In focus: Polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a prevalent and complex endocrine disorder affecting women of reproductive age. It is characterised by a combination of reproductive, metabolic, and hormonal disturbances, with significant variations in symptoms and severity among individuals. The global prevalence of PCOS has risen substantially throughout the years. It affects approximately 8-20 per cent of women of reproductive age worldwide and is considered a leading cause of infertility. Although the precise cause of PCOS remains unclear, research suggests that a combination of genetic, environmental, and lifestyle factors play a significant role in its development.^1,2,3,4

Pathophysiology

The pathophysiology of PCOS involves several interconnected mechanisms, the most prominent being hyperandrogenism, insulin resistance, and ovarian dysfunction. These processes contribute to the characteristic symptoms seen in women with PCOS, including menstrual irregularities, hyperandrogenism, and metabolic disturbances. Several genetic studies have also revealed that many potential genes with single-nucleotide polymorphisms or mutations are connected to a variety of PCOS symptoms.^2,5,6

Hyperandrogenism is a key feature of PCOS, with elevated levels of androgens such as testosterone being produced by the ovaries and, to a lesser extent, the adrenal glands. The increase in androgen production is linked to the dysregulation of the hypothalamic-pituitary-ovarian axis. In women with PCOS, there is often an abnormal increase in luteinising hormone (LH) secretion, which stimulates the ovaries to produce more androgens. Insulin resistance also plays a major role in the development of PCOS. Up to 70 per cent of women with PCOS exhibit insulin resistance, independent of obesity. As a result, the body compensates by producing higher levels of insulin, a condition known as hyperinsulinemia. The excess insulin stimulates the ovaries to produce androgens, exacerbating the hyperandrogenic state.^5,6,7

Insulin resistance also reduces the levels of sex hormone-binding globulin (SHBG), a protein that binds to androgens in the blood. With lower SHBG levels, there is an increase in the free and bioavailable androgens, which intensifies symptoms such as hirsutism, acne, and male-pattern baldness. At the same time, the increased insulin levels impair normal follicular development in the ovaries. In PCOS, multiple small follicles develop, but they do not mature properly, resulting in chronic anovulation and irregular menstrual cycles.^5,6,8

Clinical manifestations

PCOS presents with a wide range of clinical manifestations, making diagnosis challenging. The most common symptoms are related to menstrual irregularities, hyperandrogenism, and metabolic disturbances. Many women with PCOS experience oligomenorrhea or amenorrhea, due to the failure of normal ovulation. The lack of ovulation can also lead to infertility, which is one of the most distressing symptoms for many women.^1,2,5

Hyperandrogenism manifests as physical signs such as hirsutism on the face, chest, and back, acne, and androgenic alopecia. These symptoms are often the most noticeable and can have a profound impact on a woman’s self-esteem and quality of life.^2,6

Metabolic complications are common in PCOS. Women with the condition are at a higher risk of developing metabolic syndrome, a cluster of risk factors that includes obesity, insulin resistance, dyslipidaemia, and hypertension. Obesity is a common feature of PCOS, although the condition can also occur in women of normal weight. Insulin resistance, irrespective of body mass index, increases the risk of T2D, and studies have shown that women with PCOS have a significantly higher lifetime risk of developing the disorder compared to the general population.^1,2

Diagnosis

There is growing evidence that PCOS is also associated with an increased risk of cardiovascular disease. Women with PCOS often have elevated levels of low-density lipoprotein cholesterol, reduced high-density lipoprotein cholesterol, and elevated triglycerides, contributing to the development of atherosclerosis. Other potential long-term complications include an increased risk of endometrial cancer, due to the unopposed oestrogen exposure from chronic anovulation.^1,2,6

Three sets of diagnostic criteria, Androgen Excess Society, Rotterdam, and National Institute of Health are commonly used for PCOS, and all require the exclusion of other known disorders. Among the different diagnostic criteria used to define PCOS, the Rotterdam criteria are the most widely used and recommended, and, like the more liberal AES criteria, they allow for different phenotypes of the disorder. Based on the Rotterdam criteria, a diagnosis of PCOS requires two out of three of the following: Hyperandrogenism, menstrual irregularities, and polycystic ovaries on ultrasonography. Other potential causes of hyperandrogenism, such as adrenal hyperplasia, androgen-secreting tumours, and Cushing’s syndrome, must be excluded before making a diagnosis of PCOS.⁴

Differential diagnoses for polycystic ovarian disease include: The use of androgenic steroids; hypothyroidism; late-onset congenital adrenal hyperplasia; idiopathic/familial hirsutism; and ovarian malignancies.⁴

Laboratory testing is important in the evaluation of PCOS, primarily to assess hormone levels. Elevated testosterone and LH levels, with normal or low follicle-stimulating hormone, are commonly seen. Other tests include fasting glucose, insulin levels, lipid profiles, and screening for thyroid and adrenal function. It is also important to routinely screen for T2D and hypertension in view of the increased associated risks.^1,2,5,6

