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March 2007: Detecting polycystic ovary syndrome

Are blood tests and scans crucial to the diagnosis of polycystic ovary syndrome?

Can insulin resistance be predicted?

What treatments are effective?

Are blood tests and scans crucial to the diagnosis of polycystic ovary syndrome?

Can insulin resistance be predicted?

What treatments are effective?

Polycystic ovary syndrome (PCOS) is commonly seen in younger women who are seeking fertility treatment. It comprises a mixed group of symptoms, which may include anovulation, obesity, androgenisation and oligomenorrhoea or amenorrhoea. In some women the presenting symptoms are mild, in others they are severe.

A joint consensus meeting of the American Society for Reproductive Medicine and the European Society of Human Reproduction and Embryology1 defined the syndrome as the presence of two of the following:

• Oligo- and/or anovulation

• Hyperandrogenisation (clinical and/or biochemical). Symptoms include acne, hirsutism, frontal balding and, very occasionally, voice changes.

• Polycystic ovaries.

The prevalence of PCOS using these new criteria suggests that the syndrome is more common than previously thought.

There is, however, considerable confusion between the syndrome and the presence of polycystic ovaries. Polycystic ovaries occur in 20–25 per cent of women during their reproductive years and are diagnosed by ultrasound scanning. Many women with PCOS will have few or no symptoms, but approximately 50 per cent will have the syndrome as defined above.2,3 The prevalenceappears to differ according to ethnic group and may be higher in South Asian women.4

There appears to be an underlying genetic cause linked to disordered insulin metabolism.

The term ‘polycystic ovaries' is a misnomer. The condition is characterised by an increased number of follicles and increased ovarian stroma. It would be better referred to as polyfollicular ovaries. The follicles are usually around 5mm in diameter but may vary from 2mm to 9mm, and there are usually 12 or more present.1 This is the same histological appearance as in polycystic ovaries without PCOS. Although classically located at the periphery of the ovary, giving the well-known ‘pearl necklace' appearance on ultrasound scanning, the follicles can be distributed throughout the stroma. Increased ovarian volume (>10cm3) is specific for polycystic ovaries.

Diagnosis

The clinical features of the condition are classically:

• Truncal obesity (BMI>30)

• Oligo- or amenorrhoea and signs of excess androgens, including hirsutism, acne and frontal balding.

The biochemical findings are:

• Elevated serum levels of luteinising hormone (LH>12iu/l or three times FSH level when blood is taken during menstruation, when present)

• Suppressed sex hormone-binding globulin (SHBG), together with the characteristic features of polycystic ovaries as seen on ultrasound scanning.

41136054See box 1, left, for the typical presentation.

However, abnormalities of the hormones together with androgenisation may be seen in women with normal ovaries, and women with a normal BMI may have abnormal biochemistry and polycystic ovaries. The feature that links these women and explains the broader definition of the syndrome is insulin resistance and this may have long-term health implications.

The diagnosis is initially made on history and examination. Confirmation is made by transvaginal ultrasound screening to demonstrate the polycystic ovaries, together with SHBG, FSH?and LH.

Measuring testosterone levels and other androgens is of limited use. Testosterone exists in free and bound forms in the blood. Levels may be raised or normal. However, with a low SHBG, there will be an excess of free testosterone and the woman will probably show signs of androgenisation.

Fasting blood glucose is a useful test, especially in the obese, along with a lipid profile. Testing for insulin tolerance is best left to specialised units. If the woman has amenorrhoea, then FSH and LH levels can be measured at any time.

Possible consequences of PCOS

Type 2 diabetes

Insulin resistance in PCOS has been linked with the development of type 2 diabetes in later life. The risk is quoted as between 10 and 20 per cent.5,6 A sensible approach to women presenting with PCOS, especially those with a family history of diabetes, might be annual determination of fasting blood glucose levels.

