Clinical Context

Polycystic ovary syndrome (PCOS) is a common endocrine disorder worldwide, characterized by ovulatory dysfunction, hyperandrogenism, and polycystic ovarian morphology. PCOS diagnosis requires various combinations of these criteria.

Cross-sectional studies suggest differences in prevalence, hirsutism, and hyperandrogenemia among women with PCOS in different countries. There are also important global differences in metabolic risk for PCOS.

Study Synopsis and Perspective

Geographic location within the United States appears to have an effect on the specific symptoms of PCOS that any particular woman will develop, according to a new prospective cohort study.

Women in California were more likely to exhibit high levels of testosterone (hyperandrogenism), whereas women in Alabama with PCOS had more metabolic dysfunction and hirsutism.

And although the women in Alabama were younger and had a higher body mass index (BMI), even after adjusting for these factors, the clinical differences were still present between the geographic locations, the authors say.

"This study suggests there are regional differences in hormonal and metabolic parameters in women with PCOS in California and Alabama, highlighting the impact of differing genetic and environmental modulators on PCOS development," Katherine VanHise, MD, from Cedars-Sinai Medical Center, Los Angeles, California, and colleagues write in their article published online in the Journal of Clinical Endocrinology and Metabolism.

Genetic and Environmental Factors Play a Role

Prior research has looked at variations in symptoms of PCOS across countries and identified differences in hirsutism and its prevalence, which is greater in Middle Eastern, Mediterranean, and Indian women, noted senior author Margareta D. Pisarska, MD.

And women of some other backgrounds "are at increased risk of developing metabolic syndrome and insulin resistance, including South Asian, African, and Hispanic women, so they are at a greater risk trajectory of developing manifestations later on in life that can ultimately lead to adverse outcomes in overall health," Dr Pisarska, director of the division of reproductive endocrinology and infertility in obstetrics and gynecology at Cedars-Sinai, told Medscape Medical News.

"We do see regional differences in the diagnosis of PCOS [in the US] as well as the manifestations of PCOS including hyperandrogenemia, hirsutism, and metabolic parameters. . .and we need to better understand it because, at least in the entire population, weight was not the entire factor contributing to these differences," she explained.

"So there are definitely environmental factors and possibly genetic factors that we need to take into consideration as we try to study these women and try to help them decrease their risk of metabolic syndrome later in life," she noted.

Differences Not Attributable to Race Either

PCOS is a common endocrine disorder affecting women and female adolescents worldwide. Diagnosis usually requires at least 2 of the following to be present: ovulatory dysfunction, hyperandrogenism, and/or polycystic ovarian morphology.

Because of the prior work that had identified differences in symptoms among women with PCOS in different countries, the investigators set out to determine whether women of the same race would have distinct hormonal and metabolic traits of PCOS in 2 geographical locations in the United States, suggesting geo-epidemiologic contributors of the disease.

They evaluated 889 women at the University of Alabama at Birmingham and 721 at Cedars-Sinai Medical Center in California. Participants in Birmingham were a mean age of 28 years and had a mean BMI of 33.1 kg/m², a mean waist-to-hip ratio of 0.8, and a mean hirsute rate of 84.6%. Participants in California were a mean age of 29.5 years, had an average BMI of 30.1 kg/m², a mean waist-to-hip ratio of 0.9, and a mean hirsute rate of 72.8%.

The study team gathered data on menstrual cycle history, metabolic and hormonal parameters, and demographic data for each participant. They assessed hirsutism based on modified Ferriman-Gallwey scores of 4 or more. Patients were classified as having hyperandrogenemia if they had elevated androgen values greater than the 95th percentile of all values or androgen values that exceeded laboratory reference ranges.

The findings showed that Alabama women with PCOS had elevated homeostatic model assessment for insulin resistance scores (adjusted beta coefficient, 3.6; P<.001) and were more likely to be hirsute (adjusted odds ratio, 1.8; P<.001), after adjustment for BMI and age, than those in California.

In contrast, women with PCOS in California were more likely to have elevated free testosterone and total testosterone values than women in Alabama (both P<.001). These findings persisted after adjusting for age and BMI.

When stratified by White race, these findings were similar. Notably, BMI and waist-to-hip ratio did not vary between regions in Black women with PCOS, although variations in metabolic dysfunction and androgen profiles persisted.

"This study supports regional differences in hormonal and metabolic parameters in women with PCOS in the United States, highlighting the impact of the environment on PCOS phenotype. . . .[i]ndividuals of the same race in different geographical locations of the United States may have differing genetic predispositions for developing diseases such as PCOS," the researchers say.

