Endocrine profile

An endocrine profile is best taken during a menstrual bleed, although it may need to be taken at random in an oligomenorrhoeic or amenorrhoeic woman. Follicle-stimulating hormone (FSH), LH, oestradiol, testosterone, prolactin and thyroid function should be measured. If the patient wishes to conceive, it is necessary to ascertain whether ovulation is occurring. Patients with anovulatory infertility will have oligomenorrhoea or amenorrhoea and a low luteal-phase progesterone. A progesterone concentration of more than 30 nmol/l suggests ovulation, but it can be difficult to know when to take the blood if the patient has an erratic cycle, and impossible if she is amenorrhoeic. If the progesterone concentration is 15–30 nmol/l, the timing may have been incorrect. It is then necessary to check the timing of the blood test to subsequent menstruation, and repeat the test in the following cycle (sometimes two progesterone measurements in the same cycle are helpful). The optimal way to assess ovulation in women with irregular cycles is by a combination of serial ultrasound scans and serum endocrine measurements (FSH and LH in the follicular phase, progesterone in the luteal phase).

Women with PCOS usually have a normal serum FSH concentration (Table 18.2). LH is the second gonadotrophin which, like FSH, is released by the gonadotrophs in the anterior pituitary gland, under the influence of pulsatile release of gonadotrophin-releasing hormone (GnRH). The differential control of FSH and LH secretion relies upon the need for priming of the pituitary by oestradiol before it will become responsive to GnRH and release LH. FSH secretion, on the other hand, is under tonic inhibitory control by inhibin acting in a negative feedback loop from the ovaries. Therefore, in times of oestrogen deficiency, such as weight-related amenorrhoea, LH concentrations in the circulation are lower than FSH, whilst the mid-cycle surge that is primed by rising oestradiol secretion from the ovary results in a greater release of LH than FSH.

An elevated serum concentration of LH in the follicular phase of the cycle suggests that the patient has PCOS, usually associated with a concentration of more than 10 IU/l in the early to mid-follicular phase of the cycle. In a series of over 1700 women with PCOS, approximately 40% of patients were found to have an elevated serum concentration of LH, which was associated with a significantly higher risk of infertility than in those with normal LH levels (Balen et al 1995). Other causes of an elevated LH serum concentration are the mid-cycle surge and ovarian failure (Table 18.2).

LH stimulates ovarian production of androgens, and LH is most commonly elevated in slim women with PCOS. In overweight women, hypersecretion of insulin is the main cause of androgen secretion by the ovaries.

The normal female range for total serum testosterone is 0.5–3.5 nmol/l. The most usual cause of an elevated serum testosterone level is PCOS. Most women with PCOS, however, have a normal total serum testosterone concentration. Measurement of the sex-hormone-binding globulin (SHBG) concentration (normal range 16–119 nmol/l) will permit calculation of the ‘free androgen index’ [(testosterone × 100)/SHBG], which should be less than 5. Women who are obese have high circulating levels of insulin which reduces synthesis of SHBG by the liver, so the free androgen index is often elevated when total testosterone is in the normal range.

If the serum testosterone concentration is greater than 5 nmol/l, it is necessary to exclude other causes of hyperandrogenaemia, such as late-onset CAH, Cushing’s syndrome and androgen-secreting tumours. Women with the most common form of CAH (21-hydroxylase deficiency) will have an elevated serum 17-hydroxyprogesterone concentration (17-OHP >20 nmol/l) and an exaggerated response to an intravenous bolus of adrenocorticotrophic hormone (250 mg tetracosactrin will cause an elevation of 17-OHP, usually between 65 and 470 nmol/l).

Features of hyperandrogenism

Signs of hyperandrogenism (acne, hirsutism, balding) are suggestive of PCOS, although biochemical screening helps to differentiate other causes of androgen excess. Hirsutism can be graded and given a ‘Ferriman Gallwey score’. It is useful to monitor the progress of hirsutism, or its response to treatment, by making serial records, either using a chart or by taking photographs of affected areas of the body. It is important to distinguish between hyperandrogenism and virilization, which is associated with high circulating androgen levels and causes deepening of the voice, increase in muscle bulk, breast atrophy and cliteromegaly. Virilization suggests a more profound disturbance of androgen secretion than usually seen with PCOS, and indicates the need to exclude CAH, Cushing’s syndrome and androgen-secreting tumours.

Hyperinsulinaemia

The association between insulin resistance, compensatory hyperinsulinaemia and hyperandrogenism has provided insight into the pathogenesis of PCOS. The cellular and molecular mechanisms of insulin resistance in PCOS have been investigated extensively, and it is evident that the major defect is a decrease in insulin sensitivity secondary to a postbinding abnormality in insulin-receptor-mediated signal transduction, with a less substantial, but significant, decrease in insulin responsiveness (Dunaif 1997). It appears that decreased insulin sensitivity in PCOS is potentially an intrinsic defect in genetically susceptible women, since it is independent of obesity, metabolic abnormalities, body fat topography and sex hormone levels.

