Definition and Epidemiology

Definition and Epidemiology

In 1935 Irving Stein and Michael Leventhal first documented the condition based on seven women who 'could not fall pregnant, who were overweight, had excess body and facial hair and whose ovaries showed up lots of little tiny cysts'. The Stein-Leventhal syndrome is now known as polycystic ovary syndrome or PCOS (Harris and Carey 2000).

The condition was defined in 1999 and revised in 2003 by the European Society for Human Reproduction and Embryology (ESHRE) and the American Society of Reproductive Medicine (ASRM) sponsored workshop group – see table 1 for the full definition.

Table 1 – Revised diagnostic criteria of PCOS

1999 criteria (both 1 and 2) / Revised 2003 criteria (2 out of 3)
1. Chronic anovulation / 1. Oligo- and/or anovulation
2. Clinical and/or biochemical signs of hyperandrogenism, and exclusion of all other aetiologies / 2. Clinical and/or biochemical signs of hyperandrogenism
3. Polycystic ovaries and exclusion of other aetiologies (congenital adrenal hyperplasias, androgen-secreting tumours, Cushing's syndrome)

Source: The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group

The revised definition is broader which means that previous estimates of prevalence may be underestimated according to the Royal College of Obstetricians and Gynecologists (RCOG) 2007.

Estimates of prevalence vary through 5-10 percent of reproductive age females and variations have been found across ethnic origins. For example, the RCOG explains that women of South Asian are likely to present earlier and have more severe symptoms than other populations.

Using this estimate and population figures from 2006 for the United Kingdom (Office for National Statistics, 2008),approximately 600-1,200,000 women would be likely to have this condition.

However, Franks (1995) found that 22 percent of 257 volunteers with no previous diagnosis were found to have polycystic ovaries. Of these, 94 percent were found to have at least one other symptom of PCOS which could suggest that the number of affected women are higher than current estimates.

Aetiology

According to Hopkinson et al in 1998, the aetiology of PCOS is uncertain although there is evidence of a genetic link. Franks (1995) states that the difficulty in determining how the condition is inherited is partly because the genes have not yet been identified and partly as a result of there being no clear definition of how the condition presents in men. However, he goes on to say that there is some evidence to support the view that prematurely balding men express the genetic predisposition for the condition.

Hopkinson et al also explain that insulin resistance increases as part of puberty but that it should decline in early adulthood. They suggest that women who are genetically predisposed to PCOS fail to resume normal insulin resistance and continue to 'express metabolic and endocrine features usually confined to puberty' (Hopkinson et al, 1998).

Ehrmann (2005) agrees that there is no clear aetiological factor which causes the range of symptoms and suggests that the thecal cells in the ovaries of affected women are better at converting precursors into testosterone.

Pathophysiology

Women with PCOS often develop symptoms during puberty although sometimes later depending on environmental and lifestyle factors such as weight gain. The symptoms are caused by the imbalance of hormones in the body (Ehrmann 2005).

Although both lean and obese women with the syndrome show decreased sensitivity to the hormone insulin, the resistance is more marked in obese women (Franks, 1995).

Central fat tissues become resistant to insulin which means that the body produces more insulin to compensate. Patients are often found to have high levels of insulin circulating in their blood (hyperinsulinaemia). Figure 1 shows how hyperinsulinaemia contributes to the condition by reducing the amount of sex hormone binding globulin (SHBG) available to bind to excess androgens and stimulating the thecal cells of the ovary to produce more androgens (Hopkinson et al, 1998)

Figure 1 – Probable mechanisms whereby defects in insulin metabolism promote increased androgen activity at the level of the ovary.

Source: Hopkinson et al, 1998 (British Medical Journal)

The higher levels of circulating androgens produce various physiological changes such as the development of acne, hirsutism and male pattern baldness. The measurement of androgens in the blood as a part of a diagnosis is not recommended because of the variability of androgenaemia in the normal population and limitations of testing (ESHRE/ASRM 2003).

The production of androgens such as testosterone is also a result of abnormalities in the interactions between the hypothalamus, pituitary and ovary. The hypothalamus produces pulses of gonadotrophin-releasing hormone (GnRH) which stimulates the pituitary to produce luteinising hormone (LH). Ehrmann (2005) explains that there may be an 'intrinsic abnormality' which favours LH production over follicle-stimulating hormone (FSH).

