What is polycystic ovary syndrome?

What is polycystic ovary syndrome?

Polycystic ovary syndrome (PCOS, polycystic ovary syndrome) is a condition that can occur at all stages of a woman's life. It is worth noting, however, that the full clinical picture is observed in women during their reproductive years. At this stage, PCOS can lead to ovulation disorders, excess androgens and fertility problems. It is estimated that 6-13% of women of reproductive age struggle with PCOS.

The proper functioning of the mechanisms responsible for the maturation of the ovarian follicle and its ovulation depends on the correct physiological activity of three organs:

• the hypothalamus
• the pituitary gland
• the ovaries

The mechanisms of hormonal regulation in the hypothalamic-pituitary-ovarian system operate through negative feedback axes. This means that if one of the hormones regulating the activity of the next one (e.g. a hormone from the hypothalamus) begins to be secreted, then the final hormones of the pathway (e.g. from the ovaries) will act to lower the first hormone of the pathway (the one from the hypothalamus). The concentration of hypothalamic hormones will drop, which will cause limited secretion of hormones by the pituitary gland, which in turn will result in a low level of hormones from the ovaries, which will no longer be able to block the hypothalamic hormones. At this point the hypothalamus again begins to secrete the hormones that start the pathway, and the whole mechanism runs anew.

The hypothalamus is located inside the cranial cavity. It is responsible for releasing hormones that govern the activity of the pituitary gland. These are liberins (which stimulate the pituitary gland - the secretion of hormones) and statins (which inhibit the pituitary gland - they suppress the secretion of hormones).

The pituitary gland is a gland located inside the cranial cavity. Its work consists of secreting hormones that release the hormones sent by the hypothalamus. The anterior lobe of the pituitary gland is responsible for producing hormones - prolactin, somatotropin and other tropic hormones (luteotropin - LH and follicle-stimulating hormone - FSH), which regulate the secretion of subsequent organs.

The hypothalamic-pituitary-ovarian axis begins its cycle in the hypothalamus, which secretes gonadoliberin. This hormone stimulates the anterior lobe of the pituitary gland to secrete luteotropin (LH) and follicle-stimulating hormone (FSH). These hormones stimulate the ovaries to produce sex hormones - estrogens, progesterone and testosterone. The increased concentration of hormones produced by the ovary, in accordance with the action of negative feedback, inhibits the secretion of gonadoliberin as well as LH and FSH.

Gonadoliberin (hypothalamus) is a hormone secreted in a pulsatile rhythm, and the frequency of this rhythm determines the type of gonadotropin released (pituitary gland). A low frequency of gonadoliberin pulses causes secretion of follicle-stimulating hormone (FSH), while a high frequency causes secretion of luteinizing hormone (LH).

LH is responsible for the luteinization of the corpus luteum, which, as a result of transformations, begins to produce progesterone. In turn, FSH stimulates the maturation of ovarian follicles and the secretion of estrogens. FSH also increases the activity of the enzyme responsible for the conversion of androgens (testosterone and androstenedione) into estrogens. When the concentration of the hormone LH rises in relation to FSH, an excessive production of androgens occurs, which is more common in women with PCOS.

Adipose tissue itself in excessive amounts is also capable of secreting hormones such as resistin and leptin as well as pro-inflammatory cytokines. The action of leptin affects the function of the hypothalamic-pituitary-ovarian axis by modifying the secretion of gonadotropins: LH and FSH. This can cause excessive synthesis of androgens. Adipose tissue, capable of secreting pro-inflammatory cytokines, contributes to the development of inflammation in PCOS and to an increased amount of free radicals caused by hyperglycemia. Excess adipose tissue and androgens contribute to the formation of chronic inflammation in PCOS.

Polycystic ovary syndrome criteria

For women of reproductive age, diagnosis is recommended based on the presence of 2 out of 3 of the following symptoms:

• absent or infrequent menstruation
• clinical and/or biochemical signs of excess androgens
• polycystic ovarian morphology on ultrasound examination

An abnormal ovarian image on ultrasound is characterized by an increased ovarian volume > 10 ml and/or additionally the presence of a minimum of 12 follicles in the ovary. Such cut-off values are adopted for women aged 18-35 years.

To establish a diagnosis of PCOS in young women, it is necessary to confirm:

• irregular menstruation - especially infrequent menstruation, secondary and primary amenorrhea. Irregular menstruation occurs in 93% of women with PCOS
• hyperandrogenism - biochemical or clinical (progressive hirsutism)

In addition, the symptoms should persist for at least two years after the first menstruation. If the symptoms last for a shorter time, only a diagnosis of the risk of developing PCOS is suggested, in order to avoid a false-positive diagnosis. Moreover, helpful in the diagnosis, but not mandatory for making the diagnosis, is the finding on ultrasound examination of the lesser pelvis of ovaries with a polycystic structure (PCOM) as well as cystic acne.

