Is PCOS Genetic?

Polycystic ovary syndrome is a common endocrine disorder that affects people assigned female at birth. PCOS often seems to run in families, so one question that is often asked is whether PCOS is, in fact, genetic. If so, what kind of genetic factors affect it, and how is it inherited?

What is PCOS?

Polycystic ovary syndrome is an endocrine disorder that causes significant imbalances in reproductive hormones, among others. This results in reduced fertility, weight gain, elevated androgens (male sex hormones), and a high risk of insulin resistance, which can turn into diabetes. 

Patients with PCOS have multiple cysts on the ovaries caused by egg cells not properly maturing and being released into the fallopian tubes.

Who can get PCOS?

Anyone with working ovaries can get PCOS, meaning that it primarily affects cis women of reproductive age but can also affect trans men and nonbinary individuals assigned female at birth. The main risk factors for PCOS include obesity, premature adrenarche, and having a family history of PCOS.

How common is PCOS?

PCOS is reported to affect between 8 and 13% of women of reproductive age in the US using the 2003 Rotterdam criteria. There is some variance as there are different diagnostic criteria. Many cases go undiagnosed or are only discovered when the patient attempts to become pregnant.¹

Symptoms and causes

The symptoms of PCOS are highly variable and can be different for different individuals. The common symptoms include:

• Irregular or absent periods

• Infertility

• Hirsutism (excessive hair growth, usually on the face, chest, back, or buttocks)

• Weight gain

• Male pattern baldness

• Oily skin

• Acne

Scans of the ovaries may or may not show the characteristic cysts. Many people with PCOS also show signs of insulin resistance, which can turn into diabetes.

The root causes of PCOS remain poorly understood. For example, it is unclear whether insulin resistance is a symptom of PCOS or a cause. Obesity is also complicated, as PCOS often leads to weight gain. However, there’s ample evidence to support intrinsic issues with the ovaries.

Having a family member with PCOS increases your risk of PCOS, and it is thought to be inherited as a common complex disorder with multiple involved genes.

Is PCOS hereditary?

Yes and no. PCOS sometimes runs in families, but it can also appear in individuals with no family history of the disease. Because of this, a lot of work is being done to try and establish genetic causes of PCOS. 

Studies on twins have established the heritability of PCOS to be around 70%, indicating that most PCOS risk stems from genetic factors.²

A recent review highlighted different genes and their correlation with PCOS. However, it was not in-depth, and correlation does not always indicate causation. The study showed no less than 241 gene variations that could be associated with PCOS. This could indicate that the uncertain heredity is because PCOS is a polygenic trait that is also affected by lifestyle and the environment.³

In plain English, you may get PCOS if you have multiple variants in genes and an unhealthy lifestyle or different environmental factors. This might indicate that individuals with a family history of PCOS should be particularly careful to follow healthy lifestyle guidelines such as eating well and staying active.

It's also likely that there are multiple genetic causes of PCOS and even possible that there is no one cause of the syndrome. The associated gene variations affect a variety of things. However, most of the genes found are defects in receptors that work with androgens, luteinizing hormone, follicular stimulating hormone, and leptin. All of these can be out of balance in PCOS. An imbalance in luteinizing hormone or follicular stimulating hormone explains anovulation and the development of cysts. Another defect was found affecting the pituitary gland.

This shows that there are multiple possible pathways through which PCOS can develop and an individual may have any number of these genes.

Furthermore, Genome-wide Association Studies (GWAS) have established more tangible loci as associated with PCOS. These include genes for the LH/hCG receptor as well as SNPs for THADA, which is also associated with impaired beta cell function.⁴ ⁵

Another possible pathway for hereditary PCOS is epigenetic changes. Epigenetic changes occur when genes are altered in vivo. They explain, for example, the fact that equine clones often have different facial markings from their donors.⁶

In PCOS, as many as 70% of the female offspring of people with PCOS also develop it, which is not fully explained by genetic susceptibility.

Some studies have shown that adipose tissue epigenetic dysfunction may explain insulin resistance in PCOS. There's also evidence that demonstrates resistance to FSH at a follicular level, caused by the excessive levels of anti-Müllerian hormone in individuals with PCOS.⁷

Genes potentially associated with PCOS

The following genes show a correlation with PCOS:

1. Androgen receptor gene (AR). This is a gene on the X chromosome, and disruption would alter androgen signaling and may result in elevated levels.

