Polycystic ovary syndrome: preconception, pregnancy and offspring health

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, with a reported population incidence between 6-15%. PCOS is a heterogeneous reproductive disorder, which is diagnosed when at least two out of the three following criteria are present: oligo- or anovulation, clinical or biochemical signs of hyperandrogenism and polycystic ovaries. Early manifestations of the syndrome are often irregular or absent menstrual bleeding, anovulatory infertility and/or clinical manifestations of androgen excess, such as acne or hirsutism. Subsequently, there are metabolic disturbances associated with PCOS, of which some are already present early in life (obesity, insulin resistance) and others appear later in life (dyslipidaemia, type 2 diabetes). When a pregnancy is achieved, women with PCOS have an increased risk of maternal and neonatal complications. The aims of this thesis were to gain more insight into the incidence and risk factors of pregnancy complications in women with PCOS, its pathophysiology and the impact of the syndrome on the cardiovascular and metabolic health of their offspring.

We demonstrated that women with PCOS with a singleton pregnancy have an increased incidence of developing gestational diabetes (GDM; OR 4.15), of delivering a small for gestational age infant (OR 3.76) and of induced preterm delivery (7.77). Women with the hyperandrogenic PCOS phenotype (with high levels of free testosterone) are demonstrated to have a higher incidence of pregnancy complications compared with the normo-androgenic phenotype. We developed a prediction model with preconception characteristics for one of the most common pregnancy complications in women with PCOS, gestational diabetes. The combination of fasting glucose, fasting insulin, SHBG, androstenedione and first-degree relatives with type 2 diabetes seemed to predict the development of gestational diabetes already before conception with an accuracy of 0.87. With this model, women with PCOS who are at increased risk of developing GDM could be identified and followed more intensively during pregnancy in order to prevent them from developing GDM or reduce the consequences when GDM is diagnosed. Subsequently, placentas from women with PCOS were compared with placentas from women with uncomplicated pregnancies who delivered at term. We found that placentas from women with PCOS show more signs of inflammation, thrombosis, and villous immaturity compared with placentas from women without PCOS, independent of pregnancy complications (GDM, PIH and PE). These results may reflect signs of vascular damage or foetal hypoxia. Finally, we compared the cardiovascular health of children from women with PCOS with children from a population-based reference group. We demonstrated that children from women with PCOS have obvious subclinical alterations in metabolic and cardiovascular health, which is reflected by an increased pulse pressure and a higher left ventricle diameter in the young age category as well as a higher carotid intima media thickness, subcutaneous fat mass, total cholesterol level, triglyceride and LDL-cholesterol level in the older age category. All these findings represent risk factors that are associated with an increased cardiovascular disease risk later in life.