"Ongoing research is needed to identify modifiable environmental risk factors for PCOS that may be race and ethnic specific to bring precision medicine to the management of PCOS," they conclude.

This work was supported in part by grants from the National Institutes of Health and an endowment of the Helping Hand of Los Angeles. Dr VanHise has reported no relevant financial relationships.

J Clin Endocrinol Metab. Published online October 11, 2022.^[1]

Study Highlights

• This prospective cohort study at Alabama and California tertiary-care based specialty clinics in enrolled women with PCOS by National Institutes of Health criteria from 1987 to 2010.
• Alabama participants (n=889) had mean age 28 years, BMI 33.1 kg/m², waist-to-hip ratio 0.8, and hirsute rate 84.6%.
• For California participants (n=721), these values were 29.5, 30.1 kg/m², 0.9, and 72.8%, respectively.
• Participants underwent interview, physical examination, and laboratory studies to determine demographics, menstrual history, and hormonal and metabolic parameters.
• Hirsutism was defined as modified Ferriman-Gallwey scores of at least 4, and hyperandrogenemia as androgen values greater than laboratory reference ranges or higher than the 95th percentile of all values.
• Alabama women with PCOS were younger and had a higher BMI.
• After adjustment for age and BMI, Alabama women with PCOS were more likely hirsute (aOR, 1.8; 95% CI, 1.4-2.4; P<0.001), with elevated HOMA-IR scores (8.25±8.15 vs 3.37±8.60; adjusted beta coefficient, 3.6; 95% CI, 1.61-5.5; P<0.001).
• California women with PCOS were more likely to have hyperandrogenemia (free testosterone aOR, 0.14 [95% CI, 0.11-0.18; P<0.001]; total testosterone, 0.41 [95% CI, 0.33-0.51; P<0.001]) and elevated DHEA-S (aOR, 0.07; 95% CI, 0.05-0.09; P<.001).

Figure. Regional Differences in PCOS Symptoms

DHEA-S, dehydroepiandrosterone sulfate; HOMA-IR, homeostatic model assessment for insulin resistance; PCOS, polycystic ovary syndrome.

• White women had similar results.
• Among Black women, BMI and waist-to-hip ratio were similar between locations, but androgen profiles and metabolic dysfunction differed between locations, as in the total cohort.
• The investigators concluded that regardless of race, Alabama women with PCOS were more likely hirsute with metabolic dysfunction, whereas California women with PCOS more likely had hyperandrogenemia, even after adjusting for age and BMI.
• These regional differences in hormonal and metabolic parameters in women with PCOS highlight the effect of differing genetic and environmental modulators on PCOS development.
• To bring precision medicine to PCOS management, ongoing research is needed to identify modifiable environmental risk factors for PCOS that may be race- and ethnic-specific.
• In a genetically predisposed person, environmental exposures as early as in utero may trigger development of clinically evident PCOS.
• Lifetime exposures that may modulate PCOS development and progression include geography, diet and nutrition, socioeconomic status, and environmental toxins.
• Genetic ancestry of same-race individuals also varies by US region because of various degrees of admixture of Native American, European, and African gene pools.
• For example, the gene SRD5A1 encodes the 5α-reductase type 1 enzyme, which converts testosterone to dihydrotestosterone, a more potent androgen implicated in PCOS pathogenesis.
• The finding that Alabama women were more likely hirsute than California women, despite less hyperandrogenemia, suggests differential impact of genes such as SRD5A1 between these locations.
• Food-purchasing habits and typical diets differ in California and Alabama, and starch-based foods, dairy products, and whey protein all negatively affect metabolic sequelae of PCOS.
• Several environmental exposures differ between the 2 geographical locations in this study: Los Angeles County, California, has greater population density, more unhealthy Air Quality days per year, and larger amount of toxic releases per square mile, than Jefferson County, Alabama.
• Bisphenol A (BPA) and vitamin D are both specific environmental factors affecting PCOS: BPA exposure can contribute to elevated androgen levels in women with PCOS, and vitamin D-deficient vs vitamin D-sufficient women with PCOS are more likely to have dysglycemia. Study limitations include possible selection bias and use of National Institutes of Health criteria for PCOS diagnosis, limiting generalizability to women with PCOS phenotypes reliant on ultrasound findings.

Clinical Implications

• Regardless of race, Alabama women with PCOS were more likely hirsute with metabolic dysfunction, whereas those in California more likely had hyperandrogenemia, even after adjusting for age and BMI.
• Regional differences in hormonal and metabolic parameters highlight the effect of differing genetic and environmental modulators on PCOS development.

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