Although the insulin resistance may occur irrespective of body mass index (BMI), the common association between PCOS and obesity has a synergistic deleterious impact on glucose homeostasis, and can worsen both hyperandrogenism and anovulation. An assessment of BMI alone is not thought to provide a reliable prediction of cardiovascular risk. It has been reported that the association between BMI and coronary heart disease almost disappeared after correction for dyslipidaemia, hyperglycaemia and hypertension. Some women have profound metabolic abnormalities in the presence of a normal BMI, and others have few risk factors with an elevated BMI. It has been suggested that rather than BMI itself, it is the distribution of fat that is important, with android obesity being more of a risk factor than gynaecoid obesity. Hence the value of measuring the waist:hip ratio or waist circumference, which detect abdominal visceral fat rather than subcutaneous fat. It is the visceral fat which is metabolically active and, when increased, results in increased rates of insulin resistance, type 2 diabetes, dyslipidaemia, hypertension and left ventricular enlargement. There is a closer link between waist circumference and visceral fat mass, as assessed by computer tomography, than waist:hip ratio or BMI (Lord and Wilkin 2002). Waist circumference should ideally be less than 79 cm, whilst a measurement of greater than 87 cm carries a significant risk. Exercise has a significant effect on reducing visceral fat and reducing cardiovascular risk; indeed, a 10% reduction in body weight may equate to a 30% reduction in visceral fat.

Insulin acts through multiple sites to increase endogenous androgen levels. Increased peripheral insulin resistance results in a higher serum insulin concentration. Excess insulin binds to IGF-1 receptors which enhances androgen production by theca cells in response to LH stimulation. Hyperinsulinaemia also decreases the synthesis of SHBG by the liver. Therefore, there is an increase in the serum free testosterone concentration, and consequent peripheral androgen action. Intraovarian androgen excess is responsible for anovulation by acting directly on the ovary, promoting the process of follicular atresia. This latter process is characterized by apoptosis of granulosa cells. As a consequence, there is an increasingly larger stromal compartment, which retains LH responsiveness and continues to secrete androgens. Hyperinsulinaemia also stimulates trophic changes in the skin that results in acanthosis nigricans in the skin creases (Figure 18.6).

Figure 18.6 Acanthosis nigricans as seen typically in the axilla or skin of the neck in women with insulin resistance. (A) Axilla. (B) Close-up, demonstrating hypertrophic and pigmented skin.

Insulin resistance is defined as a reduced glucose response to a given amount of insulin and may occur secondary to resistance at the insulin receptor, decreased hepatic clearance of insulin and/or increased pancreatic sensitivity. Both obese and non-obese women with PCOS are more insulin resistant and hyperinsulinaemic than age- and weight-matched women with normal ovaries. Thus, there appear to be factors in women with PCOS which promote insulin resistance and that are independent of obesity.

Insulin resistance can be measured by a number of expensive and complex tests, but it is not necessary to measure it routinely in clinical practice; it is more important to check for impaired glucose tolerance. Simple screening tests for risk of impaired glucose tolerance (IGT) include an assessment of BMI and waist circumference. If the fasting blood glucose is less than 5.2 mmmol/l, the risk of impaired glucose tolerance is low. The 2-h standard 75 g oral glucose tolerance test may be conducted in those at high risk (BMI >30 kg/m² in Caucasian women and >25 kg/m² in women from South Asia, who have a greater degree of insulin resistance at a lower body weight) (Table 18.3).

National and racial differences in expression

Approximately 75–80% of women with polycystic ovaries have signs or symptoms of PCOS. Thus, in the UK, where it has been reported that up to 33% of women have polycystic ovaries (Michelmore et al 1999), 20–25% of women may have a degree of PCOS, albeit mild in many cases. There are large national and ethnic variations in the expression of PCOS, with women from the Far East having little in the way of hirsutism, whilst those with dark hair from Mediterranean and Middle Eastern or South Asian countries have a greater degree of expression. The highest reported prevalence of polycystic ovaries has been 52% among South Asian immigrants in Britain, of whom 49% had menstrual irregularity (Rodin et al 1998). It was also shown that South Asian women with polycystic ovaries had a comparable degree of insulin resistance to controls with established type 2 diabetes. Generally, there has been a paucity of data of the prevalence of PCOS among women of South Asian origin, both among migrant and native groups. Type 2 diabetes and insulin resistance have a high prevalence among indigenous populations in South Asia, with a rising prevalence among women. Insulin resistance and hyperinsulinaemia are common antecedents of type 2 diabetes, with a high prevalence in South Asians. Type 2 diabetes also has a familial basis, inherited as a complex genetic trait that interacts with environmental factors, chiefly nutrition, commencing from fetal life. It has been shown that ethnic variations in the overt features of PCOS (symptoms of hyperandrogenism, menstrual irregularity and obesity) in women of South Asian descent are linked to the higher prevalence and degree of insulin resistance in South Asians. It has also been shown that South Asians with anovulatory PCOS have greater insulin resistance and more severe symptoms of PCOS than anovular White Caucasians with PCOS (Wijeyaratne et al 2002).