Risk factors for the development of PCOS in a young woman include:

• premature menstruation

• premature onset of pubic hair

• low birth weight

• obesity

In the diagnosis of adolescent girls, it should be noted that in the first year after the onset of the first menstruation irregular bleeding occurs in 35% of girls. In the first year after the onset of menstruation, bleeding more frequent than every 20 days or less frequent than every 90 days is considered abnormal and requiring diagnostic evaluation. Two years after the first bleeding, cycles in most girls last from 20 to 45 days. In subsequent years, however, bleeding more frequent than every 20 days or less frequent than every 45 days is considered irregular menstruation.

In the diagnosis of PCOS it is recommended to determine:

• sex hormone-binding globulin (SHBG)
• testosterone
• free testosterone
• androstenedione
• 17-hydroxyprogesterone
• dehydroepiandrosterone sulfate (DHEAS)

Polycystic ovary syndrome symptoms

Not every woman struggling with PCOS will experience all the symptoms. Each symptom may occur with varying intensity. Some women will notice in themselves menstrual problems or problems with becoming pregnant.

Among the most common symptoms are:

• irregular menstruation or absence of menstruation
• difficulty becoming pregnant (due to irregular ovulation or lack of ovulation)
• increased hair growth in the areas of the face, chest, back or buttocks (hirsutism)
• weight gain
• hair loss
• oily skin or acne

Polycystic ovary syndrome - what types do we distinguish?

Currently, 3 phenotypes of PCOS are distinguished.

Metabolic phenotype

This type of PCOS occurs most frequently. It is dominated by disorders accompanying abdominal obesity. Women with this phenotype struggle with fertility disorders, hyperandrogenism and an abnormal ovarian ultrasound image. The main cause of metabolic disorders is considered to be abdominal obesity, which occurs in 50-80% of women with PCOS. Insulin resistance has been demonstrated in 40-70% of women with PCOS and it is present both in women with abnormal and normal BMI. In these women, abnormal fat storage is found not only in adipose tissue but also in muscles or the liver, as well as an increased amount of fat within the abdominal cavity, which is the cause of insulin resistance.

In about 70% of women with PCOS there are lipid metabolism disorders, which manifest as elevated triglycerides and reduced protective HDL cholesterol. Adipose tissue in women with PCOS shows larger dimensions and increased production of pro-inflammatory factors. This causes in them a greater intensity of insulin resistance than in healthy women with the same BMI. In addition, it has been noted that women with PCOS show an increase in the production of free radicals.

Hyperandrogenic phenotype

In this type of PCOS, symptoms of clinical and biochemical hyperandrogenism are dominant. As in the phenotype above, they may be accompanied by a fertility disorder, an abnormal ovarian ultrasound image and metabolic disorders. In about 46% of women with PCOS with clinical features of hyperandrogenism, hyperandrogenemia occurs, that is, an elevated concentration of total testosterone and a free androgen index (FAI) above 5.

Reproductive phenotype

In this phenotype, the main symptom is irregular menstrual bleeding with ovulation disorders or lack of ovulation. The concentration of total testosterone is within the normal range; sometimes a slightly elevated FAI value is found. In this phenotype neither hirsutism nor acne is found, but some cases may show overweight or obesity.

Polycystic ovary syndrome causes

There are 4 main causes of PCOS:

• disorders of the hormonal synthesis of LH and FSH
• the appearance of insulin resistance
• the influence of the existing excess adipose tissue
• changes in the metabolic pathways involved in PCOS

Excess adipose tissue is involved in the development of PCOS in many ways. Adipose tissue cells are capable of secreting hormones such as resistin and leptin, and they can also secrete pro-inflammatory cytokines.

Polycystic ovary syndrome is a disease caused by many genetic and environmental factors. The most recognized theory of the development of PCOS involves disorders of intrauterine development, low birth weight, premature development of sexual hair, an increased risk of obesity, which in turn may contribute to the development of metabolic syndrome, cardiovascular complications and type 2 diabetes.

It is emphasized that a key role in this chain of events is played by insulin resistance and hyperinsulinemia.

Among the environmental factors, advanced glycation end products (AGEs, advanced glycation end products) are mentioned. Their high concentration in the body is observed in women with PCOS regardless of body weight. Grilling, baking and frying are the cause of the formation of advanced glycation end products. Their concentration in the body is also associated with a diet rich in protein and low in carbohydrates. In women with PCOS, the presence of AGEs and their receptors was observed in the layer of thecal and granulosa cells of the ovary.

Another significant factor is endocrine disruptors (EDC, endocrine disruptors). Their main representative is bisphenol A (BPA, bisphenol A). BPA is commonly used as an additive in cosmetics, food packaging and many others. BPA is a compound that causes disruption of the body's functioning, leading to hormonal disorders of many glands.

