PCOS Across the Lifespan
By Carrie Dennett, MPH, RDN
Today’s Dietitian
Vol. 25 No. 5 P. 26

New findings lend insight into the disorder’s causes and its effects on puberty and postmenopause.

Polycystic ovary syndrome (PCOS) is a complex neuroendocrine, reproductive, and metabolic disorder that affects as many as 15% of females of reproductive age, although estimates vary. It’s the main cause of female infertility worldwide and the most common endocrine disorder in females. It’s also associated with increased risk of type 2 diabetes and CVD—risks that may persist postmenopause.

PCOS involves a combination of signs and symptoms that can vary from patient to patient. However, it has three primary clinical features: hyperandrogenism, menstrual irregularities due to ovulatory dysfunction (oligo-ovulation or anovulation), and polycystic ovaries. The “polycysts” are small, immature ovarian follicles that high levels of testosterone and other androgens prevent from growing and maturing. The 2018 International Guidelines for the Assessment and Management of PCOS recommends the use of the 2003 Rotterdam diagnostic criteria, which require the presence of at least two of those three clinical features.1,2 This creates the following four PCOS phenotypes:

• Phenotype A, which includes all three clinical features;

• Phenotype B, which includes hyperandrogenism and ovulatory dysfunction;

• Phenotype C, which includes hyperandrogenism and polycysts; and

• Phenotype D, which includes ovulatory dysfunction and polycysts.

Females with phenotypes C and D tend to be leaner than those with phenotype B. Meanwhile, some studies have found no metabolic abnormalities, such as insulin resistance or dyslipidemia, in those with phenotype D compared with a control group of reproductively normal females.3 Unfortunately, most evidence in the evidence-based guidelines is rated as “low” or “very low” due to a scarcity of randomized controlled trials or high-quality observational trials. Even official diagnostic criteria are based on expert opinion.3

Origins of PCOS
The underlying cause of PCOS is unclear, but it’s thought that a combination of genetic and environmental factors may drive the condition. The good news is that the role of genetics and epigenetics in the onset and progression of PCOS is starting to explode, according to Angela Grassi, MS, RDN, founder of the PCOS Nutrition Center in Malvern, Pennsylvania, who points to a Swedish nationwide register-based study of nearly 30,000 daughters of women with and without PCOS that showed that daughters of women with PCOS had a five-fold greater risk of being diagnosed with the disorder.4

Advances in genetic analysis have increased the understanding of genetic variation in PCOS over the past decade.3 About 30 PCOS risk genes have been identified through genomewide association studies (GWAS), including some genes that regulate reproductive function and others that affect metabolic function. So far, these genetic findings account for only 10% of the observed heritability of PCOS, even though overall heritability is estimated to be 79%.5,6 It may be that GWAS-identified genetic variants are common among all females with PCOS yet have smaller effects, while other rare genetic variants—some of which have been identified—have a greater effect but are present only in specific subgroups of females with PCOS.3,5

Not all susceptibility to PCOS is inherited from genes themselves. Epigenetic changes—variations in gene expression beyond what’s encoded in DNA caused by addition or subtraction of a methyl group to DNA strands or by other chemical modifications—and developmental programming in the womb are other sources.5 “Emerging research in animal models shows PCOS could be caused by an alteration of DNA methylation that gets passed on through generations,” DeGrassi says. “A genomewide DNA methylation study on umbilical cord blood showed a prevalence of hypomethylation in women with PCOS.”7,8

During pregnancy, excess androgens or excess anti-Müllerian hormone (AMH)—which helps develop a fetus’ sex organs—in the mother may affect placental function and cause epigenetic changes in the growing fetus’ cells. This may predispose both female and male offspring to develop PCOS or PCOS-like phenotype changes that also may be passed along to the woman’s grandchildren.5

“Exposure to elevated androgen levels in utero has long been associated with fetal programming of PCOS,” DeGrassi says. “Exposure to high AMH levels in utero leading to PCOS is a more recent discovery.”4

Role of the Gut Microbiota
As research on the origins and development of PCOS evolves, the potential role of the gut microbiota has come into focus. The gut microbiota influences the intestinal environment in ways that can affect many parts of the body, which gives it endocrinelike functions.9 A few studies have observed differences in the diversity and composition of the gut microbiota in patients with PCOS when compared with healthy controls.9,10 Research suggests a possible bidirectional relationship between excess androgens and gut dysbiosis.11

“There’s so much information now about the role of the gut microbiome and PCOS,” DeGrassi says. “A correlation exists between high testosterone levels and less diverse gut bacteria. Probiotics have been shown to help lower testosterone, cholesterol, inflammation, and insulin in PCOS.”

