Polycystic ovary syndrome
Polycystic ovary syndrome is the most common hormonal disorder in women of reproductive age. The name comes from the observation of small follicles that often appear on the ovaries. However, not everyone with PCOS has these follicles, and they are not the cause of the condition.
PCOS is diagnosed when a woman has at least two of the following three features: irregular menstrual periods, high testosterone or related symptoms, or polycystic ovaries found on an ultrasound. A blood test for high levels of anti-Müllerian hormone can replace the ultrasound in the diagnosis. Other symptoms associated with PCOS are heavy periods, acne, difficulty getting pregnant, and patches of darker skin.
The exact cause of PCOS remains uncertain. There is a clear genetic component, but environmental factors are also thought to contribute. PCOS occurs in between 5% and 18% of women. The disorder is linked to insulin resistance, which is made worse by obesity. Insulin resistance and related excess insulin levels increase the risk of complications such as type 2 diabetes and liver disease. Women with PCOS also have higher risk of endometrial cancer.
Management focuses on relieving symptoms and reducing long-term risks. A healthy lifestyle and weight control are recommended for general management. In addition, hormonal contraception can help to regulate menstrual cycles, to reduce acne and excess hair growth. Metformin, a common anti-diabetes drug, increases insulin sensitivity. For fertility, ovulation can be induced with letrozole, among other methods. In addition, women can be monitored for cardiometabolic risks, and during pregnancy.
Signs and symptoms
PCOS has a wide variety of signs and symptoms. They include issues with ovulation, excess levels of androgens, and metabolism. Symptoms usually start in puberty, but may be masked if oral contraceptives are started early.Common signs and symptoms of PCOS are:
- Irregular periods: periods may stop completely or may be less frequent. When they do happen, periods can be very heavy. There may be menstrual bleeding without ovulation too; around 40% of women with PCOS who have a regular cycle have periods without ovulation.
- Infertility: PCOS is one of the leading causes of infertility in women.
- A "male" pattern of hair growth, including hair on the chin, upper lip, chest, upper thighs and on the belly. This growth pattern, called hirsutism, is present in about 60% of women with PCOS.
- Acne: acne is typically severe, persists beyond adolescence, or continues despite standard treatment.
- Pattern hair loss, at the top of the scalp
- Skin issues, such as an oily skin or a condition where dark, thick, and "velvety" patches can form
Associated conditions
Women with PCOS have an increased risk of a range of metabolic, cardiovascular, reproductive and mental health conditions. The likelihood of developing metabolic disorders is about three to seven times higher than in women without PCOS. Insulin resistance is common, even in lean women with PCOS. Overweight or obese women with PCOS are at higher risk of type 2 diabetes than women without PCOS at the same BMI. Lean women with PCOS do not appear to be at higher risks of developing diabetes. Other metabolic and cardiovascular complications commonly associated with PCOS include:- Obesity: Across different cultures and ancestries, between 30% and 80% of women with PCOS are overweight or obese. There is marked weight gain between adolescence and adulthood, compared to those without PCOS.
- Dyslipidemia – disorders of fat metabolism such as cholesterol and triglycerides: in PCOS, levels of low-density lipoprotein cholesterol are often high, while high-density cholesterol levels are low.
- Metabolic dysfunction–associated steatotic liver disease, particularly if androgen levels are high
- High blood pressure
- Metabolic syndrome, which occurs in about 40% of women with PCOS
- Cardiovascular disease: women with PCOS have about a two-fold increased risk of strokes and coronary heart disease compared to women without PCOS who have similar BMI.
PCOS is associated with mental health-related conditions including depression, anxiety, bipolar disorder, and obsessive–compulsive disorder. Those with PCOS often report reduced quality of life due to excess body weight, and to a lesser extent due to hirsutism, infertility and menstrual cycles. In regions where infertility or hirsutism are stigmatised, the impact on mental health is more severe. Body image can be negatively affected and PCOS increases the risk of eating disorders, for instance binge eating. In addition, sexual wellbeing is often lower in women with PCOS.
Women with PCOS are about three times more likely to develop endometrial cancer than other women. This is linked to a lack of periods, and lower levels of sex hormone-binding globulin and progesterone. Women with PCOS more often have sleep apnea, particularly if obesity is present.