Known risk genes for developing PCOS account for less than 10% of the heritability of PCOS.

Polycystic ovary syndrome and insulin

Insulin affects the pathogenesis of PCOS both directly and indirectly. Insulin acts synergistically with LH, increasing the production of androgens and reducing the hepatic synthesis of the main testosterone-binding protein (SHBG), which causes testosterone to circulate in an unbound, active form.

Weight gain mediates most of the disease consequences through a deterioration of insulin sensitivity. In the mutual relationship between body weight and insulin resistance, inflammatory pathways act as mediators.

Insulin resistance has been demonstrated in 40-70% of women with PCOS, and it was present both in women with elevated and normal BMI.

Gut microbiota disorders in PCOS

The microbiome, through its metabolites, has a complex influence on appetite, the metabolism of fats and carbohydrates, and can affect body weight. The gut microflora can regulate about 10% of the host's genes, which are involved in the immune response or metabolism. It has been shown that dietary fiber modulates the gut microflora in patients with type 2 diabetes. An increase in Bifidobacteria correlates with insulin secretion and increased glucose tolerance, regulates insulin resistance and helps reduce inflammation.

In turn, the metabolites of gut bacteria - short-chain fatty acids - affect glycemia through certain gut hormones. In addition, these hormones can favorably influence the feeling of satiety. Due to the significant role of the metabolites of gut bacteria - short-chain fatty acids - ensuring good condition of the microbiome is one of the therapeutic goals in combating inflammation.

How to treat polycystic ovary syndrome?

Metabolic phenotype

In the case of PCOS, the main recommended intervention is a change of lifestyle and reduction of body weight. A reduction at the level of 5-10% significantly affects the sensitivity of tissues to insulin.

Unfortunately, only 15% of women manage to maintain the effect of body weight reduction. Therefore, in order to achieve a long-term effect, treatment with metformin is introduced.

Metformin lowers glucose production by the liver, increases the sensitivity of muscles to insulin, improves the peripheral uptake and use of glucose, and also delays its absorption in the intestines. Metformin is proposed as a first-line drug in coexisting diabetes and as a drug supporting lifestyle modification in accompanying glucose intolerance, insulin resistance or heart function disorders.

Metformin in women struggling with PCOS also shows a positive effect on lipid metabolism, leading to a decrease in the concentration of total cholesterol, triglycerides and the LDL cholesterol fraction.

Apart from its effect on metabolic parameters, metformin also modifies the hormonal balance, causing an increase in estrogen secretion, a decrease in androgen production and an increase in SHBG production. This leads to a decrease in the concentration of androgens.

Therapy with metformin leads to easier reduction of adipose tissue, a decrease in BMI and an increase in the number of menstrual cycles.

Hyperandrogenic phenotype

It should be noted that metformin is not a first-line drug in intensified clinical hyperandrogenism. In this case, beneficial effects are observed when metformin is administered in combination with low-dose contraceptive therapy. Metformin is also not a first-line preparation in the treatment of irregular menstrual cycles, hyperandrogenization and infertility in women with PCOS.

In the treatment of the hyperandrogenic phenotype of PCOS, contraceptive drugs are recommended. Most often they are used in the form of tablets, a patch or a vaginal ring. The effect of such treatment is the occurrence of regular monthly bleeding with a reduction in its abundance. The first effects in blood parameters are visible after three months of treatment, while clinical effects are most often observed after six months.

The estrogen component of the contraceptive pill increases the concentration of SHBG, and the progestogen (synthetic progesterone) inhibits the secretion of LH. In addition, the progestogen has a strong antiandrogenic effect.

Reproductive phenotype

In the reproductive phenotype, the goal of treatment is the restoration of ovulation. In obese women, reduction of body weight through a change of lifestyle and diet is recommended. Cessation of tobacco smoking is also recommended. The next step is the induction of the secretion of follicle-stimulating hormone (FSH), which is necessary for the growth of the follicle. The first-line drug is clomiphene citrate.

Polycystic ovary syndrome diet

Lifestyle changes are the first line of defense in PCOS, but they will not replace pharmacological treatment. Prevention and treatment through a change of lifestyle include:

• regular physical activity
• maintaining a normal body weight
• introducing proper eating habits
• avoiding cigarette smoking

The most important change will be the introduction of caloric restriction in order to reduce body weight. Low-GI diets lowered HOMA-IR, fasting insulin levels, total and LDL cholesterol concentrations, triglycerides and total testosterone concentration compared to high-GI diets.

A very important aspect of the diet of people with PCOS is limiting the consumption of saturated fatty acids. These are fatty acids that can cause inflammation in the body. Saturated fatty acids are present in products such as butter, fatty meat or confectionery.