Inflammation and oxidative stress are both associated with the development of PCOS. Inflammation caused by gut dysbiosis and a disrupted gut barrier can worsen PCOS symptoms and may be related to ovarian dysfunction.11,12 This can be worsened by advanced glycation end products (AGEs), which also may play a role in inducing the reproductive and metabolic changes detected in females with PCOS. The body produces AGEs, and they also can be consumed from food such as those high in fat and protein that are cooked at high heat.

AGEs circulating in the blood can cause cellular damage when deposited in tissues, and both AGE levels and proinflammatory AGE receptors in the ovaries are elevated in patients with PCOS.12

Bile acids are emerging as a key regulator of metabolic diseases, possibly including PCOS. Gut bacteria transform primary bile acids into secondary bile acids, which is noteworthy because alterations in gut microbiota composition and disruptions in secondary bile acid production seem to play a role in developing PCOS, DeGrassi says. Specifically, research is finding that women with PCOS tend to have elevated levels of primary bile acids and lower levels of secondary bile acids, conditions associated with elevated androgen levels and disruptions in glucose metabolism.11,13

How PCOS Presents in Adolescence
While elevated testosterone levels in females during puberty are expected, levels that remain elevated a few years after the first menstrual period may increase the risk of PCOS. Due to limited research and an overlap between PCOS symptoms and normal physiological changes that accompany puberty, diagnosis of PCOS in adolescent females is challenging.1,14

Menstrual irregularity is common in the first year or two following the first period.6 As a result, international evidence-based guidelines from 2017 and 2018 propose that PCOS shouldn’t be diagnosed until at least two years after the first menstrual period and that hyperandrogenism must be present in addition to irregular or absent menstrual cycles.1,15 Polycystic ovaries are so common in adolescent females that it’s not recommended as a diagnostic criteria until eight years after the first menstrual period.3 As in adult PCOS patients, hyperandrogenism may cause hirsutism—excessive growth of dark or coarse hair in a malelike pattern on the face, chest, and back—and severe acne that’s resistant to topical treatment.6,12

“It’s trickier to diagnose young girls with PCOS, as some symptoms may be seen as typical adolescent symptoms like acne and hair growth, even irregular periods,” DeGrassi says. “I do think overall, more girls are getting diagnosed with PCOS rather than not.”

A 2020 study hypothesized that in adolescent females who are predisposed to PCOS due to developmental programming—exposure to psychological distress or poor nutrition, and elevated levels of androgens or AMH while in utero—PCOS develops as a consequence of stress and mood disturbances together with metabolic disturbances that may arise from eating disorders, such as bulimia, and recurrent dieting.16

PCOS and Eating Disorder Risk
Despite many clinicians noticing connections between PCOS and eating disorders, there’s not much research on the topic. A 2019 meta-analysis of eight studies including 470 women with confirmed diagnoses of PCOS and 390 controls found that those with PCOS were three times as likely to have an abnormal score based on a validated eating disorder screening tool and almost four times as likely to have an eating disorder diagnosis.17

In one Australian study, women who reported receiving a diagnosis of, or treatment for, PCOS were more likely to report being diagnosed or treated for an eating disorder compared with females who didn’t report having PCOS. This association wasn’t true for anorexia or bulimia, but it was for the “other eating disorders” category, which included binge eating disorder.18

“Most people with PCOS who I have met are eating way too little and have been for years. Because they’re also in a higher weight body, they are told to eat less,” says Julie Duffy Dillon, MS, RDN, NCC, CEDS-S, PCOS specialist and host of the Find Your Food Voice podcast. “Typical eating disorder red flags like food preoccupation, slower heart rates, hair loss, and skipping meals go unnoticed. Binge eating can occur within any eating disorder, not just in binge eating disorder.”

Dillon says when clients with PCOS report bingeing, providers often assume they have a binge eating disorder and fail to order a full eating disorder workup.

The most common eating disorder she has seen in her clients with PCOS is atypical anorexia nervosa. The “atypical” description is used when clients are in higher weight bodies, but Dillon says this is a misnomer because most people diagnosed with anorexia are in higher weight bodies. After 20 years of working with people with eating disorders, she’s noticed a trend among those who also have PCOS: “They suffer much longer and aren’t given the same options for recovery.”

Dillon’s clients with PCOS and an eating disorder have been “trapped in the diet culture void” because weight loss diets routinely are prescribed for PCOS, yet eating disorder recovery requires lifetime abstinence from dieting. “Some people with PCOS will always need to be in a higher weight body in order for their body to function well and maintain recovery. Prescribing rigid calorie-controlled meal plans literally can be fatal for PCOS clients experiencing an eating disorder; it also prevents them from experiencing full recovery,” she says.

