Polycystic Ovarian Syndrome (PCOS)

Introduction

• Hyperandrogenism
  • Hirsutism – male pattern hair growth / excessive female hair growth, acne, deep voice, oily skin
• Polycystic ovaries
• Oligo-ovulation
• Insulin resistance – weight gain
• Can also be caused by Cushings, and adrenal hyperplasia

Epidemiology

• Polycystic ovaries are a common finding on USS – affecting up to 1/3 of women of reproductive age. However, most women with polycystic ovaries do not exhibit the other systemic features required for a diagnosis of PCOS
• True PCOS effects 5-15% of women aged 18-45
• It is the most common endocrine disorder in reproductive age women

Aetiology

• Essentially unknown – probably multifactorial
• Seems to have a familial link – the exact cause of which is yet unknown
• SMOKING
• Possibly insulin resistance
  • There is certainly a relationship between the two – hard to determine cause and effect
  • Insulin resistance is also associated with obesity – and excess adipose tissue will result in the creation of excess oestrogen – a vicious cycle

Pathophysiology

• Excess androgen production by the ovaries
  • Produced by theca cells in the ovaries
  • Thought to be a result of increased LH levels and / or hyperinsulinaemia
• Insulin resistance
  • Resulting in hyperinsulinaemia
  • Hyperinsulinaemia in turn causes increased androgen production
    • In many women total testosterone levels are not raised, but free testosterone levels may be raised, due to a decrease in production of sex hormone binding globulin by the liver (SHBG)
• Weight further increases insulin resistance
• Raised LH production in the anterior pituitary gland
• PCOS can exist without cysts in the ovaries – when the underlying metabolic disturbances are present alone
  • The cysts seen on USS are actually immature follicles and not true cysts
  • Cysts are about 2-6mm in size
• PCOS can exist without raised androgen levels

Presentation

Typically presents between mid teens and mid 20s. Symptoms may include:

• Amenorrhoea
• Oligomenorrhoea
  • Defined as <9 periods per year
  • Due to anovulation (irregular / absent ovulation)
  • The anovulation can also result in reduced fertility
• Acne
• Weight gain / insulin resistance
  • There may be associated sleep apnoea
• Psychological symptoms
  • Mood swings
  • Depression
  • Anxiety
  • Low self-esteem
• Acanthosis nigricans –  dark patches of skin, particularly on the neck and in skin folds – secondary to insulin resistance
• Masculinisation – due to excessive testosterone production
  • E.g. Hirsutism – male pattern hair growth on females. Common during puberty as the hormonal axis matures, and usually transient. If persistent, or presents later in life, suspect another cause (e.g. testosterone producing tumour)
  • Male pattern balding
  • Acne
• Infertility and sub-fertility may occur – although it is often treatable. Reassure patients at the time of diagnosis that many women conceive naturally (even those who do to have regular periods) and many more can conceive with medical assistance to achieve ovulation
  • Concerns about fertility are often the most important concern for newly diagnoses patients

Symptoms usually begin around the time of puberty, and worsen at the patient gets older.

• PCOS is unlikely if regular periods have been established before amenorrhoea.

Diagnostic Criteria

According to the Rotterdam criteria at least TWO of the following is diagnostic:

• Polycystic ovaries
  • 12 or more peripheral follicles, OR
  • Ovarian volume >10 cm³
• Clinical or biochemical signs of hyperandrogenism
• Oligo-ovulation (<9 periods per year) or anovulation

Note that these criteria do not necessarily require any formal investigations.

However – be wary of diagnosing teenage girls with PCOS based purely on the above criteria. Symptoms of puberty (such as acne, and irregular periods) can mimic those of PCOS. Also, in women with <8 years of ovulation, the ovaries may appear to have multiple follicles on USS. As such, a 2017 international consortium suggested that in teenage girls, more stringent criteria are required:

• BOTH of the following
  • Oligomenorrhoea or amenorrhoea at least 2 years after menarche
  • Clinical and biochemical hyperandrogenism
• Absence of an alternative cause (e.g. Cushing’s, congenital adrenal hyperplasia)

Differential Diagnosis

• Hypothyroidism
• Hyperprolactinaemia
• Cushing’s syndrome
  • Consider dexamethasone suppression test or 24-hour urinary cortisol as screening
• Acromegaly
• Androgen secreting ovarian or adrenal tumour
  • Symptoms likely to be more severe than hirsutism seen in PCOS, often have a quicker onset and may include; testosterone >5 mol/L, clitoromegaly, deepening voice, increased musculature, male pattern balding

Investigations

• ↑ LH
  • May be normal
• ↔ FSH
  • If both LH and FSH are raised – more likely ovarian insufficiency
  • If both are low – consider hypogonadotrophic hypogonadism
• ↓ E2 (estradiol)
• ↑ or ↔ Testosterone
  • Often only slightly raised. If >5nmol/L need to exclude an androgen secreting tumour
• ↓ SHBG (sex hormon binding globulin)
• ↑ Prolactin
• ↑ oestrogen – which ultimately results in increased risk of endometrial hyperplasia / endometrial cancer
• TFTs – for hyperthyroidism, which may mimic PCOS through amenorrhoea and weight gain:
  • ↑T4
  • ↓TSH
• Fasting glucose and / or oral glucose tolerance test
  • Checks for presence of insulin resistance