It has also been shown that in the diet of women with PCOS a very important aspect will be the share of soluble dietary fiber. This fraction of fiber is present in fruits, oatmeal, whole-grain bread or legume seeds. This type of fiber has a beneficial effect on the gut microbiome and increases the production of its metabolites - short-chain fatty acids.

Herbs

A properly balanced diet supports insulin management, while it has been shown that in PCOS an important complement to therapy may be drinking infusions of aloe, cinnamon, green tea or chamomile, as well as white mulberry.

There are also medicinal herbs that can affect the lipid profile, blood glucose levels and insulin resistance. Due to their ability to regulate lipid and carbohydrate metabolism, these herbs can be used by all phenotypes of women with PCOS, e.g. marjoram.

Women with PCOS who have biochemically elevated androgen levels can also incorporate spearmint into their diet, which has an antiandrogenic effect and restores the development of follicles in the ovarian tissue. An important addition to the diet will also be flaxseed, which is rich in lignans. Flaxseed can change the activity of key enzymes involved in the synthesis of estrogen (e.g. aromatase) in order to modulate the relative levels of circulating sex hormones and their metabolites.

Turmeric, and specifically its biologically active component - curcumin - is an effective reducer of complications associated with oxidative stress in patients with PCOS. Nettle is also a herb with anti-inflammatory properties. The flavonoids present in nettle are a family of compounds with antioxidant action, which can modify certain enzymes, giving the possibility of inactivating, for example, hydroxyl radicals.

In the diet of patients with PCOS and excess body weight, it is worth considering the inclusion of herbs with a protective effect on the liver. These substances can be found in milk thistle, artichoke extract, dandelion or black cumin.

Physical activity

Regular physical activity intensifies the effect of insulin sensitivity by optimizing the transport and metabolism of insulin. Vigorous aerobic exercise and resistance training in order to improve insulin sensitivity and androgen concentrations are justified in women with PCOS. The minimum aerobic activity per week should amount to 120 min.

Sleep

Also an important intervention in the context of treating PCOS is ensuring an appropriate amount of sleep. Lack of sleep is associated with an increased risk of insulin resistance, obesity and type 2 diabetes. Sleep fragmentation can lead to a disruption of the epithelial barrier of the large intestine, which leads to inflammation. Thus, the metabolic changes caused by sleep fragmentation may be partly due to changes in the gut microflora.

The main hormone of the pineal gland, melatonin, participates in the regulation of the circadian rhythm. Patients with PCOS show a lower level of melatonin. Melatonin receptors in the ovary and in the intrafollicular fluid regulate the secretion of sex hormones in various phases of the maturation of ovarian follicles. In addition, melatonin is a strong antioxidant that protects the ovarian follicles during maturation.

Untreated polycystic ovary syndrome

PCOS is associated with an increased risk of metabolic complications from the earliest years. Diseases that often coexist with PCOS are risk factors for cardiovascular diseases. Among them are:

• obesity
• impaired glucose tolerance
• type 2 diabetes
• dyslipidemia
• hypertension

The risk of obesity in women with PCOS was 4 times higher compared to healthy individuals. A higher risk is observed in white women. The risk of impaired glucose tolerance is 3 times higher in the case of PCOS, regardless of BMI. Dyslipidemia, whose picture is a high level of triglycerides and a low level of HDL cholesterol, is the most common metabolic abnormality detected in PCOS.

Among women with PCOS, 50-80% are obese women, 30-35% are women with impaired glucose tolerance, and 8-10% are people with diabetes or having a family history of diabetes.

The relationship between hypertension and PCOS is mixed. Most studies do not indicate a higher risk of arterial hypertension regardless of BMI, although some data show that even slim women with PCOS have elevated blood pressure. Women with PCOS have a 2 times higher risk of developing metabolic syndrome, which is a set of symptoms leading to more frequent cardiovascular diseases.

Furthermore, in PCOS there is a high risk of non-alcoholic fatty liver disease (NAFLD). Women struggling with PCOS usually have insulin resistance and obesity, which provides the background for NAFLD.

A serious problem is also endometrial cancer, which is reported with an unusually high frequency in women with PCOS.

Bibliography

Szczuko M. et al.: Nutrition Strategy and Life Style in Polycystic Ovary Syndrome-Narrative Review. Nutrients, 2021, 13(7), 2452

Hoeger K.M. et al.: Update on PCOS: Consequences, Challenges, and Guiding Treatment. J Clin Endocrinol Metab, 2021, 106(3):e1071-e1083

Milewicz A. et al.: The polycystic ovary syndrome: a position statement from the Polish Society of Endocrinology. the Polish Society of Gynaecologists and Obstetricians, and the Polish Society of Gynaecological Endocrinology, Endokrynologia Polska, 2018, 69(4): 328-344

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