PCOS and Depression
In addition to eating disorders, females with PCOS are at increased risk of developing depression, anxiety, and other forms of psychological distress, including social fear.5,19 A 2018 position statement from the Androgen Excess—Polycystic Ovary Syndrome Society recommends that clinicians offer screening for anxiety and depression when diagnosing women with PCOS. Screening for disordered eating also is advised.20

Androgen levels can influence depression, and various studies have found that people with depression are more likely to be insulin resistant, a metabolic abnormality that lessens with recovery from depression. Some studies also have found elevated levels of the stress hormone cortisol—which facilitates deposition of fat in the abdominal region—in females with PCOS, and both depression and PCOS are associated with elevated levels of inflammatory markers.19

PCOS Postmenopause
PCOS is accompanied by several metabolic abnormalities caused by hyperandrogenism, including elevated insulin levels, insulin resistance, and dyslipidemia, which in turn increase the risk of type 2 diabetes, CVD, and gynecological cancers.5 However, there have been no adequately powered prospective studies to determine the long-term health effects of PCOS.3 For example, despite PCOS being associated with increases in multiple risk factors for CVD, no study has demonstrated an actual increase in cardiovascular events.3 A 2021 review found that the limited available data suggest that the risk of CVD in aging women with PCOS seems to be no different from those without PCOS and essentially lower than previously anticipated based on premenopausal risk.21

A recent study found that genetically determined PCOS didn’t appear to increase risk of coronary heart disease or stroke, but the risk may be elevated in females who develop PCOS—not because of genetics, but rather higher levels of testosterone or lower levels of sex hormone-binding globulin, a protein made in the liver that attaches to sex hormones in the blood and controls the amount that’s actively working in the body.3

“There’s not enough evidence to draw a conclusion,” DeGrassi says. “The research into cardiovascular health for PCOS is mixed. Certainly, PCOS is associated with risk factors for cardiovascular disease like dyslipidemia and insulin resistance, but we don’t know how these factors come into play in menopause. Current research does show an increased risk of type 2 diabetes later in life in PCOS patients.”

At present, there are no diagnostic criteria for PCOS after menopause. Ovarian polycysts generally don’t remain in menopause, but AMH remains elevated—something that DeGrassi says may be part of future diagnostic criteria—as do testosterone levels.21 In fact, testosterone levels may increase due to lower levels of estrogen and sex hormone-binding globulin. As a result, menstrual cycles tend to become more regular in perimenopause, DeGrassi says. It’s been suggested that women with PCOS may reach menopause two years late. Hyperandrogenism symptoms such as excess body and facial hair, acne, and hair loss persist in menopause for the majority of women.

Counseling Tips for RDs
Because of continued uncertainty about the origin of PCOS and the mechanisms that drive it—as well as a lack of robust clinical trials on nutrition and lifestyle interventions—medical management is based on symptoms.22 However, DeGrassi says new evidence-based guidelines expected to be released this year may offer guidance.

“A link between the impact of our environment on epigenetic and microbiome changes in PCOS exists yet remains unclear. Pollution, plastics, chemicals, all these endocrine disruptors affect sex hormones and fertility,” she says. “Until we have a clearer understanding of all of this, I do recommend dietitians provide an individualized approach with patients that focuses on lifestyle strategies to improve symptoms, fertility, and health. This includes nutrition, exercise, supplements, sleep, and stress management.”

A diet rich in plant foods may support healthy gut microbiota, but there’s no evidence-based “PCOS diet.” What’s routinely prescribed is weight loss—even for clients who have already tried many times to lose weight.

“We know through research that weight cycling predicts eating disorders for people with PCOS,” Dillon says. “Instead of teaching dieting and weight loss, dietitians need to teach people with PCOS how to avoid rigid eating behaviors and that the focus on the scale will only set them up for an eating disorder.”

Dillon encourages dietitians to not assume that they know how much a higher weight client with PCOS is eating or that they’re eating more than recommended. “When people with PCOS tell us the diets they have tried or the amount they eat, we need to believe them,” she says. “I usually meet with clients after they have seen many dietitians and doctors and they have taught me these health care experiences are traumatic and dismissive, and lead to health care avoidance.”

Dillon suggests dietitians start by asking clients with PCOS if they’re eating enough. “This simple question has turned out to be the most important question within my assessment,” she says. “When I ask clients with PCOS this question, they’re usually shocked then tearful. I almost always hear that no one has asked them this before because of their size.”

— Carrie Dennett, MPH, RDN, is the nutrition columnist for The Seattle Times, owner of Nutrition By Carrie, and author of Healthy for Your Life: A Non-Diet Approach to Optimal Well-Being.

 

References
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