The question remains as to whether differences in expression of PCOS are due to dietary and lifestyle factors or to genetic variations in hormone actions, such as polymorphisms in gonadotrophin subunits or receptor function (affecting the expression of androgens, gonadotrophins or insulin). A full discussion of the genetics of PCOS is beyond the scope of this chapter, and there are a number of candidate genes that have been proposed (see Franks et al 2001). It may be that some families or racial groups have genetic differences that affect the expression or presentation of PCOS.

Ischaemic heart disease

Obesity and metabolic abnormalities are recognized risk factors for the development of ischaemic heart disease (IHD) in the general population, and these are also recognized features of PCOS. In Europe, IHD accounts for 18% of deaths in men and 14% of deaths in women. In men, the incidence of IHD increases after the age of 35 years, while in women, an increased incidence is noted after the age of 55 years. The questions are whether women with PCOS are at increased risk of IHD, and whether this will occur at an earlier age than in women with normal ovaries. The basis for the idea that women with PCOS are at greater risk for cardiovascular disease is that these women are more insulin resistant than weight-matched controls, and that the metabolic disturbances associated with insulin resistance are known to increase cardiovascular risk in other populations.

Insulin resistance

In the general population, cardiovascular risk factors include insulin resistance, obesity (especially an increase in waist circumference), glucose intolerance, diabetes, hypertension and dyslipidaemia (particularly raised serum triglycerides). Insulin sensitivity varies depending upon menstrual pattern. Women with PCOS who are oligomenorrhoeic are more likely to be insulin resistant than those with regular cycles, irrespective of their BMI. Women with PCOS have a defect in insulin signalling at the insulin receptor, which causes insulin resistance. The sex-steroid-induced increase in growth hormone that initiates the adolescent growth spurt also leads to insulin resistance, and explains the timing of onset of symptoms in those prone to develop PCOS. The presence of obesity and/or type 2 diabetes worsens the degree of insulin resistance.

Insulin resistance is restricted to the extrasplanchnic actions of insulin on glucose dispersal. The liver is not affected [hence the decrease in SHBG and high-density lipoproteins (HDLs)], and neither is the ovary (hence the menstrual problems and hypersecretion of androgens) nor the skin (hence the development of acanthosis nigricans). Insulin resistance causes compensatory hypersecretion of insulin, particularly in response to glucose, so euglycaemia is usually maintained at the expense of hyperinsulinaemia.

It is reported that up to 20% of slim women and 40% of obese women with PCOS demonstrate impaired glucose tolerance. Insulin resistance combined with abdominal obesity is thought to account for the higher prevalence of type 2 diabetes in PCOS. There is a concomitant increased risk of gestational diabetes.

Dyslipidaemic women with PCOS have high concentrations of serum triglycerides and suppressed HDL levels, particularly a lower HDL₂ subfraction. HDLs play an important role in lipid metabolism and are the most important lipid parameter in predicting cardiovascular risk in women. HDLs perform the task of ‘reverse cholesterol transport’. That is, they remove excess lipids from the circulation and tissues to transport them to the liver for excretion, or transfer them to other lipoprotein particles.

In a large retrospective study, Pierpoint et al (1998) reported the mortality rate in 1028 women diagnosed with PCOS between 1930 and 1979. All of the women were over 45 years of age and 770 women had been treated by wedge resection of the ovaries. In total, 786 women were traced; the mean age at diagnosis was 26.4 years and the average duration of follow-up was 30 years. There were 59 deaths, of which 15 were from circulatory disease. Of these 15 deaths, 13 were from IHD. There were six deaths from diabetes as an underlying or contributory cause, compared with the expected 1.7 deaths. The standardized mortality rate (SMR), both overall and for cardiovascular disease, was not higher in the women with PCOS compared with the national mortality rates in women, although the observed proportion of women with diabetes as a contributory or underlying factor leading to death was significantly higher than expected [odds ratio 3.6, 95% confidence interval (CI) 1.5–8.4]. Thus, despite surrogate markers for cardiovascular disease, Pierpoint et al (1998) found no increased rate of death from cardiovascular disease. A follow-up report from the same study, however, did demonstrate an increased, although non-significant, risk of death due to diabetes [after adjustment for BMI, the odds ratio was 2.2 (95% CI 0.9–5.2) for diabetes (Wild et al 2000)]. There was still no increase in long-term coronary heart disease mortality in the PCOS group, although there was evidence of increased stroke-related mortality, even after adjustment for BMI.

