Polycystic ovarian syndrome

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Chapter 5 Polycystic ovarian syndrome

Definition. The definition of polycystic ovarian syndrome (PCOS) was revised in 2003 (Rotterdam Consensus criteria). The diagnosis is based on two out of three of the following criteria:

• oligo or anovulation

• clinical and/or biochemical signs of hyperandrogenism

• polycystic ovaries, defined as at least one of the following:

• 12 or more follicles measuring 2–9 mm in diameter

• increased ovarian volume (>10 cm³)

If there is evidence of a dominant follicle (>10 mm) or a corpus luteum, the scan should be repeated during the next cycle. Only one ovary fitting this definition or a single occurrence of one of the above criteria is sufficient to define the PCOS. It does not apply to women taking the oral contraceptive pill. Regularly menstruating women should be scanned in the early follicular phase (days 3–5). Oligomenorrhoeic and amenorrhoeic women should be scanned either at random or between days 3 and 5 after a progestogen-induced bleed and the exclusion of other aetiologies (congenital adrenal hyperplasia, androgen-secreting tumours, Cushing’s syndrome).

Prevalence. Prevalence is 5%–7% overall, 85% of oligomenorrhoeic females, 90% of women with hirsutism and 30% of infertile women.

Clinical presentation

• menstrual irregularities

• amenorrhoea or oligomenorrhoea

• variable menstrual loss

• infertility

• androgen excess, such as hirsutism or acne

Aetiology

• Aetiology is multifactorial.

• About 50% of women with PCOS have affected sisters.

• Multiple candidate genes have been identified, but it is likely that a number of different pathways, both genetic and environmental, contribute to the same phenotype.

Pathophysiology

PCOS is characterised by ovarian, hypothalamic–pituitary, peripheral and adrenal dysfunction. The phenotype develops through chronic anovulation of any aetiology and a clear sequence of events is therefore not identifiable.

Ovaries

• High luteinising hormone (LH) levels drive ovarian androgen production.

• High intraovarian androgen concentrations inhibit follicular maturation and lead to inactive granulosa cells with minimal aromatase activity.

• The large number of ovarian follicles produces a high inhibin B, which inhibits follicle-stimulating hormone (FSH).

Hypothalamus–pituitary

• Hypothalamic dysfunction is associated with increased gonadotropin-releasing hormone agonist (GnRH) frequency and tonic (i.e. non-cyclic) LH release, elevating the LH/FSH ratio. The increase in LH is more pronounced in lean patients.

• The large number of ovarian follicles produces a high inhibin B, which inhibits FSH, but as FSH is not fully suppressed, continuous follicular recruitment and stimulation proceeds, but not to the level of full maturation and ovulation.

• Increased oestrogen production stimulates an increase in prolactin.

Peripheral compartment

• Reduced sex hormone-binding globulin (SHBG) concentrations perpetuate hyperandrogenaemia:

• hyperinsulinaemia

• hepatic dysfunction

• Peripheral alteration in insulin-like growth factor (IGF-1), androgen and oestrogen levels perpetuate hypothalamic dysfunction.

• Obesity reduces SHBG and increases peripheral aromatisation of androgens (androstenedione), which produces a chronic hyperoestrogenic state with reversal of the oestrone:oestradiol ratio.

Adrenal compartment

• dysregulation of cytochrome p-450c17 (as in the ovaries), but dehydroepiandrosterone sulfate (DHEAS) (of adrenal origin) is only increased in 50% of PCOS

• exaggerated adrenarchal response

Consequences of PCOS

Metabolic consequences

• at least 50% of women with PCOS are obese

• most are also hyperinsulinemic and insulin resistant, independent of obesity

• metabolic syndrome: present in up to 40% of PCOS patients

• hyperlipidaemia: conflicting data

Cardiovascular disease

• limited epidemiological data to support increased coronary heart disease

Other

• increased sleep apnoea

• non-alcoholic steatohepatitis

Differential diagnosis

• constitutional obesity

• idiopathic hirsutism

• Cushing’s syndrome

• congenital adrenal hyperplasia

• hypothyroidism

• androgen producing tumours

Assessment

Assessment is based on clinical presentation and investigations to validate the diagnostic criteria, and exclude other endocrinopathies and sequelae.

History

• menstrual history

• reproductive history

• weight gain

• hirsutism, acne

• galactorrhoea, headaches

Examination

• evidence of virilisation

• evidence of Cushing’s syndrome, thyroid disorders

• acanthosis nigricans (a marker of insulin resistance)

Investigations

• FSH, oestradiol (LH/FSH ratio is not clinically useful)

• thyroid function test

• fasting glucose, insulin, lipids

• testosterone levels: if above 6 nmol/L, further investigations are required to check for adrenal or virilising tumours

• DHEAS: levels above 18 nmol/L necessitate exclusion of Cushing’s syndrome

• 17-hydroxyprogesterone: if the morning level is <5.5 nmol/L, no further investigations are needed; if the levels are raised, check for congenital adrenal hyperplasia

• endometrial sampling, especially if history or prolonged amenorrhoea or heavy menses

Management

Management is dictated by the clinical presentation (e.g. menstrual changes, hirsutism and/or infertility).

