Polycystic Ovaries. Polycystic ovary syndrome (PCOS) is a complex, heterogeneous. Diagnosis and treatment of PCOS SPOTLIGHT

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Dr Seng Shay Way is a Consultant Obstetrician and Gynaecologist at the Raffles Fertility Centre in Raffles Hospital. Dr Seng graduated from the Royal College of Surgeons in Ireland. He pursued his internship and subsequently obstetrics and gynaecology training at TTSH and KKH, before being admitted to the Royal College of Obstetricians and Gynaecologists in London. Dr Seng is a MOH-certified reproductive specialist with expertise and knowledge from over 15 years of experience in teaching and in the treatment of reproductive disorders and infertility. He served as an executive council member in the Obstetrical and Gynaecological Society of Singapore (OGSS) from 2001 to 2003 and is currently a member of OGSS. His main research interests are in polycystic ovary syndrome (PCOS), recurrent miscarriages, the use of antagonist in IVF cycles, endometriosis treatments and surgery. He has undergone training in gynaecological surgery including abdominal laparoscopy, with emphasis on fertility treatment and preservation.

P

olycystic ovary syndrome (PCOS) is a complex, heterogeneous disorder of uncertain aetiology and is thought to be one of the leading causes of female subfertility and the most frequent endocrine problem in women of reproductive age.1

Currently, there is no consensus on the causes of PCOS but there is strong evidence that it can be classified as a genetic disease. This is observed in familial clustering of cases, with greater concordance in monozygotic compared to dizygotic twins and heritability of endocrine and metabolic features of PCOS.2-4 Recent data also suggest that the genetic

variant maybe inherited in an autosomal dominant fashion with high genetic penetrance but variable expressivity in females.3-5 The genetic

variant(s) can be inherited from either the father or the mother, and can be passed along to both sons (who may be asymptomatic carriers or may have symptoms such as early baldness and/or excessive hair) and daughters, who will show signs of PCOS.5

Clinical Signs and Symptoms

PCOS produces symptoms in approximately 5% to 10% of women of reproductive age (12 to 45 years old). The symptoms of PCOS may begin in adolescence with menstrual irregularities, or a woman may not know she has PCOS until later in life when symptoms and/or infertility occur. Women of all ethnicities may be affected.

PCOS includes a heterogeneous collection of signs and symptoms with varying degrees of severity in affecting the reproductive, endocrine and

Polycystic

Diagnosis and treatment of PCOS

by Dr Seng Shay Way

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greater proportion of clinicians worldwide accepts and uses the Rotterdam criteria published in 2003 or the National Institute of Health criteria (1990) for recognising PCOS.

In 1990, a consensus workshop sponsored by the NIH/NICHD suggested that a patient has PCOS if she has all of the following:8

• Oligoovulation

• Signs of androgen excess (clinical or biochemical). Androgen excess can be tested by measuring total and free testosterone levels. Other androgens, such as DHEA-S, may be normal or slightly above the normal range in patients with polycystic ovarian syndrome (PCOS), while levels of sex hormone–binding globulin (SHBG) are usually low in patients with PCOS. Androstenedione levels are also elevated in women with PCOS. • Other entities are excluded that would cause polycystic ovaries.

In 2003, a PCOS diagnosis consensus workshop sponsored by ESHRE/ ASRM in Rotterdam indicated PCOS to be present if any two out of the following three criteria are met and other entities are excluded that would cause these:1,9,10

• Oligoovulation and/or anovulation

• Excess androgen activity (clinical or biochemical). Androgen excess can be tested by measuring total and free testosterone levels. Other androgens, such as DHEA-S, may be normal or slightly above the normal range in patients with polycystic ovarian syndrome (PCOS) while levels of sex hormone–binding globulin (SHBG) are usually low in patients with PCOS. Androstenedione levels are also elevated in women with PCOS. • Polycystic ovaries

(by gynaecologic ultrasound or any other imaging modalities) with at least one of the following criteria should be present to establish polycystic ovaries: either 12 or more follicles measuring 2mm to 9mm in diameter, or increased ovarian volume (>10cm3).11

Some other blood tests are suggestive but not diagnostic.

• The ratio of LH (luteinising hormone) to FSH (follicle stimulating hormone), when measured in international units, is greater than 1:1 (sometimes more than 3:1),18 as tested on Day 3 of the menstrual cycle.

Symptoms Frequency Oligomenorrhea 29% to 52% Amenorrhea 19% to 51% Hirsutism 64% to 69% Obesity 35% to 41% Acne 27% to 35% Alopecia 3% to 6% Acanthosis nigricans <1% to 3% Infertility 20% to 74% Elevated Serum LH 40% to 51% Elevated testosterone 29% to 50%

Table 1. Clinical signs and symptoms associated with PCOS7

Currently, there is no consensus

on the causes of PCOS but there

is strong evidence that it can be

classified as a genetic disease. This

is observed in familial clustering of

cases, with greater concordance in

monozygotic compared to dizygotic

twins and heritability of endocrine

and metabolic features of PCOS.

