Maternal Polycystic Ovarian Syndrome and Pubertal Development in Daughters and Sons

A Population-based Cohort Study

Lea Lykke Harrits Lunddorf; Linn Håkonsen Arendt; Andreas Ernst; Nis Brix; Ulla Brent Knudsen; Jørn Olsen; Cecilia Høst Ramlau-Hansen

Disclosures

Hum Reprod. 2022;37(11):2623-2634. 

In This Article

Abstract and Introduction

Abstract

Study Question: Does maternal polycystic ovarian syndrome (PCOS) affect the timing of pubertal development in daughters and sons?

Summary Answer: Maternal PCOS was associated with earlier adrenarche in daughters.

What is Known Already: Female adolescents with PCOS often experience earlier adrenarche compared to adolescents without PCOS, due to hyperandrogenism. Likewise, they usually have hyperandrogenism during pregnancy, which might potentially affect the development of the foetus, including its future reproductive health.

Study Design, Size, Duration: In this population-based cohort study, we included 15 596 mothers–child pairs from the Danish National Birth Cohort (DNBC) Puberty Cohort, who were followed from foetal life until full sexual maturation or 18 years of age.

Participants/Materials, Setting, Methods: Using register-based and self-reported information on maternal PCOS and menstrual irregularities, collected during pregnancy, we categorized the mothers as having PCOS (n = 251), oligomenorhoea (n = 134), 'other menstrual irregularities' (n = 2411) or no menstrual abnormalities (reference group, n = 12 800). The children provided self-reported information on pubertal development every 6 months from the age of 11 years. The main outcome measures were adjusted mean age differences (in months) at attaining several individual pubertal milestones using an interval-censored regression model, as well as the average difference in age at attaining all pubertal milestones combined into a single estimate using Huber–White robust variance estimation.

Main Results and the Role of Chance: We found that maternal PCOS was associated with an accelerated pubertal development in daughters with an overall average difference of −3.3 (95% CI: −6.3; −0.4) months based on all pubertal milestones compared to the reference group. When further looking into the average difference for adrenarche only (pubarche, axillary hair and acne), the average difference was −5.4 (95% CI: −8.7; −2.1) months compared to the reference group; whereas thelarche and menarche did not occur earlier in daughters of mothers with PCOS (average difference: −0.8 (95% CI: −3.9; 2.4) months). Oligomenorrhoea and 'other menstrual irregularities' were not associated with pubertal development in daughters. Neither PCOS, oligomenorrhoea nor 'other menstrual irregularities' were associated with pubertal development in sons.

Limitations, Reasons for Caution: We expect some degree of non-differential misclassification of maternal PCOS and menstrual irregularities as well as pubertal development in the children.

Wider Implications of the Findings: Maternal PCOS might accelerate adrenarche in daughters. Whether this is due to genetics, epigenetics or prenatal programming by hyperandrogenism in foetal life remains unsolved. The results from the present study can be generalized to Caucasian populations.

Study Funding/Competing Interest(S): The study is funded by the Faculty of Health at Aarhus University. The authors have no financial relationships or competing interests to disclose.

Trial Registration Number: N/A.

Introduction

Polycystic ovarian syndrome (PCOS) is the most common endocrine pathology of women of reproductive age with an observed prevalence varying from 6% to 20% (Yildiz et al., 2012). Generally, PCOS is underdiagnosed due to its complexity and pronounced heterogeneity. Rather vague symptoms, such as prolonged or irregular menstrual cycles, might indicate PCOS, but might not necessarily lead to a diagnosis.

The major endocrine characteristic of PCOS is excess androgens (Ehrmann, 2005), primarily from the ovaries (Franks and Hardy, 2018), which usually persists during pregnancy (Sir-Petermann et al., 2002). Additionally, women with PCOS have high levels of GnRH, LH and anti-Müllerian hormone (AMH), as well as high ratio of LH/FSH (Sir-Petermann et al., 2002; Tata et al., 2018). Although testosterone is lipophilic and can cross the placental barrier, high placental aromatase activity will normally convert androgens to oestrogen. Nonetheless, maternal PCOS is associated with foetal hyperandrogenism perhaps due to altered aromatase activity, placental androgen overproduction (Maliqueo et al., 2013) or the effect of high AMH levels (Tata et al., 2018).

The origin of PCOS is relatively uncertain, but genetics, epigenetics and foetal programming through prenatal hyperandrogenism have been recognized as important potential aetiological factors of PCOS; thereby making PCOS a hereditary disorder (Filippou and Homburg, 2017; Sanchez-Garrido and Tena-Sempere, 2020; Stener-Victorin and Deng, 2021).

Studies have previously found that maternal PCOS increases the risk of pregnancy complications (Palomba et al., 2015) and adverse birth outcomes (Doherty et al., 2015), and that children of women with PCOS are at higher risk of congenital malformations (Doherty et al., 2015), overweight (Zhang et al., 2022), metabolic and neuropsychiatric disorders (Doherty et al., 2015; Dubey et al., 2021; Stener-Victorin and Deng, 2021), as well as altered hormonal profiles and inherited PCOS in daughters (Barry et al., 2010; Torchen et al., 2019). The causal link between maternal PCOS and pubertal development in the children is still unknown.

Puberty involves the adrenarche and the gonadarche. The adrenarche is the onset of androgen secretion from the adrenal cortex, which phenotypically results in pubarche, axillary hair growth, as well as differentiation and activation of apocrine and sebaceous glands in the skin in both sexes. In boys, these physiological changes will be accompanied by development of the genitals and vocal changes due to both adrenarche and gonadarche (activation of the hypothalamus–pituitary–gonads (HPG) axis). In girls, gonadarche results in development of the oestrogen-dependent pubertal milestones, thelarche and menarche.

In this study, we investigate whether the timing of pubertal development is altered in children exposed to maternal PCOS in foetal life compared to unexposed children. As studies have found premature adrenarche to be an initial sign in girls with PCOS (Voutilainen and Jääskeläinen, 2015), we hypothesize that daughters of mothers with PCOS have earlier adrenarche due to prenatal hyperandrogenism or inherited PCOS. Additionally, we hypothesize that prenatal hyperandrogenism induced by maternal PCOS can lead to earlier pubertal development in sons as well.

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