The impact of prenatal influences on lifelong health is well-established. Unfortunately, many children are born with compromised lifetime health trajectories. Fetal development can be affected by disruptions in hormonal interactions, which can have consequences for the entire lifespan. Polycystic ovary syndrome (PCOS) is an example.

WHAT IS POLYCYSTIC OVARY SYNDROME?

PCOS is a common endocrine disorder that affects over 10% of women. It is characterised by reproductive and metabolic abnormalities. Women with PCOS have irregular periods and difficulty getting pregnant. They may also have an array of metabolic problems, including insulin resistance, type 2 diabetes, obesity, dyslipidaemia and non-alcoholic fatty liver disease (NAFLD). A common hallmark of PCOS is that women have increased androgen concentrations, including during pregnancy.

There is ongoing debate about the causes of PCOS. Although it runs in families, a robust genotype has not been identified. However, there is evidence that androgens may play a role in the programming of PCOS. Pregnant women with PCOS have higher androgen concentrations and decreased placental aromatase activity when compared with pregnant controls.¹ Daughters of women with PCOS are more likely to develop PCOS.² They have increased cord blood testosterone concentrations, longer anogenital distance (a marker of gestational androgen excess exposure) and increased sebum production, collectively indicative of increased in utero androgen exposure.³ There is also strong evidence from animal studies that prenatal androgen overexposure in rodents, monkeys and sheep results in adult reproductive and metabolic disorders that parallel those seen in women with PCOS.⁴

‘MALE PCOS’ – HUMAN EVIDENCE

Women with PCOS also have sons. Is there any evidence from human studies that males from the pregnancies of women with PCOS are also affected? And, if so, to what extent?

To date, there have been relatively few studies on the sons and brothers of women with PCOS. Emerging evidence indicates that they develop hyperinsulinaemia and dyslipidaemia, characterised by elevated triglycerides and cholesterol, which, alongside an increased risk of obesity, predict a potentially increased risk of cardiovascular disease.⁵

The increased cholesterol levels in pubertal sons of patients with PCOS seem to be an early indication of metabolic dysfunction.⁶ The metabolic changes in these sons are likely to be independent of gonadotrophin and sex steroid levels, although they have elevated anti-Müllerian hormone (AMH) concentrations during childhood.⁷ Besides hormonal and metabolic abnormalities, ‘PCOS’ males experience early-onset alopecia, excessive hair growth or acne. Early-onset androgenetic alopecia is suggested to be a prominent marker of ‘male PCOS’.

‘MALE PCOS’ – ANIMAL STUDIES

A recent study using a clinically realistic ovine model of fetal androgen overexposure demonstrated that adolescent male sheep that were prenatally androgenised are accurate phenocopies of males from pregnancies in human PCOS, with elevated AMH, hyperinsulinaemia and evidence of dyslipidaemia, such as increased triglycerides and cholesterol.⁸ Further hepatic omics analysis revealed that 1,084 genes and 408 proteins were altered in the livers of these ‘PCOS’ males. Perhaps counterintuitively, cholesterol synthesis was decreased in these ovine males, but their hepatic cholesterol uptake and secretion were dysregulated. These males had decreased expression of hepatic CYP7A1, which is the rate-limiting enzyme responsible for converting cholesterol to bile acids. As a result of this perturbed cholesterol metabolism, ‘PCOS males’ had increased concentrations of hepatic total and free cholesterol, as well as increased expression of markers of lipid droplet accumulation.

Hepatic cholesterol accumulation is an important factor underlying the development and progression of NAFLD. There is strong evidence showing that increased cholesterol accumulation can impact mitochondrial membrane fluidity and overall mitochondrial function. Consequently, mitochondrial function was altered in ‘PCOS’ males.⁹ Nearly 50% of hepatic genes and proteins associated with oxidative phosphorylation were downregulated, indicating decreased oxidative phosphorylation, functionally realised in decreased hepatic ATP generation in these adolescent ovine males.

The study also demonstrated that ‘PCOS’ males had a significantly increased hepatic bilirubin content coupled with decreased hepatic detoxification and antioxidant potential, mirrored in the circulation. They also had an increased hepatic reactive oxygen species, with an indication of increased DNA damage. As a result of hepatic metabolic dysfunction, prenatally androgenised males had increased expression of profibrotic genes and proteins, coupled with increased hepatic collagen deposition, indicating early fibrosis, again reflected in the circulation by increased concentrations of fibrotic proteins, which positively correlated with plasma cholesterol levels.

IN CONCLUSION: NAMES ARE IMPORTANT!

Sons born to mothers with PCOS are at risk of developing hyperinsulinaemia, dyslipidaemia and obesity. Elevated cholesterol concentration is an early marker of metabolic dysfunction in pubertal sons of patients with PCOS.

In a preclinical ovine model, male offspring exposed to high levels of androgens during fetal life develop markers of metabolic dysfunction found in sons from PCOS pregnancies. These adolescent ovine males also develop a hepatic gene and protein signature reminiscent of an intrahepatic cholestasis-like condition, with altered cholesterol trafficking, increased hepatic cholesterol accumulation, altered mitochondrial metabolism of lipids, mitochondrial dysfunction, and early-life liver damage, which may result in lifelong health issues.

Therefore, it is important to recognise that fetal androgen excess associated with PCOS pregnancies is a risk factor for poor metabolic health for both sexes. This awareness has prompted the suggestion that PCOS be acknowledged as ‘metabolic reproductive syndrome’, thus encompassing the potential for poorer lifelong health in both males and females.¹⁰

KATARZYNA SIEMIENOWICZ
Lecturer in Biomedical Science, Edinburgh Napier University

REFERENCES

1. Maliqueo M et al. 2012 European Journal of Obstetrics, Gynecology & Reproductive Biology https://doi.org/10.1016/j.ejogrb.2012.10.015.
2. Risal S et al. 2019 Nature Medicine https://doi.org/10.1038/s41591-019-0666-1.
3. Barrett ES et al. 2018 Journal of Developmental Origins of Health & Disease https://doi.org/10.1017/s2040174417001118.
4. Stener-Victorin E et al. 2020 Endocrine Reviews https://doi.org/10.1210/endrev/bnaa010.
5. Risal S et al. 2023 Cell Reports Medicine https://doi.org/10.1016/j.xcrm.2023.101035.
6. Crisosto N et al. 2017 Endocrine Connections https://doi.org/10.1530/EC-17-0218.
7. Recabarren SE et al. 2008 Journal of Clinical Endocrinology & Metabolism https://doi.org/10.1210/jc.2008-0255.
8. Siemienowicz KJ et al. 2019 Scientific Reports https://doi.org/10.1038/s41598-019-56790-4.
9. Siemienowicz KJ et al. 2022 Biomedicines https://doi.org/10.3390/biomedicines10061291.
10. Joham AE & Teede HJ 2022 Nature Reviews Endocrinology https://doi.org/10.1038/s41574-022-00636-z.