Homocysteine

A moderately increased total plasma homocysteine (Hcy) concentration is associated with an increased risk of atherosclerosis. Hcy is an essential intermediate in the transfer of activated methyl groups from tetrahydrofolate to S-adenosylmethionine, in the synthesis of cysteine from methionine, and in the production of homocysteine thiolactone. An abnormal elevation of Hcy in plasma and urine is caused by an imbalance between Hcy production and metabolism, which can be of demographic, genetic, nutritional or metabolic aetiology, and is associated with premature vascular disease. Mild hyperhomocysteinaemia has been demonstrated to induce sustained injury to the arterial endothelial cells that accelerate the development of thrombosis and atherosclerosis. Normal concentrations of total plasma Hcy are in the range of 5–16 µmol/l, although 10 µmol/l is considered to be the desirable upper limit; there is an age-related rise and lower concentrations are found in women. There have been reports of elevated plasma Hcy in Caucasian women with PCOS, and this may be greater in the South Asian population (Rendeva et al 2002). Weight reduction and regular physical exercise are recognized interventions that help to reduce insulin resistance and the metabolic syndrome.

Endometrial cancer

Endometrial adenocarcinoma is the second most common female genital malignancy, but only 4% of cases occur in women under 40 years of age. The risk of developing endometrial cancer has been shown to be adversely influenced by a number of factors including obesity, long-term use of unopposed oestrogens, nulliparity and infertility. The relative risk of endometrial cancer is 1.6 in women with a menarche before the age of 12 years, and 2.4 in women who have their menopause after the age of 52 years (Elwood et al 1977). Women with endometrial carcinoma have had fewer births compared with controls, and it has also been demonstrated that infertility per se gives a relative risk of 2. Hypertension and type 2 diabetes have long been linked to endometrial cancer, with relative risks of 2.1 and 2.8, respectively; these conditions are now known to be associated with PCOS.

A study by Coulam et al (1983) examined the risk of developing endometrial carcinoma in a group of 1270 patients who were diagnosed with chronic anovulation syndrome. The defining characteristics of this group included pathological or macroscopic evidence of the Stein–Leventhal syndrome, or a clinical diagnosis of chronic anovulation. This study identified the excess risk of endometrial cancer to be 3.1 (95% CI 1.1–7.3), and proposed that this might be due to abnormal levels of unopposed oestrogen. However, the true risk of endometrial carcinoma in women with PCOS is difficult to ascertain.

Endometrial hyperplasia

Endometrial hyperplasia may be a precursor to adenocarcinoma, with cystic glandular hyperplasia progressing in perhaps 0.4% of cases and adenomatous hyperplasia in up to 18% of cases over 2–10 years. Precise estimation of the rate of progression is impossible to determine. Some authors have reported conservative management of endometrial adenocarcinoma in women with PCOS, with a combination of curettage and high-dose progestogens. The rationale is that cancer of the endometrium often presents at an early stage, is well differentiated, has a low risk of metastasis, and therefore is not perceived as being life threatening, while poorly differentiated adenocarcinoma in a young woman has a worse prognosis and warrants hysterectomy. In general, however, the literature on women with PCOS and endometrial hyperplasia or adenocarcinoma suggests that this group has a poor prognosis for fertility. This may be because of the factors that predispose to the endometrial pathology — chronic anovulation often combined with severe obesity — or secondary to the endometrial pathology disrupting potential embryonic implantation. Thus, a more traditional and radical surgical approach (i.e. hysterectomy) is suggested as the safest way to prevent progression of the cancer (Balen 2001).

Although the degree of risk has not been clearly defined, it is generally accepted that for women with PCOS who experience amenorrhoea or oligomenorrhoea, the induction of artificial withdrawal bleeds to prevent endometrial hyperplasia is prudent management. Indeed, the author considers it important that women with PCOS should shed their endometrium at least every 3 months. For those women with oligomenorrhoea or amenorrhoea who do not wish to use cyclical hormone therapy, an ultrasound scan is recommended to measure endometrial thickness and morphology every 6–12 months (depending upon menstrual history). An endometrial thickness of more than 10 mm in an amenorrhoeic woman warrants an artificially induced bleed, which should be followed by a repeat ultrasound scan and endometrial biopsy if the endometrium has not been shed. Another option is to consider a progestogen-secreting intrauterine system, such as the Mirena.

Breast cancer

Obesity, hyperandrogenism and infertility occur frequently in PCOS, and are features known to be associated with the development of breast cancer. However, studies examining the relationship between PCOS and breast carcinoma have not always identified a significantly increased risk. The study by Coulam et al (1983) calculated a relative risk of 1.5 (95% CI 0.75–2.55) for breast cancer in their group of women with chronic anovulation, which was not statistically significant. After stratification by age, however, the relative risk was found to be 3.6 (95% CI 1.2–8.3) in the postmenopausal age group. More recently, Pierpoint et al (1998) reported SMRs calculated for patients with PCOS compared with the normal population. The SMR for all neoplasms was 0.91 (95% CI 0.60–1.32) and the SMR for breast cancer was 1.48 (95% CI 0.79–2.54). In fact, breast cancer was the leading cause of death in this cohort.