The ratio between LH and FSH is important because a) LH promotes androgen production in the ovary and b) FSH cannot stimulate the ovarian follicle to mature in the presence of high levels of LH. When the follicles do not mature and they fail to release eggs, small cysts form on the ovaries giving the condition its name (American Society for Reproductive Medicine 2003).

Clinical Signs and Symptoms

The diagnosis of the syndrome is based on the presence of signs and symptoms in two of the categories below when pathologies with similar results have been excluded (ESHRE/ASRM 2003). A summary of the prevalence of symptoms can be found in table 2 below.

1. Polycystic Ovaries

Defined as 'the presence of 12 or more follicles in each ovary measuring 2-9 mm in diameter, and/or increased volume (>10ml)'.

An ultrasound scan is used to establish if this definition is met – see figure 2 (ESHRE/ASRM 2003).

1. Oligo- or anovulation

This would present as oligomenorrhea or amenorrhea (infrequent, light or absent menses). Oligomenorrhea is defined as less than nine menses in a year (Ehrmann 2005).

1. Clinical and/or biochemical signs of hyperandrogenism

The clinical signs of hyperandrogenism include hirsutism and acne (RCOG, 2007). Increased muscle mass and an enlarge clitoris may also be present (Willacy, 2008)

Hirsutism is measured by the Ferriman-Gallwey score which measures terminal (coarse) hair at specific sites. A value of 8 is indicative of androgen excess (Rosenfield, 2005).

The biochemical signs are increased free androgen index (total testosterone divided by sex hormone binding globulin) and increased luteinising hormone (Hopkinson et al, 1998). Hyperinsulinaemia is also likely to be present but is not recommended as a diagnostic measurement (ESHRE/ASRM 2003).

In addition, hyperinsulinaemia may present as abnormal fat distribution and in severe cases as acanthosis nigricans which is a manifestation of insulin resistance (Willacy, 2008). Sleep apnoea is also more common in women with PCOS even when adjustments have been made for body mass index. The strongest indicator for sleep apnoea is fasting insulin levels and glucose-to-insulin ratios (RCOG, 2007).

Signs of hyperandrogenism, oligo- or anovulation and acanthosis nigricans should be treated as red flags to rule out or confirm a serious underlying problem such as an androgen-secreting tumour or diabetes mellitus.

Figure 2 – Ultrasound scan of a polycystic ovary

Source: America Society of Reproductive Medicine (2003)

Table 2 – Prevalence of classic PCOS symptoms

Symptom / Percentage of women presenting
Irregular cycle (oligomenorrhoea) / 52
No periods (amenorrhoea) / 28
Irregular spotting / 14
Extra facial or body hair (hirsutism) / 64
Acne / 27
Obesity / 35
Infertility / 52

Source: Harris and Carey (2000) pg. 13

Differential Diagnosis

Several conditions can produce the same signs and symptoms as PCOS and would need to be excluded if clinically suspected (ESHRE/ASRM 2003).

Hyperprolactinemia (Schlechte, 2003)

High levels of prolactin in the blood.

Causes infertility, irregular menses and can stimulate lactation.

Can be caused by prolactinoma (pituitary gland tumor which secretes prolactin), drugs, severe head trauma and acromegaly.

blood tests would show elevated prolactin levels and prolactinoma would be diagnosed following magnetic resonance imaging scan and biopsy (see figure 3).

Figure 3 – MRI scans and histologic findings of prolactinoma

Source: Gazzeri et al (2007), New England Journal of Medicine p.2411 (357;23)

Non-classic congenital adrenal hyperplasia (Spieser and White, 2003)

This condition arises because of a deficiency in an adrenal cortex enzyme which affects the ability to produce cortisol and is rare.

The non-classic form of this condition is less severe and can be asymptomatic .

Symptoms in women include hirsutism (60%), oligomenorrhea (54%) and acne (33%).

Diagnosis is made through corticotropin (cosyntropin) stimulation test.

Cushing's syndrome (Merck online, 2008)

Collection of symptoms which can include obesity, glucose intolerance and menstrual irregularities, hirsutism and male-pattern hair loss in women.

Obesity is limited to face and trunk with characteristic 'moon' face.

Caused by increased function of the adrenal cortex and consequent high levels of cortisol in the blood often as result of pituitary or adrenal tumours.

Diagnosis is based on clinical observation of signs followed by blood tests and imaging tests.

Figure 4 – Physical evidence of Cushing's syndrome. Includes 'moon' face (A), body fat in the upper back / chest (B) and hirsutism (C).