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metabolic function. The classic triad of the disorder includes hirsutism, menstrual dysfunction, and obesity. Some common symptoms of PCOS include:

• Menstrual disorders – PCOS mostly produces oligomenorrhea or amenorrhea, but other types of menstrual disorders may also occur.1

• Infertility – this generally results directly from chronic anovulation.1

• Hyperandrogenism – the most common signs are acne and hirsutism (male pattern of hair growth), but it may produce hypermenorrhea (very frequent menstrual periods) or other menstrual disorders.1

• Metabolic syndrome – this appears as a tendency towards central obesity and other symptoms associated with insulin resistance.1 Serum

insulin, insulin resistance and homocysteine levels are higher in women with PCOS.6

Diagnosis

Even though PCOS was described primarily in 1935 by Stein and Leventhal, to date we are lacking the commonly accepted agreement in the issue of diagnosis of this syndrome. Contemporarily, a

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The pattern is not very specific and was present in less than 50% in one study.12

Other assessments for associated conditions or risks:

• Fasting biochemical screen and lipid profile13

• Two-hour oral glucose tolerance test (GTT) in patients with risk factors (obesity, family history, history of gestational diabetes)1 may indicate

impaired glucose tolerance (insulin resistance) in 15% to 33% of women with PCOS.13 Fifty to eighty percent of PCOS patients may have insulin

resistance at some level.1

• Thyroid function tests • Pregnancy test • Prolactin levels

• Endometrial sampling if there is prolonged amenorrhea or ultrasound evidence of endometrial hyperplasia.

Differential Diagnosis

Other causes of irregular or absent menstruation and hirsutism, such as hypothyroidism, congenital adrenal hyperplasia (21-hydroxylase deficiency), Cushing's syndrome, hyperprolactinaemia, androgen secreting neoplasms, and other pituitary or adrenal disorders, should be investigated.1,13

Management

Medical treatment of PCOS is tailored to the patient's needs and goals. These can be broadly classified into five categories:

• Lowering of insulin levels • Restoration of fertility

• Treatment of hirsutism or acne

• Restoration of regular menstruation, and prevention of endometrial hyperplasia and endometrial cancer

• Psychological stress of PCOS

In each of these categories, there is considerable debate as to the optimal treatment. One of the major reasons for this is the lack of large scale evidence-based clinical trials comparing the different treatments. General interventions that help to reduce weight or insulin resistance can be beneficial for all these aims, because they address what is believed to be the underlying cause.

Diet

Where PCOS is associated with overweight or obesity, successful weight loss is the most effective method of restoring normal ovulation and menstruation, but many women find it very difficult to achieve and sustain significant weight loss. Low-carbohydrate diets and sustained regular exercise14 may help. Some experts recommend a low GI diet in which a

significant part of total carbohydrates are obtained from fruit, vegetables and whole grain sources.15 Vitamin D deficiency may play some role in

the development of the metabolic syndrome,14 so treatment of any such

deficiency is indicated.

Medications

Reducing insulin resistance by improving insulin sensitivity through

medications such as metformin, and thiazolidinedione (glitazones), has been a promising approach, and initial studies seemed to show effectiveness.14,16 However,

subsequent reviews in 2008 and 2009 have noted that randomised control trials have, in general, not shown the promise suggested by the early observational studies.17

Infertility

Not all women with PCOS have difficulty becoming pregnant. For those who do, anovulation or infrequent ovulation is a common cause. Other factors include changed levels of gonadotropins, hyperandrogenaemia and hyperinsulinaemia.18 Like women

without PCOS, women with PCOS who are ovulating may be infertile due to other causes, such as tubal blockages, endometriosis or uterine fibroids.

For overweight, anovulatory women with PCOS, weight loss

Figure 1. Ultrasound pictures of polycystic ovaries

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and diet adjustments, especially to reduce the intake of simple carbohydrates, are associated with resumption of natural ovulation.

For those who, after weight loss, are still anovulatory or for anovulatory lean women, then the ovulation-inducing medications clomiphene citrate14 and FSH are

the principal treatments used to promote ovulation. Previously, the anti-diabetes medication metformin was the recommended treatment for anovulation, but it appears less effective than clomiphene.

For patients who do not respond to clomiphene, diet and lifestyle modification, there are options available, including assisted reproductive technology (ART) procedures such as controlled ovarian hyperstimulation with follicle-stimulating hormone (FSH) injections followed by in-vitro fertilisation (IVF).