Ovarian cancer

In recent years, there has been much debate about the risk of ovarian cancer in women with infertility, particularly in relation to the use of drugs to induce superovulation for assisted conception procedures. Inherently, the risk of ovarian cancer appears to be increased in women who have multiple ovulations; that is, those who are nulliparous (possibly because of infertility) with an early menarche and late menopause. Thus, it may be that inducing multiple ovulations in women with infertility will increase their risk; a hypothesis that is by no means proven. Women with PCOS who are oligo-ovulatory or anovulatory might therefore be expected to be at low risk of developing ovarian cancer if it is lifetime number of ovulations rather than pregnancies that is critical. Ovulation induction to correct anovulatory infertility aims to induce unifollicular ovulation and so, in theory, should increase the risk of a woman with PCOS compared with that of a normal ovulating woman. The polycystic ovary, however, is notoriously sensitive to stimulation and it is only in recent years, with the development of high-resolution transvaginal ultrasonography, that the rate of unifollicular ovulation has attained acceptable levels. The use of clomiphene citrate and gonadotrophin therapy for ovulation induction in the 1960s, 1970s and 1980s resulted in many more multiple ovulations (and indeed multiple pregnancies) than in recent times, and might therefore present with an increased rate of ovarian cancer when these women reach their 60s, the age of greatest incidence.

A few studies have addressed the possibility of an association between polycystic ovaries and ovarian cancer. The results are conflicting, and generalizability is limited due to problems with the study designs. In the large UK study of Pierpoint et al (1998), the SMR for ovarian cancer was 0.39 (95% CI 0.01–2.17).

Psychological support and quality of life

The symptoms typically associated with the condition have also been shown to lead to a significant reduction in health-related quality of life (Jones et al 2004). Health-related quality of life is a multidimensional, dynamic concept that encompasses physical, psychological and social aspects that are associated with a particular disease or its treatment. Therefore, any management of the woman with PCOS needs to consider and understand the negative impact that this condition may have upon these psychosocial parameters. For example, although the management of hirsuitism may be considered as a purely cosmetic issue, excessive facial hair has been shown to be one of the major causes of marked psychological stress in women with PCOS, often caused by embarrassment about the excessive hair growth. Infertility and weight issues have also been found to affect other social and psychological parameters. Infertility can cause tensions within the family, altered self-perception and problems at work. Whilst obesity worsens the symptoms, the metabolic scenario conspires against weight loss; many women experience frustration in attempts to lose weight and suffer from low-esteem and poor body image.

Obesity

The management of women with PCOS should be focused on the patient’s particular problems. Obesity worsens both symptomatology and the endocrine profile, so obese women (BMI >30 kg/m²) should be encouraged to lose weight by a combination of calorie restriction and exercise. Weight loss improves the endocrine profile, the likelihood of ovulation and the likelihood of a healthy pregnancy.

Menstrual irregularity

The simplest way to control the menstrual cycle is the use of a low-dose combined oral contraceptive preparation (COCP). This will result in an artificial cycle and regular shedding of the endometrium. It is also important, once again, to encourage weight loss. As women with PCOS are thought to be at increased risk of cardiovascular disease, a ‘lipid friendly’ combined contraceptive pill should be used. The third-generation oral contraceptives are lipid friendly but present the potential disadvantage of venous thromboembolism, particularly in overweight women. Dianette^® is a COCP that has antiandrogenic properties and will have additional benefits for women with hyperandrogenism, and Yasmin^® contains a newer antiandrogen, drosperinone, which is a derivative of spironolactone. Alternatives to the COCP include a progestogen, for example medroxyprogesterone acetate (Provera) or dydrogesterone (Duphaston), for 12 days every 1–3 months to induce a withdrawal bleed, or simply the insertion of a Mirena intrauterine system.

In women with anovulatory cycles, the action of oestradiol on the endometrium is unopposed because of the lack of cyclical progesterone secretion. This may result in episodes of irregular uterine bleeding and, in the long term, endometrial hyperplasia and even endometrial cancer (see above). An ultrasound assessment of endometrial thickness provides a bioassay for oestradiol production by the ovaries and conversion of androgens in the peripheral fat. If the endometrium is thicker than 10 mm, a withdrawal bleed should be induced; if the endometrium fails to shed, endometrial sampling is required to exclude endometrial hyperplasia or malignancy.

Hyperandrogenism and hirsutism

The bioavailability of testosterone is affected by the serum concentration of SHBG. High levels of insulin lower the production of SHBG and therefore increase the free fraction of androgen. Elevated serum androgen concentrations stimulate peripheral androgen receptors, resulting in an increase in 5-α reductase activity, directly increasing the conversion of testosterone to the more potent metabolite, dihydrotestosterone. Symptoms of hyperandrogenism include hirsutism and acne, which are both distressing conditions. Hirsutism is characterized by terminal hair growth in a male pattern of distribution, including chin, upper lip, chest, upper and lower back, upper and lower abdomen, upper arm, thigh and buttocks. A standardized scoring system, such as the modified Ferriman and Gallwey score, should be used to evaluate the degree of hirsutism before and during treatments (Figure 18.7).