Source: Horvard et al (2008), New England Journal of Medicine. p. 750 (358;7)

Androgen-secreting neoplasm (Azziz et al, 2004)

Tumours may secrete androgens and present as hyperandrogenism.

The symptoms are likely to appear quickly and suddenly.

Consistently high levels of free testosterone may indicate a neoplasm and an ultrasound scan may show a mass.

Diagnosis would be made by 'resection and histopathology of the tumour' (Azziz, 2004).

Acromegaly (Melmed, 2006)

The condition is caused by adenomas on the anterior pituitary gland which can cause insulin resistance, glucose intolerance, sleep apnoea and menstrual irregularities.

Although some of the presentation is similar, symptoms such as coarsening of features (see figure 5) are not present as part of PCOS.

Diagnosis would be made by measuring the level of circulating growth hormone and then magnetic resonance imaging of the pituitary gland.

Figure 5 – The patient's hands (A) and face (B) show clinical signs of acromegaly

Source: Beuschlein et al (2000), New England Journal of Medicine p. 1871 (342;25)

Orthodox Medical Treatment

The symptoms of PCOS are wide ranging and differ from patient to patient. Treatment is made based on the symptoms of the individual and their needs. If a patient is overweight or obese it is advised that they control their weight even though it can be 'demoralisingly difficult' to do. Excess weight greatly exacerbates PCOS symptoms (Willacy, 2008). Table 3 summarises orthodox treatments.

Oral contraceptives

This treatment is effective but clearly not appropriate if pregnancy is desired. It is also reduced the amount of free testosterone by increasing the levels of sex hormone binding globulin. It is not recommended for women who are obese because the pill makes insulin resistance more pronounced (Hopkinson et al, 1998).

According to the RCOG (2007), there is insufficient evidence that the contraceptive pill treats acne or hirsutism but it is licensed for their treatment.

Antiandrogens

Cyproterone acetate or spironolactone are effective in treating hirsutism but have a negative effect on the menstrual cycle and are contraindicated for anyone trying to conceive (Hopkinson et al, 1998)

Metformin

This is an insulin-sensitising drug which is used to treat patients with type II diabetes. Its use in the treatment of PCOS is still controversial. It is not recommended by the RCOG although it has been shown to improve fasting insulin levels, blood lipid profiles, blood pressure, reduce free testosterone and encourage ovulation (Ehrmann, 2005).

Clomiphene Citrate

This drug is an antioestrogen which can help to stimulate ovulation but some women are resistant (Franks, 1995). There is an increased risk of multiple pregnancy which requires close monitoring. The treatment period is limited to six months to reduce the risk of ovarian cancer (Hopkinson et al, 1998).

Ovarian drilling

Where drug treatments fail to start ovulation, laser or electrocautery of the ovary may be considered. The treatment has been show to be effective although may effect fertility in the long term (RCOG, 2007).

Cosmetic treatments

Hirsutism may be treated by laser, electrolysis, bleaching, waxing or shaving (RCOG, 2007).

Table 3 – Summary of current and potential treatments

Treatment / Problems addressed
Oral contraceptives / Menstrual disturbance
Clomiphene / Anovulatory infertility
Ovarian diathermy or laser treatment / Anovulatory infertility
Assisted conception techniques / Anovulatory infertility
Cyptroterone acetate + ethinyloestradiol / Hirsutism and acne
Spironolactone / Hirsutism and acne
Weight loss / Menstrual disturbance and anovulatory infertility, but also improvement of metabolic perturbances and thus risk of coronary heart disease
Insulin sensitising agents (such as Metformin) [Metformin is not licensed for treatment of PCOS in the UK] / Obesity and central obesity, androgen excess, menstrual disturbance, anovulatory infertility and metabolic perturbances

Source: Hopkinson et al (1998), British Medical Journal p. 331 (317)

Natural Medicine

The symptoms and underlying endocrine disorder are believed to respond well to a wide range of complementary therapies. The treatments are less intrusive and harmful than some orthodox treatments. It should be noted that some therapies, particularly herbal remedies, should be checked to make sure that there are no adverse interactions with orthodox drugs.

The patient should be comfortable with whichever therapy they choose and should inform their general practitioner.

Verity (the PCOS self-help organisation) and Harris and Carey (2000) describe the following therapies:

Herbal Medicine

There are several herbal remedies to treat the different symptoms of the syndrome. Vitex agnus castus has a long history of success with a variety of women's health issues and is supported by clinical research (Harris and Carey, 2000 / Marshall 2001). The herb is thought to work on the pituitary gland and be adaptogenic (i.e. it works in the way the individual patient needs it to).