USS

• Shows >5 follicles per ovary
  • Despite the name, they are not true “cysts”!
• Sometimes said to look like a string of pearls
• Scans in women under the age of 20 (or <8 years of ovulation) should be interpreted with caution as physiologically they often have follicles / cysts visible

Examination

• May show excessive cervical mucus – consistent with excess oestrogen
• Signs of hirsutism (male pattern facial hair, acne)

Risks / complications

• Insulin resistance and possibly later, Type II diabetes
• Cardiovascular disease
  • Including MI and stroke
• Hypertension
• Dyslipiaemia – disorders of lipid metabolism
• Weight gain
• Miscarriage
• Autoimmune thyroid disease
• Acanothosis nigricans – patches of dark skin, typically under the arms and on the back of the neck
• Increased risk of endometrial cancer due to unopposed oestrogens.
  • Particularly if periods are <3 monthly
  • This is why when the oral contraceptive pill is recommended – it is recommended to have a withdrawal bleed at least once every 3 months

Management

PCOS is a lifelong condition. Early diagnosis and treatment minimises the risks of complications and improves quality of life. In particular, warn about the risks of diabetes and increased cardiovascular disease risk.

There is no cure. In particular, lifestyle factors should be emphasised.

• Weight loss
  • For all patients with BMI >25, weight loss will improve symptoms
  • Patients should aim for a weight loss of 5%
  • This may induce normal menstrual cycles and alleviate the need for hormonal and other medical treatments
• Advise increased exercise to all patients
  • Proven to improve psychological symptoms, metabolic features, pregnancy rates and anovulation – even regardless of weight loss
  • Aim for 150 minutes of moderate intensity exercise (brisk walk or equivalent) per week – e.g. 5×30 minutes
• Avoid or cease smoking
• Offer screening for T2DM
  • Treat if present – e.g. with metformin
• Ask about sleep apnoea symptoms and test if indicated
• Treat hypertension if present
• Treat hyperlipidaemia if present
  • No evidence for use of statins if cholesterol is normal. Same guidelines as for general population
• Oral contraceptives – combined hormonal contraceptive (CHC) is the hormonal treatment of choice. They reduce the androgenic symptoms, as well as reduce endometrial cancer risk. Usually recommended to have 3-monthly withdrawal bleeds.
  • Be wary of contraindications in patients with increased BMI
    • BMI >40 – contraindicated
    • BMI 35 to 39 – benefits outweigh risks if no other risk factors
    • BMI 30 to 34 – benefits outweigh risks if also one other risk factor present
  • If withdrawal bleeds do not occur when they should, USS of the endometrium should be performed. If endometrial thickness is >7mm, refer for biopsy
• Metformin may be helpful to treat insulin resistance, even if T2DM is not present. It can not only improve diabetic symptoms, but can also help menstrual problems (amenorrhoea / oligomenorrhoea), and can help ovulation
  • Metformin is recommended by NICE in those trying to conceive, but otherwise has been shown to be inferior to hormonal contraceptive pill to treat other symptoms of PCOS. As such, NICE recommends that it not be used unless to treat T2DM, or for fertility.

Treatment of hirsutism – if a problem, consider cosmetic treatments (hair removal) or an anti-androgen e.g. cyproterone (an anti-androgen prednisolone – which is available in some CHC preparations).

• Cyproterone has been shown to be no more effective than CHC at controlling androgenic symptoms. It is also usually only initiated by a gynaecologist (not by GP)
• Spironolactone and finasteride – are antiandrogenic alternatives, but also teratogenic, so avoid pregnancy! They should be used with an additional form of contraception. Can be initiated by a GP.
  • e.g. spironolactone 100mg daily
  • Check potassium once month after starting spironolactone
  • If not effective after 6 months, consider combining with a CHC

Fertility Advice

The risk of infertility increases with age, particularly after the age of 30. Advise patients to consider starting a family as early as practicable. Lifestyle factors (particularly weight loss) improve fertility.

• Metformin – has been shown to improve fertility in women with a BMI <30. Evidence is less clear in patients with BMI >30
  • Evidence is not conclusive
  • It improve pregnancy rates, but has not been conclusively shown to improve live birth rates. 
• Refer to specialist if unable to conceive despite the above advice and treatment
• Clomifene – usually used in conjunction with metformin, will help ovulation.
  • Induces ovulation
  • Increases the riks of multiple pregnancy and ovarian cancer
  • Monitor effect with USS in at least the first cycle
  • Should not be used for more than 6 months
  • Usually used in conjunction with metformin
• Ovarian drilling – is recommended as second line if clomiphene is not working. Helps to reduce steroid production.

Also be aware that there is a higher incidence of gestational diabetes in women with PCOS (thought to be >2x risk), as well as increased risk of premature birth, and pre-eclampsia.

Flashcard

References

• Polycystic Ovary Syndrome – patient.info
• PCOS – HealthPathways
• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.

Read more about our sources

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