Developmental origins of polycystic ovary syndrome : role of early adverse life events on adult health

The research focus of this thesis is polycystic ovary syndrome (PCOS), the most common endocrine disorder among women of reproductive age, associated with reproductive, cardio-metabolic, and mental health complications. Despite the high prevalence, little is known about the etiology of the syndrome. The scope of the current thesis was to investigate aspects of the developmental origins of the syndrome, with focus on the impact of adverse environmental factors during pregnancy on PCOS-associated features in the offspring. To reach these aims we employed three mouse model of PCOS and data from a Swedish national register-based cohort study.

The thesis is divided into two parts. Part 1 investigates the effects of maternal androgen excess and maternal obesity on the mental health of adult male and female offspring. Study I demonstrated that maternal androgen exposure increases anxiety-like behavior in the first generation of female mouse offspring, but not male offspring, while maternal obesity affects male offspring behavior, but not female offspring. This sexually dimorphic response to the two prominent environmental stimuli was further supported by sex-specific changes in gene expression within the amygdala and hypothalamus. Study II provided evidence that daughters of women with PCOS are at increased risk to be diagnosed with anxiety disorders, but not the sons, using a Swedish national register-based cohort study. It further showed that maternal androgen exposure can lead to transgenerational transmission of anxiety-like behavior in the third generation of female mice, but not the male offspring, without major impact of maternal obesity. Finally, the male germline (first generation of male offspring with no change in behavior) did also transgenerationally transmit an anxiety-like behavior to the third generation of male offspring.

Part 2 investigates the effects of an adverse maternal and/or postnatal environment on the cardiovascular and metabolic health of females, using mouse models of PCOS. Study III revealed that maternal androgen excess leads to cardiac hypertrophy in adult female offspring, accompanied by gene expression changes in the left ventricle, without the presence of metabolic dysfunction. It was further shown that this adverse cardiac phenotype is the result of an early cardiac reprogramming. In addition, cardiovascular assessment of a mouse model of PCOS with continuous exposure to androgens from prepuberty to adulthood, demonstrated cardiac hypertrophy and increased vasocontractile responses, while simultaneous administration of the antiandrogen flutamide could only partially prevent the observed phenotype. Finally, in study IV, developmental, reproductive and metabolic complications were revealed in a transgenic mouse model of PCOS that overexpresses ovarian nerve growth factor. Ovarian excess of nerve growth factor led to developmental defects in the female fetus, including growth restriction, reduction of germ cell number and delayed primary oocyte maturation. In addition, the adult transgenic female mice displayed disrupted estrous cyclicity and ovarian expression changes of steroidogenic genes and epigenetic markers. Lastly, these mice developed metabolic complications, as shown by impaired glucose metabolism, aberrant adipose tissue function, and liver steatosis.

List of scientific papers

I. Manti M, Fornes R, Qi X, Folmerz E, Linden Hirschberg A, de Castro Barbosa T, Maliqueo M, Benrick A, Stener-Victorin E. (2018). Maternal androgen excess and obesity induce sexually dimorphic anxiety-like behavior in the offspring. FASEB J. 32, 4158-4171.
https://doi.org/10.1096/fj.201701263RR

II. Risal S, Manti M, Lu H, Fornes R, Larsson H, Benrick A, Deng Q, Cesta CE, Rosenqvist MA, Stener-Victorin E. Prenatal androgen exposure causes a sexually dimorphic transgenerational increase in offspring susceptibility to anxiety disorders. [Manuscript]

III. Manti M, Fornes R, Pironti G, McCann Haworth S, Zhengbing Z, Benrick A, Carlström M, Andersson D, Stener-Victorin E. (2019). Maternal androgen excess induces cardiac hypertrophy and left ventricular dysfunction in female mice offspring. Cardiovasc Res. pii: cvz180.
https://doi.org/10.1093/cvr/cvz180

IV. Manti M*, Pui HP*, Edström S, Risal S, Lu H, Lindgren E, Jerlhag E, Benrick A, Deng Q, Stener-Victorin E. Excess of ovarian nerve growth factor impairs embryonic development and causes reproductive and metabolic dysfunction in adult mice. *Equal contribution. [Manuscript]