Other herbal preparations such as white peony and liquorice may be indicated depending on the individual. Herbal medicine can be potent and can cause interactions with other drugs. For example, St John's Wort might be suggested as a treatment for mild depression or emotional stress resulting from PCOS but is listed as a interaction for several orthodox drugs in the British National Formulary (BNF 55).

Acupuncture and Traditional Chinese Medicine

There is evidence that acupuncture is effective in improving the LH/FSH ratio, improving ovulation and lowering testosterone levels (Stener-Victorin, 2002).

Reflexology

This treatment is non invasive and a reflexologist would concentrate on the areas of the foot relating to the problems experienced by the patient. For example the pituitary gland for hormonal balance or liver for the skin. There is no evidence that it is unsuitable to work alongside orthodox medicine, however, it is contraindicated in the early stages of pregnancy (Verity, 2001).

Nutritional therapy

Weight reduction is a specific aim for many women with PCOS because overweight can make the condition worse. Nutritional therapy can help by producing a tailored management plan which will help the patient achieve better health (Harris and Carey 2000).

Specific nutritional supplementations thought to help the condition include sufficient dietary fibre to increase insulin sensitivity, flaxseed to promote sex hormone binding globulin as well as fish oil and chromium to regulate insulin levels and reduce resistance (Marshall, 2001)

Prognosis

Metabolic

Women with PCOS are seven times more likely to develop type II diabetes than women without the condition in the same age and weight group (Franks, 1995). Although this is more pronounced in women who have central obesity, there is still an increased risk for lean women with PCOS. The RCOG recommend regular glucose tolerance testing for early detection and weight control to reduce the risk of developing diabetes.

Obstructive sleep apnoea

Sleep apnoea is more common in women with PCOS even when 'controlled for BMI' (RCOG, 2007). The disturbances in sleep are likely to lead to tiredness during the day.

Cardiovascular risk

There is some evidence that there is an increased risk of myocardial infarction - probably due to abnormal blood lipid profiles caused by androgen excess – compared with 'age-matched referents' (Hopkinson et al, 1998). The RCOG suggest that the increased risk factors are due to obesity, hyperandrogenism, hypelipidaemia and hyperinsulinaemia.

Sub-fertility and infertility

The infrequency of ovulation means that there are less opportunities for a woman to get pregnant. If a woman is anovulatory drugs can be used to encourage ovulation. Surgery in the form of ovarian drilling is also an option (Harris and Carey, 2000).

Endometrial cancer

There is limited evidence for an increased risk of endometrial cancer caused by unopposed oestrogen as a result of oligo- or anovulation (ESHRE/ASRM, 2003).

Resource List

The self-help group for PCOS suffers in the UK is Verity. It was established in 1997 and is run by volunteers. Members are given leaflets about the condition and a magazine twice a year and there are currently about 1,500 members.

Costs of membership at the moment are:

1 year: £20 (£15 concessions, £30 overseas)

3 year: £40

5 year: £60

Contact details:

New Bond House, 124 New Bond Street, London W1S 1DX

Other useful contacts available can be found in Appendix 1.

WORD COUNT: 2,417 (excluding figures, tables and headings)

References

Page numbers in brackets refer to this document.

ASRM - American Society for Reproductive Medicine (2003)

Hirsutism and Polycystic Ovarian Syndrome: A Guide for Patients, Patient Information Series

Pages: (3-4) 11-12

Azziz R., Sanchez L.A., Knochenhauer E.S, Moran C. Lazenby J. Stephens K.C., Taylor K. and Boots L.R. (2004)

Androgen Excess in Women: Experience with over 1000 Consecutive Patients, The Journal of Clinical Endocrinology and Metabolism 89;2

Pages: (7) 453-4, 460

British National Formulary, accessed 12 July, 2008

St John's Wort interactions:

Pages: (10)

Ehrmann D.A. (2005)

Polycystic Ovary Syndrome, The New England Journal of Medicine 352;12

Pages: (2) 329, (2) 330, (3) 330, (4) 329, (8) 331, (9) 331, (12) 331

ESHRE/ASRM-sponsored PCOS consensus workshop group (Rotterdam) (2003)

Revised 2003 consensus on diagnostic criteria and long term health risks related to polycystic ovary syndrome (PCOS), Human Reproduction 19;1