Cause
The root cause of PCOS is unknown. Risk factors include a family history of PCOS, early development of pubic hair and sweat gland development and obesity. A low birth weight, exposure to androgens in the womb, and exposure to hormone disruptors may also predispose people to developing PCOS.Genetics
PCOS has a clear genetic component and high heritability. Evidence of the genetic basis comes from family and twin studies, as well as from large genome-wide association studies. The correlation in PCOS occurrence between identical twin sisters was found to be twice as high as that between non-identical twins, suggesting a significant genetic influence. Twenty-five different genetic loci have been found to correlate with PCOS in genome-wide association studies, of which thirteen were replicated in at least one other study. Genes near some of these loci imply neuroendocrine and metabolic dysfunction, but the role of other genes is not yet clear.Men with a family history of PCOS also display some of the symptoms associated with the syndrome. For instance, brothers of women with PCOS show a higher likelihood of high AMH levels, insulin resistance and abnormal lipid levels in the blood. Men with the genetic risk factors associated with PCOS also have higher levels of obesity, type-2 diabetes, male pattern hair loss and cardiovascular disease. Not all similarities between family members are likely due to genetics, as PCOS and obesity in mothers can have an impact on fetal development, making it more likely for men to get metabolic disorders with age.
Mendelian randomization is a method in genetic epidemiology that seeks to identify causal relationships between risk factors and diseases. It uses the randomness of inheriting different genes to do so. Using Mendelian randomization, it was found that PCOS has causal links to sex hormone-binding globulin level, anti-Müllerian hormone level, menopause age, body fat percentage, insulin resistance, depression, breast cancer, ovarian cancer, obsessive-compulsive disorder, and lung capacity. Other factors do not seem causally linked: anxiety disorder, schizophrenia, type 2 diabetes, coronary heart disease, stroke, or birth weight.
Environment
PCOS may also be impacted by epigenetics, which regulates how active genes are. High levels of androgens and AMH during pregnancy and early weight gain can negatively impact the fetal environment. In studies of PCOS in mice, exposure to AMH or the androgen dihydrotestosterone, still has an effect three generations later. If that were the same in humans, it implies that PCOS can be inherited via epigenetic changes. Blood in the umbilical cord of babies whose mothers have PCOS show specific epigenetic changes suggestive of PCOS.There is little evidence on the effect of environmental pollutants on PCOS risk. Hormone disruptors are chemicals that disturb the hormonal system, by blocking or mimicking natural hormones. Of these, bisphenol A and phthalates and possibly octocrylene exposure may raise the risks of PCOS.
Obesity is implicated in PCOS development. As fat tissue can produce androgens, obesity leads to increased androgen levels. It also leads to suppression of the SHBG hormone, increased insulin resistance and abnormally increased insulin levels. Some of the effects go two ways: PCOS might impact appetite, so that weight gain becomes more likely. Weight loss using diet is equally effective in people with and without PCOS.
Mechanism
PCOS involves both hormonal and metabolic changes. Women with PCOS often have higher levels of androgens, mainly produced by the ovaries, as part of a disrupted hypothalamus–pituitary–ovarian axis. In the brain, the hypothalamus sends out gonadotropin-releasing hormone pulses with higher frequency. This raises luteinising hormone, while follicle-stimulating hormone stays the same or is slightly lower. The higher LH stimulates theca cells in the ovary to produce more androgens.The disrupted hormonal environment, including high levels of androgens, suppresses the growth and development of ovarian follicles. This leads to an accumulation of many small follicles, a feature referred to as polycystic ovarian morphology. The lack of ovarian follicle development also leads to a reduction in ovulation. Granulosa cells in these small follicles produce high levels of anti-Müllerian hormone, which reduces the conversion of testosterone to oestradiol.
Metabolic changes are common in PCOS. Many women develop insulin resistance, which causes the pancreas to produce extra insulin. High insulin levels reduce liver production of sex hormone-binding globulin, increasing free circulating androgens. Low-grade inflammation can worsen insulin resistance, creating a reinforcing loop between metabolic and reproductive disturbances. Insulin resistance is present not only in overweight women with PCOS, but also in lean women; however, obesity makes it worse.
PCOS is associated with cardiovascular and liver dysfunction. For instance, women with PCOS can have coronary and aortic calcification. Obesity, impaired glucose metabolism and excess androgens are all risk factors for liver dysfunction.