Investigating polycystic ovarian syndrome

Aleisha Moore was recently awarded one of two Dean's Prizes for the best summer research project in the OSMS.

Aleisha worked with Dr Rebecca Campbell in the Department of Physiology.

Polycystic ovarian syndrome (PCOS) is the most common cause of infertility among women of reproductive age worldwide.

The syndrome manifests as a variety of detrimental reproductive and metabolic symptoms, and is therefore a prominent health issue.

While classically identified as an ovarian disorder, PCOS has been more recently identified as a state of impaired signalling in the brain.

Fertility is ultimately controlled by a network of cells within the brain.

The final output cells in this neuronal network are the gonadotropin-releasing hormone (GnRH) neurons.

To function appropriately, these neurons require feedback information from circulating gonadal steroid hormones, which are delivered via a connected neuronal network.

Steroid hormone receptors are critical for relaying feedback information about peripheral gonadal steroid hormones to the GnRH neuronal network.

We therefore hypothesised that impaired steroid hormone feedback may occur as a result of altered steroid hormone receptor expression in brain regions that are known to regulate GnRH neurons.

Although the aetiology of PCOS is unclear, prenatal androgen (PNA) exposure has been linked with the development of PCOS in adolescence and adulthood.

This project employed a mouse model of PCOS generated by delivering high levels of androgens to dams during late pregnancy, a critical period of foetal brain development.

Female offspring were investigated as adults.

We initially examined ovarian morphology to characterise the murine model of PCOS.

We found that PNA treatment significantly reduced the area of the adult ovary containing corpora lutea, a structure that is formed post-ovulation and is essential for maintaining pregnancy.

This observation matches the diagnostic criteria of anovulation and subfertility in women with PCOS.

In addition, investigation of the cell layers composing antral follicles revealed the area of the granulosa cell layer was significantly reduced and the area of the thecal cell layer significantly increased in PNA-treated mice.

This disrupted morphology is suggestive of altered hormone synthesis and matches the prominent symptom of high circulating androgens in women with PCOS.

We next looked in the brain for changes in steroid hormone receptor expression.

Immunocytochemistry was performed to label the androgen receptor (AR) throughout hypothalamic and brainstem nuclei that contain projections to GnRH neurons.

We hypothesised that high circulating androgens in utero would lead to a differential expression of AR in the adult female brain.

However, no significant differences in AR expression were identified between PNA and vehicle-treated mice.

Immunocytochemistry was performed in hypothalamic nuclei to label the progesterone receptor (PR), which plays an essential role in feedback mechanisms.

Compared to vehicle-treated mice, PR expression in PNA-treated mice was significantly decreased in nuclei that are identified as important in steroid hormone feedback.

This suggests that the ability of progesterone to relay feedback information to the brain is impaired in PCOS.

Overall, ovarian morphology suggests PNA exposure creates an appropriate model for the study of PCOS.

Additionally, our receptor expression findings support the idea that PCOS is a state of impaired ovarian hormone feedback to the brain.