PCOS

Polycystic ovary syndrome (PCOS) is an endocrine condition characterised by menstrual dysfunction and features of hyperandrogenism.

PCOS is one of the most common endocrine disorders in women of reproductive age, with features often developing at puberty. It is a heterogeneous condition presenting with a wide clinical spectrum. Some women experience relatively mild symptoms whilst others suffer from debilitating effects.

Clinical features are those of menstrual irregularity (oligo/amenorrhoea), hyperandrogenism (e.g acne, hirsutism) and anovulatory infertility. Management depends on the manifestation of the condition in each individual but often involves the restoration of ovulation, preventing endometrial hyperplasia, reducing hyperandrogenism and screening for metabolic complications.

PCOS is a common endocrine/metabolic condition affecting women of reproductive age.

The estimated prevalence of PCOS varies depending on the studied population and the diagnostic criteria used. The Royal College of Obstetricians and Gynaecologists (RCOG) advise the use of the Rotterdam Criteria (described below) for the diagnosis of PCOS. Based on this criteria, a meta-analysis by Bozdag et al estimated prevalence to be 10% (8-13%).

The aetiology of PCOS remains poorly understood.

Genetics: It is known that PCOS has a strong genetic component. A Dutch twin study by Vink et al indicated a correlation of 0.71 for monozygotic twin sisters and 0.38 for dizygotic twin sisters and other sisters. Genome-wide association studies (GWAS) have gone on to identify a number of loci that may be involved in the development of PCOS. Many of these regions are related to hormone production and insulin resistance.

Increased LH: Changes to luteinising hormone (LH) are commonly seen. Serum levels are elevated in around 40% of women and its pulse frequency and amplitude can be increased. In addition to these changes, increased expression of LH receptors may be seen in the thecal and granulosa cells of the ovary. These changes result in an increased LH to FSH ratio which leads to excess androgens production by theca cells (in the ovary).

Insulin resistance: Insulin resistance is common in patients with PCOS, the underlying cause is still not completely understood. It results in hyperinsulinaemia, due to increased pancreatic production of insulin, in an attempt to compensate for the resistance. This stimulates theca cells, causing secretion of more androgens and a reduction in sex hormone-binding globulin (SHBG), leading to increased biologically active free androgens.

The features of PCOS are those of androgen excess and menstrual irregularity.

The clinical manifestations of PCOS can vary significantly between patients. Menstrual abnormalities are common and consist of oligomenorrhoea (infrequent menstruation) or amenorrhoea (absent menstruation). Ovulation is often less frequent or absent (oligo/anovulation) in women with PCOS meaning sub-fertility and infertility are common.

There is an increased frequency of pregnancy complications in patients with PCOS. The risk of spontaneous abortion is 20-40% higher than the general population, this is thought to be related to a multitude of factors including insulin resistance, excess androgens and increased BMI. Other pregnancy-related complications that are seen with increased frequency in PCOS include gestational diabetes and pre-term labour.

Androgen excess or hyperandrogenism manifests itself with acne and hirsutism (terminal hair in male pattern distribution). Obesity is common in PCOS and metabolic complications include an increased risk of T2DM and non-alcoholic fatty liver disease.

Symptoms

• Oligo/amenorrhoea
• Infertility/sub-fertility
• Acne
• Hirsutism
• Obesity
• Sleep apnea
• Anxiety/depression

Signs

• Hirsutism
• Obesity
• Male pattern baldness
• Acanthosis nigricans (dry, thickened, 'velvety' skin with a grey/brown pigmentation most commonly seen in the axilla, neck and groin)

It is essential to exclude other causes of similar symptoms.