Though surgery is not commonly performed, the polycystic ovaries can be treated with a laparoscopic procedure called "ovarian drilling”, which often results in either resumption of spontaneous ovulation14 or

ovulation after adjuvant treatment with clomiphene or FSH. There are, however, concerns about

cyproterone acetate or drospirenone are common locally available contraceptive pills that are effective. On the other hand, progestogens such as norgestrel and levonorgestrel should be avoided due to their androgenic effects.14

Other drugs with anti-androgen effects include flutamide19 and

spironolactone,14 which can give some improvement in hirsutism.

Metformin can reduce hirsutism, perhaps by reducing insulin

resistance, and is often used if there are other features such as insulin resistance, diabetes or obesity that should also benefit from metformin.

Eflornithine is a drug which is applied to the skin in cream form, and acts directly on the hair follicles to inhibit hair growth. It is usually applied to the face.14 Medications that reduce acne by indirect hormonal

effects also include ergot dopamine agonists such as bromocriptine. 5-alpha reductase inhibitors may also be used. They work by blocking the conversion of testosterone to dihydrotestosterone.

Although these agents have shown significant efficacy in clinical trials (for oral contraceptives, in 60% to 100% of individuals14), the

reduction in hair growth may not be enough to eliminate the social embarrassment of hirsutism, or the inconvenience of plucking or shaving. It is usually worth trying other drug treatments if one does not work, but drug treatments do not work well for all individuals. For removal of facial hairs, electrolysis or laser treatments are – at least for some – faster and more efficient alternatives than the above mentioned medical therapies.

Menstrual Irregularity and Endometrial Hyperplasia

If fertility is not the primary aim, then menstruation can usually be regulated with a contraceptive pill.14 The purpose of regulating

menstruation is essentially for the woman's convenience and perhaps her sense of well-being. There is no medical requirement for regular periods, so long as they occur sufficiently often.

If a regular menstrual cycle is not desired, then therapy for an irregular cycle is not necessarily required – most experts consider that if a menstrual bleed occurs at least every three months, then the endometrium is being shed sufficiently often to prevent an increased risk of endometrial abnormalities or cancer.20 If menstruation occurs

less often or not at all, some form of progestogen replacement is

Where PCOS is associated with

overweight or obesity, successful

weight loss is the most effective

method of restoring normal ovulation

and menstruation, but many women

find it very difficult to achieve and

sustain significant weight loss.

the long-term effects of ovarian drilling on ovarian function.14

Hirsutism and Acne

When appropriate, a standard oral contraceptive pill (OCP) is frequently effective in reducing hirsutism.14 A common choice

of OCP is one that contains a progestogen with anti-androgen effects that block the action of male hormones that are believed to contribute to acne and the growth of unwanted facial and body hair. OCP containing

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recommended. Some women prefer a uterine progestogen device such as the intrauterine system or the progestin implant, which provides simultaneous contraception and endometrial protection for years. An alternative is oral progestogen taken at intervals (e.g. every three months) to induce a predictable menstrual bleeding.12

Psychological Stress of PCOS

In addition, as PCOS appears to cause significant emotional distress, these stresses can come in the form of frustration from fertility treatment, physical stress of acne and hirsutism or stress of long term risk. It is recommended that clinicians discuss emotional aspects of PCOS with patients and refer for appropriate support where necessary and in accordance with patient preference.21

Long Term Risks

Women with PCOS are at risk for the following:

• Endometrial hyperplasia and endometrial cancer due to lack of progesterone resulting in prolonged stimulation of uterine cells by estrogen.22 It is not clear if this risk is directly due to the

syndrome or from the associated obesity, hyperinsulinaemia, and hyperandrogenism.

• Insulin resistance/type 2 diabetes.22 A review published in 2010

concluded that women with PCOS had an elevated prevalence of insulin resistance and type 2 diabetes, even when controlling for body mass index (BMI). PCOS also makes a woman, particularly if obese, prone to gestational diabetes.22

• High blood pressure, particularly if obese and/or during pregnancy22

• Depression/depression with anxiety

• Dyslipidaemia22 – disorders of lipid metabolism — cholesterol

and triglycerides. PCOS patients show decreased removal of atherosclerosis-inducing remnants, seemingly independent of insulin resistance/type 2 diabetes.

• Cardiovascular disease,22 with a meta-analysis estimating a

two-fold risk of arterial disease for women with PCOS relative to women without PCOS, independent of BMI.22

• Weight gain/obesity22

• Miscarriage23

• Sleep apnoea, particularly if obesity is present22

• Non-alcoholic fatty liver disease, again particularly if obesity is present22

Conclusion

In general, PCOS is a very complex condition that may require a multidisciplinary team to manage. Although there is no cure for PCOS, most women can control the symptoms with just lifestyle and dietary changes. It is also important to recognise the potential long term condition as early diagnosis and intervention may reduce the risk of some of these complications, such as type 2 diabetes, stroke and heart disease12, and promote long-term health.

References

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