In women showing signs of androgen excess, it is recommended to check serum total testosterone levels. If the testosterone level exceeds twice the upper limit of normal, referral to a specialist is advised for further evaluation. Based on clinical presentation, additional tests such as beta-HCG, thyroid function tests, prolactin levels, a 1mg overnight dexamethasone suppression test, and early morning serum 17-hydroxyprogesterone may be required. Mild increases in serum prolactin are often observed in PCOS, but if macroprolactin is ruled out and levels exceed twice the normal limit, further investigation is necessary. Elevated anti-Müllerian hormone levels, produced by ovarian follicle granulosa cells, are also frequently found in PCOS and can aid in diagnosis.^2,6,7

Screening for coronary artery disease and obstructive sleep apnoea should be considered for women at high risk. In women with PCOS, obesity increases the likelihood of developing endometrial cancer three-fold. Although routine screening for endometrial cancer with ultrasonography is not currently recommended, it is important to maintain a heightened awareness for patients experiencing prolonged oligomenorrhea, with more than three months between menstrual cycles.^2,5,9

Iron deficiency is frequently observed in PCOS and may contribute to symptoms like fatigue and androgenic alopecia. It is advisable to screen for iron deficiency and provide treatment if needed, aiming for serum ferritin levels in the upper quartile of the reference range. Vitamin D deficiency is common in PCOS patients and can exacerbate issues related to fertility, insulin resistance, and glucose intolerance. Screening for vitamin D levels and addressing deficiencies may prove beneficial.^2,5,9

Psychological wellbeing is a key concern in PCOS due to the physical effects such as weight gain, acne, and hirsutism, which impact on self-esteem. It is important to be aware and observe for signs of poor mental health like depression, anxiety, and self-harm.^1,2,4

Treatment and management

The management of PCOS is individualised, depending on the symptoms and concerns of the patient, and it often requires a multidisciplinary approach involving endocrinologists, gynaecologists, dermatologists, and dietitians.¹ Lifestyle modification, particularly weight loss through diet and exercise, is considered the first-line treatment for women with PCOS, especially those who are overweight or obese. Even modest weight loss (5-10 per cent of body weight) can improve insulin sensitivity, regulate menstrual cycles, and reduce androgen levels. An ideal diet is rich in fibre and low in saturated fats and carbohydrates. Exercise and physical activity play a key role in weight reduction and may be beneficial to improve insulin sensitivity.^1,6,7

Pharmacological interventions are tailored to the patient’s symptoms and goals, whether they are focused on menstrual regularity, fertility, or hyperandrogenism.⁷ For women seeking to regulate their menstrual cycles or reduce symptoms of hyperandrogenism, combined oral contraceptive pills (COCPs) are a commonly prescribed option. COCPs suppress ovarian androgen production and increase SHBG levels, reducing the symptoms of hirsutism, acne, and androgenic alopecia.

Anti-androgen medications, such as spironolactone, may be added to further reduce androgenic symptoms. Antibiotics and retinoic acid derivatives can also be used for acne treatment. Retinoids reduce the formation of comedones and cystic acne by reducing inflammation and desquamation of follicular epithelial cells.^1,2,6

It is important for patients to understand that improvements in hirsutism and other symptoms of androgen excess, such as acne, often take at least six months to become noticeable. For more immediate control of facial hirsutism, topical application of eflornithine can be used, although consistent application is essential for effectiveness. Laser hair removal offers a more permanent solution and can be a valuable option for patients experiencing significant distress from their symptoms.^1,2

In women with insulin resistance, metformin, an insulin-sensitising agent, may be used to improve insulin sensitivity and restore ovulatory function. Metformin is particularly beneficial in women with PCOS who are at risk of or have already developed T2D.^2,5

For women with PCOS who are seeking to conceive, ovulation induction is usually required. Clomiphene citrate has been a first-line agent for many years, but recent evidence suggests that letrozole, an aromatase inhibitor, is more effective for achieving ovulation and pregnancy in women with PCOS. Gonadotropins or in vitro fertilisation are considered if oral agents fail. Metformin may also be used in conjunction with clomiphene or letrozole to improve ovulation rates, particularly in women with obesity or insulin resistance.^1,2

Emerging therapies

Several promising new therapies for PCOS are currently being developed, focusing on a variety of pharmacological approaches to address androgen excess, neuroendocrine dysfunction, and metabolic abnormalities. Although no androgen receptor antagonists are currently approved specifically for PCOS treatment, there is increasing interest in the therapeutic potential
of modulating SHBG levels to help control hyperandrogenism.^10,11,12

There is growing interest in the use of inositol, particularly myo-inositol and D-chiro-inositol, as a treatment for PCOS. These compounds are insulin sensitisers that have been shown to improve ovulation and metabolic parameters. While promising, larger randomised controlled trials are needed to establish their role in the standard treatment of PCOS.^10,12

Another area of research is the gut microbiome’s role in PCOS. Alterations in the gut microbiota have been observed in women with PCOS, and there is evidence to suggest that restoring a healthy microbiome through diet, probiotics, or faecal microbiota transplantation may improve metabolic and reproductive outcomes. However, these treatments currently remain experimental.^5,10