Figure 18.7 Ferriman and Gallwey score. Each area is given a score from 1 to 4 (1 = mild, 2 = moderate, 3 = complete light coverage, 4 = heavy coverage).

Treatment options include cosmetic and medical therapies. As drug therapies may take 6–9 months or longer before any improvement in hirsutism is perceived, physical treatments including electrolysis, waxing and bleaching may be helpful whilst waiting for medical treatments to work. For many years, the most ‘permanent’ physical treatment for unwanted hair has been electrolysis. It is time consuming, painful and expensive, and should be performed by an expert practitioner. Regrowth is not uncommon and there is no really permanent cosmetic treatment, but the last few years have seen much development in the use of laser and photothermolysis techniques. There are many different types of laser in production and each requires evaluation of dose intensity, effectiveness and safety. The technique is promising, being faster and more effective than shaving, waxing or chemical depilation. Repeated treatments are required for a near-permanent effect because only those hair follicles in the growing phase are obliterated at each treatment. Hair growth occurs in three cycles so 6–9 months of regular treatments are typical. Patients should be appropriately selected (dark hair on fair skin is best), and warned that complete hair removal cannot be guaranteed and some scarring may occur. At present, it is not widely available and is still an expensive option.

Vaniqa (eflornithine) has recently been developed as a topical treatment for hirsutism. It works by inhibiting the enzyme ornithine decarboxylase in hair follicles, and may be a useful therapy for those who wish to avoid hormonal treatments, but may also be used in conjunction with hormonal therapy.

Medical regimens should stop further progression of hirsutism and decrease the rate of hair growth. Therapy for acne should aim to lower sebum excretion, alter follicular cell desquamation, reduce propionibacteria and reduce inflammation.

If using antiandrogen therapy, adequate contraception is important in women of reproductive age as transplacental passage of antiandrogens may disturb the genital development of a male fetus.

The best pharmacological treatment of proven effectiveness is a combination of the synthetic progestogen cyproterone acetate, which is antigonadotrophic and antiandrogenic, with ethinyl oestradiol. Dianette contains ethinyloestradiol (35 µg) in combination with cyproterone, although at a lower dose (2 mg). Dianette is licensed for moderate to severe hirsutism and severe acne. The antiandrogen effect reduces sebum excretion in 2–3 months and results in clinical improvement in acne in 4–6 months.

Oestrogens lower circulating androgens by a combination of a slight inhibition of gonadotrophin secretion and gonadotrophin-sensitive ovarian steroid production, and by an increase in hepatic production of SHBG resulting in lower free testosterone. Cyproterone acetate can rarely cause liver damage and liver function should be checked regularly (after 6 months and then annually). There is conflicting data about a possible increased risk of thromboembolism, although there are many women who take Dianette on a long-term basis without any ill effects.

Spironolactone is a weak diuretic with antiandrogenic properties, and may be used at a daily dose of 25–100 mg in women with either hirsutism and/or acne in whom the COCP is contraindicated. Drosperinone is a derivative of spironolactone and contained in the new COCP, Yasmin, which also appears to be effective for women with PCOS. Other antiandrogens such as ketoconazole, finasteride and flutamide have been tried, but are not widely used in the UK for the treatment of hirsutism in women due to their adverse and potentially serious side-effects. Furthermore, they are no more effective than cyproterone acetate.

Topical antiacne agents can be safely and successfully combined with systemic antiandrogen therapy in an attempt to target as many aetiological factors as possible. However, these topical treatments alone have little effect on sebum production, so are not generally successful when utilized alone in acne associated with PCOS. Topical retinoids impact on the microcomedo which is the precursor to non-inflammatory and inflammatory acne lesions. They also have direct comedolytic and anti-inflammatory activity. These agents are useful adjuvant therapies in combination with antiandrogen treatments, and can be used as maintenance treatment after discontinuation of systemic therapy. Topical antimicrobials (benzoyl peroxide/antibiotics) have good anti-inflammatory activity and should help to reduce inflammatory lesions when used alongside antiandrogen treatment.

Oral isotretinoin, a hospital-only prescribed medication, is the single systemic therapy that targets the four main aetiological factors implicated in acne. However, it is currently only licensed for severe acne that has not responded to alternative therapies. A recent European Directive concerning isotretinoin has enforced a strict pregnancy prevention programme due to the high risk of teratogenecity with this drug. COCPs can be used safely alongside oral isotretinoin and are recommended by the European Directive. Although clinical clearance of acne lesions with oral isotretinoin is very likely, relapse rates post therapy are higher than average when acne is associated with PCOS.