Cardiovascular disease

Women with PCOS have a greater truncal abdominal fat distribution, independent of BMI. It is associated with raised insulin levels and raised triglyceride concentration, with reduced high-density lipoprotein levels. These are all surrogate risk factors for CVD,7 and patients should therefore have annual lipid profiles. However, women with PCOS have not been shown to have a markedly higher than average mortality from CVD.8

Miscarriage and pregnancy

Miscarriage rates have been quoted as between 30 and 60 per cent for women with PCOS.9,10 Pregnancy itself is associated with an increased risk of gestational diabetes with concomitant risks to the baby. Gestational diabetes is more prevalent in obese women.

Endometrial cancer

Endometrial cancer is relatively uncommon in premenopausal women, occurring in about 4 per cent of women under 40 years of age. Women with PCOS are likely to have consistently high levels of circulating oestrogen and oligo- or amenorrhoea. Both oligo- and amenorrhoea are associated with anovulation and therefore low or absent progesterone levels. This unopposed oestrogen activity leads to endometrial proliferation and, if untreated, to adenomatous hyperplasia and finally endometrial carcinoma.

Patients with amenorrhoea should have a withdrawal bleed induced with a seven-day course of progestogens, such as medroxyprogesterone acetate 10mg bd or northisterone 5mg bd, on a three-monthly basis. This precaution almost always prevents progression to malignancy.

Breast cancer

The possible association of breast cancer with PCOS has been investigated by a large cohort study and there was no evidence that PCOS sufferers were more likely to develop the condition than controls.4

Ovarian cancer

Controversy surrounds the link between ovarian cancer and PCOS. Women who ovulate less frequently (for example those on the contraceptive pill or who have frequent pregnancies) have a lower incidence of ovarian cancer. PCOS sufferers are usually anovulatory and this might have a protective effect. However, it is known that women undergoing fertility treatment involving hyperstimulation have a slightly increased risk of ovarian cancer. This might be caused by overstimulation of the ovaries or an inherent defect of the ovaries. Results from studies are conflicting, but in a large UK study of PCOS patients who had had fertility treatment, the standardised mortality rate was 0.39.11

Infertility

Infertility remains the overwhelming problem for women with PCOS. Because the syndrome is commonly associated with anovulation, spontaneous pregnancy rates are low. A variety of treatment strategies have been studied and these are discussed below.

Treatments

Obesity

Unfortunately, the more obese a sufferer is, the worse her endocrine profile is likely to be. Most women will say that they have tried numerous diets with little effect. A low-carbohydrate and low-fat diet should help, but may be difficult to sustain.

The use of anti-obesity drugs may have a place. Claims have been made for metformin (see later) in reducing weight but there is no evidence that the drug has a direct effect. It is associated with gastrointestinal disturbance and this may incline the user to eat less. Experience indicates that where an active interest is being taken in the patient's welfare and steps are being taken to rectify the problem, compliance is better.

Hirsutism

High levels of insulin tend to lower SHBG levels and hence the amount of circulating free testosterone. This can lead to acne and, far more worryingly for the patient, an increase in unwanted hair growth. This becomes acute when the face is involved. Treatment is dependent on the patient's predominant need. As many of the treatments preclude pregnancy, their wish for a pregnancy must be established at the outset.

Medical treatments will usually cure acne and stop further hair growth. As a first line, co-cyprindiol has been used extensively, although any of the third-generation contraceptive pills are of use.

If this fails then high-dose cyproterone acetate (50mg a day), given either in combination with estradiol valerate for 21 days out of 28, or alone for the first ten days of the cycle, is effective. It is very important for the patient to understand that for facial hair to disappear or become less obvious, treatment must be taken for a minimum of nine months and, where possible, for much longer. Cyproterone acetate has been reported to have an adverse effect on liver function in rare cases; liver function tests should therefore be carried out before initiation of treatment and on a regular basis thereafter (at least annually).

