Endocrine Abstracts

Background: Polycystic ovary syndrome (PCOS) is believed to be a primeval condition with the earliest hints of its existence found in ancient Egyptian literature. Despite its negative impact on fertility, it has emerged as the most common endocrine disorder in women of reproductive age, creating what is called the PCOS paradox. We hypothesized that this phenomenon can be explained by testosterone-mediated high bone mineral density (BMD) in women with PCOS, providing a survival advantage in harsh ancient environments.

Methods: Using the mendelian randomization (MR) analysis, we evaluated the association of genetic risk of excess testosterone in PCOS with BMD and fractures. The MR analysis was performed using linear regression analysis with the weighted genetic risk score as an independent variable adjusting for age, body mass index (BMI), and population eigenvectors. Horizontal pleiotropy in the MR analysis was tested using MR-Egger regression analysis.

Results: The study consisted of 2,21,086 Caucasian women with a mean age of 56.7 ± 7.9 years, mean BMI of 27.0 ± 5.1 kg/m² and a mean BMD of 0.50 ±11 g/cm². The study participants reported 24,797 (11%) fractures during their lifetime. The regression analysis showed that one standard deviation increase in the genetic risk for high testosterone levels in PCOS was associated with significantly higher BMD and a significantly reduced risk of fractures.

Conclusions: In PCOS, genetic predisposition to high testosterone levels is associated with high BMD and reduced risk of fractures. This could have offered a survival benefit in ancient environments and explains why this disorder has persisted in human evolution despite resulting in sub/infertility.