Clomiphene citrate

Antioestrogen therapy with clomiphene citrate or tamoxifen has traditionally been used as first-line therapy for anovulatory PCOS. A recent meta-analysis confirmed that clomiphene is effective in increasing pregnancy rates when compared with placebo as first-line therapy (fixed odds ratio 5.8, 95% CI 1.6–21.5; number needed to treat 5.9, 95% CI 3.6–16.7) (Beck et al 2005). Antioestrogen therapy is usually commenced on day 2 of the cycle and given for 5 days. If the patient has oligomenorrhoea or amenorrhoea, it is necessary to exclude pregnancy and then induce a withdrawal bleed with a short course of a progestogen, such as medroxyprogesterone acetate 5–20 mg/day for 5–10 days. The starting dose of clomiphene citrate is 50 mg/day for 5 days beginning on days 3–5 of the menstrual cycle. The dose of clomiphene citrate should only be increased if there is no response after three cycles, as of those women who will respond to 50 mg/day, only two-thirds will do so in the first cycle. Doses of 150 mg/day or more do not appear to be of benefit. If there is an over-response to 50 mg/day, as in some women with PCOS, the dose can be decreased to 25 mg/day.

Clomiphene citrate may cause an exaggeration in the hypersecretion of LH and have antioestrogenic effects on the endometrium and cervical mucus. All women who are prescribed clomiphene citrate should be carefully monitored with a combination of endocrine and ultrasonographic assessment of follicular growth and ovulation because of the risk of multiple pregnancies, which is approximately 10% (Figures 18.8 and 18.9). Clomiphene therapy should therefore be prescribed and managed by specialists in reproductive medicine.

Figure 18.8 Stimulation of a single mature follicle in a polycystic ovary (transvaginal ultrasound scan).

Figure 18.9 Transvaginal ultrasound scan of an overstimulated polycystic ovary. Both ovaries are likely to have this appearance, and the treatment must be discontinued to minimize the risk of multiple pregnancy and ovarian hyperstimulation syndrome.

Aromatase inhibitors

Aromatase inhibitors have been proposed as an alternative treatment to clomiphene citrate therapy, as the discrepancy between ovulation and pregnancy rates with clomiphene citrate has been attributed to its antioestrogenic action and oestrogen receptor depletion. The aromatase inhibitors suppress oestrogen production and thereby mimic the central reduction of negative feedback through which clomiphene citrate works. Letrozole, the most widely used antiaromatase for this indication, has been shown to be effective, in early trials, in inducing ovulation and pregnancy in women with anovulatory PCOS. Anastrozole is a possible alternative. Evidence from larger trials is still awaited, but some encouragement may be taken from the solidity of the working hypothesis and the success of the preliminary results.

Gonadotrophins

Gonadotrophin therapy is indicated for women with anovulatory PCOS who have been treated with antioestrogens if they have failed to ovulate or if they have a response to clomiphene that is likely to reduce their chance of conception (e.g. persistent hypersecretion of LH or antioestrogenic effect on cervical mucus).

In order to prevent the risks of overstimulation and multiple pregnancy, the traditional standard step-up regimens (when 75–150 IU is increased by 75 IU every 3–5 days) have been replaced by low-dose step-up regimens. The low-dose step-up regimen employs a starting dose of 25–50 IU, which is only increased after 14 days if there is no response, and then by only half an ampoule every 7 days. Treatment cycles using this approach can be quite long (up to 28–35 days), but the risk of multiple follicular growth is lower than with conventional step-up regimens (Tarlatzis et al 2008) (see Chapter 17, Ovulation induction, for more information).

It can be extremely difficult to predict the response to stimulation of a woman with polycystic ovaries; indeed, this is the greatest therapeutic challenge in all ovulation induction therapies. The polycystic ovary is characteristically quiescent, at least when viewed by ultrasound, before often exhibiting an explosive response to stimulation. It can be very challenging to stimulate the development of a single dominant follicle, and while attempts have been made to predict a multifollicular response by looking at mid-follicular endocrine profiles and numbers of small follicles, it is more difficult to do so prior to commencing ovarian stimulation and hence determine the required starting dose of gonadotrophin. In order to prevent the risks of OHSS and multiple pregnancy, however, the cycle should be cancelled on day 8 of stimulation if there are more than five to seven follicles ≥8 mm. Ovulation is triggered with a single injection of human chorionic gonadotrophin (hCG) 5000 units (i.m. or s.c.). The inclusion criterion for hCG administration should be the development of at least one follicle with a largest diameter of at least 17 mm. In order to reduce the risk of multiple pregnancy and OHSS, the exclusion criterion for hCG administration is the development of a total of three or more follicles larger than 14 mm in diameter. In overstimulated cycles, hCG is withheld and the patient is counselled about the risks and advised to refrain from sexual intercourse.