Supportive

• lifestyle changes: the most important intervention

• weight reduction: 5%–10% of body weight over 6 months is sufficient to reestablish ovarian function in more than 50% of patients

• hirsutism: see management of hirsutism (Ch 6)

Not wanting to conceive

COCP

• protects endometrium

• oestrogen increases SHBG, resulting in reduced free testosterone

• progestins inhibit 5-alpha-reductase in the skin, resulting in decreased hirsutism

• progestins suppress LH, resulting in decreased androgen production

Progesterone (cyclical oral or depot medroxyprogesterone acetate (DMPA))

• negative feedback decreases GnRH production, resulting in decreased oestrogen and androgen

• protects endometrium

Insulin-sensitising drugs

• thiazolidinediones (TZDs)

• insulin sensitisers

• specifically contraindicated for conception and associated with an increased risk of weight gain; unlikely to become a major component of PCOS management

• no change in BMI, waist:hip ratio

• no effect on clinical hyperandrogenaemia (e.g. hirsutism)

• reduced fasting glucose (statistically but not clinically significant)

• reduced fasting insulin

• reduced biochemical androgens

• altered lipids

• increased nausea and gastronintestinal side effects, but nil serious

• oral contraceptive pill (OCP) and metformin

• OCP is more effective than metformin in improving menstrual pattern and reducing serum androgen levels

• limited evidence demonstrating that the addition of metformin to the OCP is more effective than the OCP alone in improving hirsutism score and increasing serum SHBG levels

• insufficient evidence to demonstrate any benefit to adding metformin to the OCP in terms of reducing body weight, reducing serum androgen levels, and reducing fasting serum levels of metabolic parameters such as insulin, glucose or lipids

Wanting to conceive

See Figure 5.1.

Figure 5.1 Patients with a diagnosis of PCOS wishing to conceive

Medical

• selective oestrogen receptor modulator

• central oestrogen receptor antagonism leads to reflex elevation in FSH and thereby ovulation

• commence on low dose

• 85% ovulation

• 50% conception: possibly due to negative effect of clomiphene on endometrium/mucus

• 7% multiple pregnancy

Metformin

• metformin: increased ovulation rate but not clinical pregnancy rate

• clomiphene and metformin

• increased live-birth rate: effective also in clomiphene resistance

• increased ovulation rate

• metformin and gonadotrophin treatment: does not increase pregnancy rate, but reduces total FSH requirement and risk of ovarian hyperstimulation syndrome (OHSS)

Other medical treatment

• ketoconazole: limited benefit

• aromatase inhibitors

• effective in ovulation induction

• no difference between letrozole and anastrozole

• mechanism is selective reversible inhibition of aromatase (a product of the CYP19 gene, part of the cytochrome P450 complex), which catalyses the rate-limiting step in the production of oestrogens

• supposed benefit over clomiphene is reduced negative effects on target tissues such as endometrium and cervix

• increased benefit from addition of dexamethasone to clomiphene: resulted in a significant improvement in the pregnancy rate

• pulsatile GnRH (Cochrane): insufficient evidence from trials to show the effectiveness of pulsatile GnRH in PCOS

• FSH: chronic low-dose stimulation protocol has lower OHSS and multiple pregnancy rate

• in vitro fertilisation (IVF)

• 7% of PCOS patients need IVF

• high risk of OHSS (20%)

• wedge resection: high incidence of adnexal adhesions

• laparoscopic golf balling/pepper potting/ovarian drilling (LOD) (see Table 5.1)

• high incidence of adnexal adhesions

• unknown long-term effect on ovarian function

• effect may be permanent

• consider in failed ovulation induction

Table 5.1 Comparison of laparoscopic ovarian drilling and FSH stimulation in fertility management in patients with PCOS

	Laparoscopy	FSH
Benefits	Comparable success rates One treatment affects multiple cycles Usually produces mono-ovulation No increased risk of OHSS May lower miscarriage rate No medications required No intensive monitoring required Lower cost	Comparable success rate Non-operative
Problems	Surgical risks Adhesion Ovarian atrophy Long-term effect on ovarian function uncertain	Multiple cycles required Intensive monitoring required Increased risk of multiple pregnancy Increased risk of OHSS Increased cost

Further reading and references

Ehrmann D.A. Polycystic ovary syndrome. New England Journal of Medicine. 2005;352:1223.

Legro R.S. Type 2 diabetes and polycystic ovary syndrome. Fertility and Sterility. 2006;86(Suppl1):S16-S17.

Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Human Reproduction. 2004;19(1):41-47.

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