2. Follicular stimulating hormone receptor (FSHR). This gene encodes a protein that plays a role in gonad development. If mutated, it can affect levels of FSH and reproductive function.

3. Fat mass obesity (FTO). This gene is also known as alpha-ketoglutarate-dependent dioxygenase. It is associated with obesity and type 2 diabetes. Affected individuals have difficulty controlling weight.

4. CAPN10. Also known as calcium-dependent cysteine proteases. Associated with type 2 diabetes and potentially type 1 diabetes. Abnormality here causes insulin resistance.

5. A variety of aromatase genes, which play a role in steroid conversion. These genes convert androgens to estrogen, so if they are faulty, this may result in higher androgen and lower estrogen.

6. CYPA1A, which encodes cytochrome P450 proteins that are present in the endoplasmic reticulum. CYP P450 is a superfamily of enzymes, and some, like CYPA1A, are tasked with detoxification, and thus a mutation may result in increased toxin levels and possibly associated cysts.

7. CYP11A1, which codes for cholesterol side-chain cleavage enzyme that catalyzes cholesterol to pregnenolone. Polymorphisms of the gene have been shown to increase androgen levels by altering luteinizing hormone levels.

8. CYP11B2, which codes for aldosterone synthase, is involved in the biosynthesis of aldosterone. Polymorphisms of the promoter of the gene may be associated with elevated levels of aldosterone and testosterone seen in the context of PCOS.

9. CYP17A1, polymorphisms of which have been associated with weight gain and insulin resistance in the context of PCOS.

10. CYP1A1 is another CYP tasked with the metabolism of various endogenous agents as well as xenobiotics and drugs. CYP1A1 variants with high isoleucine/valine balances were associated with PCOS in different studies.

11. CYP3A7, which is mainly expressed in the liver, plays a major role in the metabolism of pharmaceuticals. Polymorphisms of this gene have been shown to confer a protective benefit on PCOS with decreased androgen levels and lessened androgenic phenotypes.

12. CYP19A1, i.e., aromatase is responsible for a key step in estrogen metabolism. Thus, polymorphisms have been associated with PCOS, among other diseases.

There may be a lot more genes that are associated, and it is likely there is no one genetic cause of PCOS. There is currently no "genetic test for PCOS," but as more research is done, it is possible that individuals with PCOS may be tested for certain genes to determine the specific cause of their PCOS and develop more personalized treatments.

Is PCOS linked to other health problems?

PCOS is strongly associated with insulin resistance, and drugs used for diabetes, particularly metformin, are sometimes also prescribed to treat PCOS. The argument about whether the reproductive hormone disruption causes insulin resistance or vice versa may turn out, based on the known genetic factors, to be a non-argument.

That is, for some people with PCOS, the problem may start with hormonal imbalances, while for others, insulin resistance may come first. 

Regardless, if you have PCOS, you should monitor your blood sugar carefully as your risk of developing diabetes is very high.

People with PCOS who become pregnant are also at higher risk of gestational diabetes, which can lead to type 2 diabetes for both individuals. People with PCOS are also at higher risk of:

• Heart disease

• High blood pressure

• High cholesterol

• Sleep apnea, which can also increase the risk of both heart disease and type 2 diabetes

• NAFLD

• Depression

• Endometrial hyperplasia/cancer

The connection with mental health issues is also poorly understood and may be at least partly linked to the stigmas related to infertility and symptoms that change appearance, such as acne and excessive hair growth.

Managing PCOS can reduce your risk of developing these other conditions as well as increase your chances of successful conception and pregnancy and reduce symptoms associated with PCOS.

When to see a doctor

As of right now, there is no one approved genetic test for PCOS. However, if you have symptoms of PCOS, you should talk to your doctor. You should also consider talking to them if you are assigned female at birth and your mother had PCOS, due to the strongly elevated risk. PCOS cannot be cured, but it can be managed and treated.

While many people with PCOS have symptoms, others do not find out until they attempt to get pregnant.

The lowdown

PCOS is a complex condition with multiple causes that remain poorly understood. While there is genetic susceptibility, there is no one genetic marker that can be used to screen for PCOS. 

Both genetic and environmental factors appear to contribute to the development of the disease. This means that genetic testing for PCOS is unlikely to be of use, although testing for specific genes that may affect the way it manifests might allow for more personalized treatments in the future.

However, there are hereditary risk factors for PCOS that can increase your risk if other members of your family have the condition.