Insulin-sensitizing agents

It is logical to assume that therapy that achieves a fall in serum insulin concentrations should improve the symptoms of PCOS. The biguanide metformin inhibits the production of hepatic glucose, thereby decreasing insulin secretion, and also enhances insulin sensitivity at the cellular level. Early studies involved a small number of participants and were encourgaing, whereas more recent large studies looking at the use of metformin either alone or combined with clomiphene citrate have failed to demsonstrate significant benefit with respect to weight reduction, improved menstrual cycle function or livebirth rates (Moll et al 2006, Tang et al 2006, Legro et al 2007).

In summary, although the initial studies appeared promising, subsequent large randomized-controlled trials have not demonstrated the anticipated beneficial effects of metformin as a first-line therapy for treatment of the anovulatory patient with PCOS. The study authors concur that the primary aim for overweight women with PCOS is to make lifestyle changes with a combination of diet and exercise in order to lose weight and to improve ovarian function. In conclusion, the position of metformin in the management of PCOS is by no means clear and, on the basis of current evidence, it is not the first-line treatment of choice (Tarlatzis et al 2008).

Surgical ovulation induction

An alternative to gonadotrophin therapy for clomiphene-resistant PCOS is laparoscopic ovarian surgery, which has replaced the more invasive and damaging technique of ovarian wedge resection. Laparoscopic ovarian surgery is free of the risks of multiple pregnancy and ovarian hyperstimulation, and does not require intensive ultrasound monitoring. Furthermore, ovarian diathermy appears to be as effective as routine gonadotrophin therapy in the treatment of clomiphene-insensitive PCOS. In addition, laparoscopic ovarian surgery is a useful therapy for anovulatory women with PCOS who fail to respond to clomiphene and who persistently hypersecrete LH, or who need a laparoscopic assessment of their pelvis, or who live too far away from the hospital to be able to attend for the intensive monitoring required in gonadotrophin therapy. Surgery does, of course, carry its own risks and must only be performed by fully trained laparoscopic surgeons.

Wedge resection of the ovaries resulted in significant adhesions (100% of cases) in some published series. The risk of adhesion formation is far less after laparoscopic ovarian diathermy (10–20% of cases), and the adhesions that do form are usually fine and of limited clinical significance. The author’s technique involves instilling 200 ml Hartmann’s solution or Adept^® into the pouch of Douglas, which, by cooling the ovaries, prevents heat injury to adjacent tissues and reduces adhesion formation. It is suggested that a minimum amount of ovarian destruction should be employed. Furthermore, a combined approach may be suitable for some women, whereby low-dose diathermy is followed by low-dose ovarian stimulation.

An additional concern is the possibility of ovarian destruction leading to ovarian failure; an obvious disaster in a woman wishing to conceive. Cases of ovarian failure have been reported after both wedge resection and laparoscopic surgery. An unfortunate vogue has developed whereby women with polycystic ovaries who have over-responded to superovulation for in-vitro fertilization (IVF) are subjected to ovarian diathermy as a way of reducing the likelihood of subsequent OHSS. If one accepts that appropriately performed ovarian diathermy works by sensitizing the ovary to FSH, one could extrapolate that ovarian diathermy prior to superovulation for IVF should make the ovary more, and not less, likely to overstimulate. The amount of ovarian destruction that is required to reduce the chance of overstimulation is therefore likely to be considerable. Great caution is urged before proceeding with such an approach because of concerns about permanent ovarian atrophy.

After laparoscopic ovarian surgery, serum concentrations of LH and testosterone fall with restoration of ovarian activity. Whether or not patients respond to laparoscopic ovarian diathermy (LOD) appears to depend on their pretreatment characteristics, with patients with high basal LH concentrations having a better clinical and endocrine response. Ovarian diathermy appears to be as effective as routine gonadotrophin therapy in the treatment of clomiphene-citrate-insensitive PCOS, and the Cochrane Database concludes that whilst there is insufficient evidence to demonstrate a difference between 6–12 months follow-up after LOD and three to six cycles of ovulation induction with gonadotrophins, multiple pregnancy rates are considerably reduced with LOD (Farquhar et al 2002). The largest randomized controlled trial to date is a multicentre study performed in The Netherlands in which 168 patients, resistant to clomiphene citrate, were randomized to either LOD (n = 83) or ovulation induction with recombinant FSH (rFSH, n = 65) (Bayram et al 2004). The initial cumulative pregnancy rate after 6 months was 34% in the LOD arm vs 67% in the rFSH arm. Those who did not ovulate in response to LOD were first given clomiphene citrate and then rFSH, so by 12 months, the cumulative pregnancy rate was similar in each group at 67%. Thus, those treated with LOD took longer to conceive, and 54% required additional medical ovulation induction therapy.

Laparoscopic ovarian diathermy is associated with a low risk of multiple pregnancy and so does not need the same intensity of monitoring as the use of drugs to stimulate ovulation. Indications for LOD are listed in Table 18.4. A strategy for ovulation induction for women with PCOS is outlined in Table 18.5.

Table 18.4 Indications for laparoscopic ovarian diathermy (LOD)

Table 18.5 Strategy for ovulation induction in anovulatory polycystic ovary syndrome