnant women with polycystic ovary syndrome
Eur J Obstet Gynecol Reprod Biol
(2013) - et al.
Androgen dependent mechanisms of pro-angiogenic networks in placental and tumor development
Placenta
(2017) - et al.
Effect of maternal PCOS and PCOS-like phenotype on the offspring's health
Mol Cell Endocrinol
(2016) - et al.
Neuroendocrine consequences of androgen excess in female rodents
Horm Behav
(2008) - et al.
Formation and early development of follicles in the polycystic ovary
Lancet
(2003) - et al.
Animal models of the polycystic ovary syndrome phenotype
Steroids
(2013) Reproductive system outcome among patients with polycystic ovarian syndrome
Endocrinol Metab Clin North Am
(2015)- et al.
Puberty arises with testicular alterations and defective AMH expression in rams prenatally exposed to testosterone
Domest Anim Endocrinol
(2017) - et al.
The association between digit ratio (2D:4D) and overweight or obesity among Chinese children and adolescents: a cross-sectional study
Early Hum Dev
(2019)
Abnormal instability, excess density, and aberrant morphology of dendritic spines in prenatally testosterone-exposed mice
Neurochemistry Int
Maternal polycystic ovary syndrome and risk for attention-deficit/hyperactivity disorder in the offspring
Biol Psychiatry
Attention deficit hyperactivity disorder
Lancet
Maternal androgen levels during pregnancy are associated with early-life growth in Geoffroy's marmosets, Callithrix geoffroyi
Gen Comp Endocrinol
Gastrointestinal microbiota in children with autism in Slovakia
Physiol Behav
Prevalence of polycystic ovary syndrome in women in China: a large community-based study
Hum Reprod
Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenization
Hum Reprod
Metabolic phenotype in the brothers of women with polycystic ovary syndrome
Diabetes Care
Pregnancy complications in women with polycystic ovary syndrome
Hum Reprod Update
Gestational diabetes mellitus and long-term consequences for mother and offspring: a view from Denmark
Diabetologia
Preeclampsia, placental insufficiency, and autism spectrum disorder or developmental delay
JAMA Pediatr
Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition and metabolic outcomes at 7-9 years of age
BMJ Open Diabetes Res Care
Impact of maternal obesity on offspring obesity and cardiometabolic disease risk
Reproduction
Maternal insulin resistance multigenerationally impairs synaptic plasticity and memory via gametic mechanisms
Nat Commun
Macroscopic and microscopic findings of the placenta in women with polycystic ovary syndrome
Human Reprod
Evidence for increased 5α-reductase activity during early childhood in daughters of women with polycystic ovary syndrome
J Clin Endocrinol Metab
Anogenital distance in newborn daughters of women with polycystic ovary syndrome indicates fetal testosterone exposure
J Dev Orig Health Dis
Intrauterine environment and polycystic ovary syndrome
Semin Reprod Med
The developmental origins of adult disease (Barker) hypothesis
Aust N Z J Obstet Gynaecol
Developmental programming, a pathway to disease
Endocrinology
Developmental programing: impact of testosterone on placental differentiation
Reproduction
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
Prenatal testosterone excess disrupts placental function in a sheep model of polycystic ovary syndrome
Endocrinology
Elevated testosterone levels during rat pregnancy cause hypersensitivity to angiotensin II and attenuation of endothelium-dependent vasodilation in uterine arteries
Hypertension
Chronic hyperandrogenemia and western-style diet beginning at puberty reduces fertility and increases metabolic dysfunction during pregnancy in young adult, female macaques
Human Reprod
Prenatal testosterone-induced fetal growth restriction is associated with down-regulation of rat placental amino acid transport
Reprod Biol Endocrinol
Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome
Nat Med
Androgen receptor and histone lysine demethylases in ovine placenta
PLoS One
Early embryonic androgen exposure induces transgenerational epigenetic and metabolic changes
Mol Endocrinol
Fetal, infant, adolescent and adult phenotypes of polycystic ovary syndrome in prenatally androgenized female rhesus monkeys
Am J Primatol
Sexual differentiation of reproductive neuroendocrine function in sheep
Rev Reprod
Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome?
Human Reprod Update
The critical time window for androgen-dependent development of the Wolffian duct in the rat
Endocrinology
Metabolic and reproductive features before and during puberty in daughters of women with polycystic ovary syndrome
J Clin Endocrinol Metab
Adrenal function during childhood and puberty in daughters of women with polycystic ovary syndrome
J Clin Endocrinol Metab
Early metabolic derangements in daughters of women with polycystic ovary syndrome
J Clin Endocrinol Metab
Elevated androstenedione in young adult but not early adolescent prenatally androgenized female rats
PLoS One
Endocrine antecedents of polycystic ovary syndrome in fetal and infant prenatally androgenized female rhesus monkeys
Biol Reprod
Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: implications for a common fertility disorder
Proc Natl Acad Sci USA
The role of GABA in the regulation of GnRH neurons
Front Neurosci
Cited by (0)
Supported by the National Natural Science Foundation of China, China (81874480; 81873837), and the Zhejiang Province Science Foundation for Distinguished Young Scholars (LR16H040001). The authors declare no conflicts of interest.
- ∗
Contributed equally.