• Cushing’s syndrome: is caused by prolonged exposure to an excess of glucocorticoids. It often features oligo/amenorrhoea, there may also be symptoms of androgen excess. Tests for Cushing's include a low-dose dexamethasone suppression test.
• Thyroid dysfunction: both hypothyroidism and hyperthyroidism can result in menstrual irregularity including oligo/amenorrhoea.
• Hyperprolactinaemia: excess prolactin release by the lactotroph cells in the pituitary (may be physiological e.g. pregnancy or pathological e.g. lactotroph adenoma) can result in oligo/amenorrhoea. Serum prolactin levels are increased.
• Androgen-secreting tumour: these tumours, affecting the adrenals or ovaries, tend to result in severe features of hyperandrogenism with a rapid onset. Serum androgens tend to be markedly increased.
• Non-classic congenital adrenal hyperplasia (NCCAH): is a late-onset form of congenital adrenal hyperplasia caused by reduced levels of the enzyme 21-hydroxylase. It can closely mimic PCOS with menstrual irregularity, hyperandrogenism and polycystic ovaries. There may be an indicative family history and certain groups are at increased risk including Ashkenazi Jewish people and Hispanics. Elevated morning 17-hydroxyprogesterone levels indicate a diagnosis of NCCAH.
• Premature ovarian failure: refers to the loss of ovarian function before the age of 40. FSH tends to be elevated helping to distinguish it from PCOS.

Investigations are important to exclude other causes of oligo/amenorrhoea and hyperandrogenism and to identify evidence supportive of a diagnosis of PCOS.

The exact set of investigations depend, in part, on the constellation of symptoms each individual presents with. Alternative causes of oligo/amenorrhoea, including thyroid dysfunction and hyperprolactinaemia, should be excluded.

In patients with significant evidence and/or rapid onset of hyperandrogenism and virilisation, androgen-secreting tumours should be excluded. Non-classic congenital adrenal hyperplasia (discussed above) can often mimic PCOS and should be excluded particularly in those with a suggestive family history or from an at-risk ethnic group (e.g. Ashkenazi Jewish people and Hispanics).

Bloods

• Total testosterone: tends to be normal or moderately elevated in PCOS.
• Sex hormone-binding globulin (SHBG): tends to be normal or low in patients with PCOS. Low levels are associated with an increase in free testosterone and more severe disease.
• LH/FSH: LH is elevated in around 40% of patients with PCOS, resulting in an increased LH/FSH ratio. Of note, the LH/FSH ratio is not used in the diagnostic criteria. FSH is normally elevated in those affected by premature ovarian failure (another cause of oligo/amenorrhoea).
• Prolactin: hyperprolactinaemia can cause oligomenorrhoea and should be excluded. Levels can be mildly elevated in PCOS.
• Thyroid profile: thyroid dysfunction commonly results in menstrual irregularity and should be excluded.
• 17-hydroxyprogesterone: morning levels are elevated in non-classic congenital adrenal hyperplasia.

USS

Transvaginal USS can reveal polycystic ovaries. The Rotterdam criteria (discussed below) define the radiological threshold of 12 or more follicles (2-9mm) on one ovary or increased ovarian volume (>10cm³).

It should be noted these findings are not required for a diagnosis of PCOS (see the Rotterdam criteria in full for more information). Where polycystic ovaries are not found on USS, careful exclusion of other causes of oligomenorrhoea and hyperandrogenism is of the utmost importance.

Polycystic ovary seen on ultrasound

Case courtesy of Dr J. Ray Ballinger, Radiopaedia.org. From the case rID: 23638

The RCOG advise the Rotterdam criteria be used to make a diagnosis of PCOS.

PCOS is indicated by the presence of two of the following three points:

1. Polycystic ovaries (12 or more follicles (2-9mm) on one ovary or increased ovarian volume (>10cm3))
2. Oligo-anovulation or anovulation
3. Clinical and/or biochemical signs of hyperandrogenism

Management of PCOS is complex and may require ongoing long-term care.

PCOS is an endocrine condition with systemic effects. Its management must be tailored to each individual's features and their own wellbeing goals. Aspects of management include:

• Menstrual irregularity and endometrial cancer risks
• Improving fertility
• Reducing hyperandrogenism
• Reducing metabolic and cardiovascular complications
• Psychological wellbeing

Here we discuss some key aspects of the management of PCOS in adults.