Drospirenone combined with ethinylestradiol has also been used with effect. Drospirenone is related to spironolactone, which has anti-androgenic activity. It can be used alone in patients in whom the contraceptive pill is contraindicated.

Physical treatments include waxing, sugaring, laser therapy, electrolysis and bleaching. Although shaving is effective it is disliked, particularly where it affects the face, perhaps because of the unsubstantiated belief that it makes the hair thicker.

Infertility

Traditionally, PCOS was treated by a surgical procedure known as wedge resection of the ovary. This involved laparotomy, removal of a section of each ovary and subsequent suturing. Although this frequently led to a return of menstruation, pregnancy did not often result, probably because of adhesion formation over the ovaries. Subsequently a laparoscopic approach with ovarian drilling with a diathermy needle has proved effective in the short term, without the development of adhesions.

Medical treatments are more commonly used. Once again it should be emphasised that weight loss is the key to success. Clomifene has been used extensively, with variable success. The major danger is multiple pregnancy, and treatment must be carefully monitored by ultrasound scanning to avoid this.

More recently, metformin has come to play an increasingly important role in the treatment of PCOS. The rationale for its use is the close association between insulin resistance and anovulation. The mechanism remains unclear, but high levels of insulin are associated with androgen production from ovarian stromal cells, which in turn impairs follicular development. In addition there is impairment of local steroidogenesis within the ovaries. There is clear evidence that metformin used alone improves menstrual regularity and ovulation rates; however, there is noclear evidence that it improves pregnancy rates. Five trials comparing the combination therapy (metformin plus clomifene) with clomifene alone showed a significant benefit with the combined therapy (OR 4.88, 95 per cent CI 2.46–9.67).12

A more recent paper suggests that clomifene is more useful than metformin alone for helping women with PCOS to achieve pregnancy. However, the findings confirmed that the combination therapy was superior to clomifene alone. The researchers randomly assigned 626 infertile women with PCOS to one of three treatments: clomifene plus placebo, metformin plus placebo, or metformin plus clomifene. After six months' follow-up, fewer women in the metformin-only group had given birth compared with either of the clomifene groups (7.2 per cent for the metformin-only group compared with 22.5 per cent for the clomifene-only group and 26.8 per cent for those taking metformin plus clomifene).13

Similar results using gonadotrophins plus metformin have shown an increased pregnancy rate compared with gonadotrophins alone. In addition, hyperstimulation appears to be less of a problem (personal communication). However, metformin is not licensed for use in PCOS and is unlikely ever to be so.

Similarly its use in pregnancy, although beneficial in reducing miscarriage rates, remains unlicensed. However, no animal studies have shown a teratogenic effect and the drug has been used successfully in gestational diabetes.

Patients requiring fertility treatment, especially if they are anovulatory, should be referred. Patients seeking help with obesity or hirsutism can be initially treated in primary care.

Conclusion

PCOS may occur in as many as 50 per cent of women with polycystic ovaries. The main problems are obesity, androgenisation and anovulation. Strict dieting is of considerable benefit, medical treatments for hirsutism are effective when used long term (for three years or more), and treatments involving a combination of metformin plus an ovulation-inducing agent improve pregnancy rates.

Useful information

Verity is the UK charity for women whose lives are affected by PCOS.
www.verity-pcos.org.uk

PCOS UK is a new multidisciplinary society for healthcare professionals caring for women with PCOS. It is the healthcare professional section of Verity, and provides educational support to improve awareness and knowledge of PCOS and related conditions among healthcare professionals in the UK
www.pcos-uk.org.uk

Women's Health Concern is a charitable organisation that aims to help educate and support women with their healthcare by providing unbiased, accurate information.
www.womens-health-concern.org.uk

Royal College of Obstetricians and Gynaecologists
www.rcog.org.uk

Author

Mr Peter Bowen-Simpkins
MA FRCOG FFFP
consultant gynaecologist and Medical Director of the London Women's Clinic

Key points PCOS_box1

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