Menstrual irregularity

The combination of oligo/amenorrhoea and pre-menopausal oestrogen levels lead to endometrial hyperplasia and possibly an increased risk of endometrial carcinoma.

It is recommended that in patients with oligo/amenorrhoea, a withdrawal bleed is induced every 3-4 months. In adult patients with oligo/amenorrhoea for 3 months or longer, NICE CKS advises a cyclical progestogen to induce a withdrawal bleed and referral for a TV USS (any abnormalities will require further investigation).

Long-term treatment may be required to prevent endometrial thickening in those with oligo/amenorrhoea. A number of therapies may be used:

• Cyclical progestogen
• Combined oral contraceptive
• Levonorgestrel-releasing intrauterine system

Some patients may be unwilling to take any hormonal therapy. Ensure they are aware of the potential health risk, they will also need specialist care and regular TV USS.

Fertility

Sub/infertility is common in patients with PCOS due to oligo/anovulatory cycles. Despite it frequently being related to PCOS, other causes of reduced fertility must still be excluded. Lifestyle factors, in particular weight loss (where appropriate), should be optimised.

The goal of treatment is to induce normal ovulatory cycles. There are a number of medications that can be used by specialists to induce ovulation, these include:

• Letrozole: this is an aromatase inhibitor (AI). AIs work by inhibiting aromatase, an enzyme involved in the conversion of androgens to oestrogens. It is typically used in the treatment of breast cancer in post-menopausal women.
• Clomiphene: this is a selective oestrogen receptor modulator (SERM) commonly used in the treatment of oligo/anovulatory infertility.

Historically metformin was more commonly used, however, today its role in management is less clear. We discuss its use separately in a chapter below.

Hyperandrogenism

Hirsutism is a troubling feature for many, though not all, patients. If the patient wants to consider hair removal techniques (e.g. shaving, waxing) these should be discussed.

For those with PCOS and acne, the combined oral contraceptive should be considered first-line therapy if there are no contraindications. Consider other therapies as part of normal acne management. For more see our notes on Acne vulgaris.

Weight loss (if overweight) may help reduce hyperandrogenism and as such help with hirsutism and acne. Weight loss in patients with PCOS can often be challenging and support (e.g. dietician referral) should be offered.

Metabolic complications

Obesity is common in those affected by PCOS. It is a key modifiable risk factor, weight loss can help to:

• Reduce metabolic risks
• Reduce hyperandrogenism
• Restore ovulatory cycles

Appropriate dietary and exercise advice should be given, with clear, gradual and attainable goals. Smokers should be advised to quit and offered a referral to smoking cessation services. The majority of patients should be screened for diabetes, dyslipidaemia and hypertension at the time of diagnosis.

Patients are at increased risk of gestational diabetes. Those planning a pregnancy should have an oral glucose tolerance test, if they are already pregnant it should be conducted prior to 20 weeks. Additional testing should be carried out at 24-28 weeks.

Metformin

Metformin is a biguanide, a medication commonly used first-line in the treatment of type 2 diabetes. Insulin resistance, and the resulting hyperinsulinaemia, is a common finding in PCOS. As such, metformin, a medication that improves insulin sensitivity, has been used for many years (off label) in the treatment of PCOS. Early evidence indicated it helped with both inducing ovulation and reducing serum androgens.

However many of these trials were small, had design flaws and often omitted an appropriate placebo group. Based on current evidence metformin is not used routinely. It should be noted that it may still be prescribed by a specialist following appropriate counselling of the patient.

Psychological wellbeing

PCOS is a chronic condition with long-term implications for a women’s health. Each patient should receive counselling on the nature of the condition from a medical professional. The potential implications for fertility and cardiovascular health should be explained.

Anxiety and depression are common and should be screened for. Other issues such as psychosexual difficulties and eating disorders may occur and require specialist referral.

Support groups exist and can be a source of comfort and information. See the further reading section below for more information.

• RCOG: Long-term Consequences of Polycystic Ovary Syndrome, Green-top Guideline No. 33, Nov 2014.
• Verity: A UK based charity that provides support to those with PCOS.