47 Adam Balen Leeds Centre for Reproductive Medicine, Seacroft Hospital, Leeds, UK The current understanding of polycystic ovary syndrome (PCOS) is that it is a condition that presents with ovarian dysfunction and endocrine problems and is also associated with hyperinsulinaemia and metabolic disease. PCOS is a heterogeneous condition which is defined by the presence of two of the following three criteria: (i) oligo‐ovulation and/or anovulation, (ii) hyperandrogenism (clinical and/or biochemical), or (iii) polycystic ovaries as seen by ultrasound scan, with the exclusion of other causes of androgen excess and menstrual cycle irregularity or amenorrhoea. PCOS therefore encompasses symptoms of menstrual cycle disturbance and as such is the commonest cause of secondary amenorrhoea and also of anovulatory infertility. The second part of the chapter discusses the pathophysiology and management of other causes of secondary amenorrhoea. Amenorrhoea is the absence of menstruation, which may be temporary or permanent. Amenorrhoea may occur as a normal physiological condition, such as before puberty and during pregnancy, lactation or the menopause, or as a feature of a systemic or gynaecological disorder. Primary amenorrhoea may be a result of congenital abnormalities in the development of the ovaries, genital tract or external genitalia, or a perturbation of the normal endocrinological events of puberty. Most of the causes of secondary amenorrhoea can also cause primary amenorrhoea. A thorough history and a careful examination should always be carried out before investigations are instigated, looking particularly at stature and body form, signs of endocrine disease, secondary sexual development and the external genitalia. A history of secondary amenorrhoea may be misleading, as the ‘periods’ may have been the result of exogenous hormone administration in a patient who was being treated with hormone replacement therapy (HRT) for primary amenorrhoea. In most cases, however, a history of secondary amenorrhoea excludes congenital abnormalities. A family history of fertility problems, autoimmune disorders or premature menopause may also give clues as to the aetiology. It is always important to exclude pregnancy in women of any age, and whereas some may think this statement superfluous, it is not infrequent for women to present with amenorrhoea who are pregnant despite denying the possibility. Measurement of height and weight should be performed in order to calculate the patient’s body mass index (BMI). The normal range is 20–25 kg/m2, and a value above or below this may suggest a diagnosis of weight‐related amenorrhoea (which is a term usually applied to underweight women). Signs of hyperandrogenism – acne, hirsutism, balding (alopecia) – are suggestive of PCOS, although biochemical screening helps to differentiate other causes of androgen excess. It is important to distinguish between hyperandrogenism and virilization, which also occurs with high circulating androgen levels and causes deepening of the voice, breast atrophy, increase in muscle bulk and cliteromegaly (see Summary box 47.1). A rapid onset of hirsutism suggests the possibility of an androgen‐secreting tumour of the ovary or adrenal gland. Hirsutism can be graded and given a Ferriman–Gallwey score by assessing the amount of hair in different parts of the body (e.g. upper lip, chin, breasts, abdomen, arms, legs). It is useful for monitoring the progress of hirsutism, or its response to treatment, by making serial records, either by using a chart or by taking photographs of affected areas of the body. It should be remembered, however, that not all hair on the body is necessarily responsive to hormone changes (e.g. the upper thighs). There may also be big ethnic variations in the expression of hirsutism, with women from South Asia and Mediterranean countries often having more pronounced problems, whereas those from the Far East may not have much in the way of bodily hair. Furthermore, the degree of hirsutism does not correlate that well with the actual levels of circulating androgens. A measurement of total testosterone is considered adequate for general screening (Table 47.1). It is unnecessary to measure other androgens unless total testosterone is above 5 nmol/L (this will depend on the normal range of your local assay). Insulin may be elevated in overweight women and suppresses the production of sex hormone‐binding globulin (SHBG) by the liver, resulting in a high free androgen index in the presence of a normal total testosterone. The measurement of SHBG is not required in routine practice but is a useful surrogate marker for insulin resistance. Table 47.1 Endocrine normal ranges. * Denotes those tests performed in routine screening of women with amenorrhoea. AMH, anti‐Müllerian hormone; FSH, follicle‐stimulating hormone; LH, luteinizing hormone; SHBG, sex hormone‐binding globulin; TBG, thyroid‐binding globulin; TSH, thyroid‐stimulating hormone. One should be aware of the possibility of Cushing’s syndrome in women with stigmata of PCOS and obesity as it is a disease of insidious onset and dire consequences; additional clues are the presence of central obesity, moon face, plethoric complexion, buffalo hump, proximal myopathy, thin skin, bruising and abdominal striae (which alone are a common finding in obese individuals). Acanthosis nigricans is a sign of profound insulin resistance and is usually visible as hyperpigmented thickening of the skin folds of the axilla and neck; acanthosis nigricans is associated with PCOS and obesity (Fig. 47.1). Fig. 47.1 Acanthosis nigricans, as seen typically in the skin folds (axilla, neck, elbow, vulva). Source: Balen AH. Infertility in Practice, 4th edn. London: Informa Healthcare, 2014. Reproduced with permission of CRC Press. Amenorrhoeic women might have hyperprolactinaemia and galactorrhoea. It is important, however, not to examine the breasts before taking blood as the serum prolactin concentration may be falsely elevated as a result of physical examination. Stress may also cause minor elevation of prolactin. If there is suspicion of a pituitary tumour, the patient’s visual fields should be checked, as bitemporal hemianopia secondary to pressure on the optic chiasm requires urgent attention. Thyroid disease is common and the thyroid gland should be palpated and signs of hypothyroidism (dry thin hair, proximal myopathy, myotonia, slow‐relaxing reflexes, mental slowness, bradycardia) or hyperthyroidism (goitre with bruit, tremor, weight loss, tachycardia, hyperreflexia, exophthalmos, conjunctival oedema, ophthalmoplegia) elicited. A bimanual examination is inappropriate in a young woman who has never been sexually active, and examination of the external genitalia of an adolescent should be undertaken in the presence of the patient’s mother. Furthermore, it may be more appropriate to defer this from the first consultation in order to assure the patient’s confidence in future management. A transabdominal ultrasound examination of the pelvis is an excellent non‐invasive method for obtaining valuable information in these patients. Although an examination under anaesthetic is sometimes indicated for cases of disorders of sexual development with primary amenorrhoea, it is rarely required in cases of secondary amenorrhoea (Table 47.2). Table 47.2 Classification of secondary amenorrhoea. A baseline assessment of the endocrine status should include the measurement of serum prolactin and gonadotrophin concentrations and an assessment of thyroid function. Prolactin levels may be elevated in response to a number of conditions, including stress, a recent breast examination or even having a blood test; however, the elevation is moderate and transient. A more permanent, but still moderate, elevation (>700 mIU/L) is associated with hypothyroidism and is also a common finding in women with PCOS, where prolactin levels up to 2500 mIU/L have been reported [1]. PCOS may also result in amenorrhoea, which can therefore create diagnostic difficulties, and hence appropriate management, for those women with hyperprolactinaemia and polycystic ovaries. Amenorrhoea in women with PCOS is secondary to acyclical ovarian activity yet oestrogen production by the ovaries continues and so the endometrial thickness will be greater than 6 mm. A positive response to a progestogen challenge test, such as medroxyprogesterone acetate 10–20 mg (depending on body weight) daily for 7 days which induces a withdrawal bleed, will distinguish patients with PCOS‐related hyperprolactinaemia from those with polycystic ovaries and unrelated hyperprolactinaemia, because the latter causes oestrogen deficiency and therefore failure to respond to the progestogen challenge because the endometrium is thin. A serum prolactin concentration of greater than 1000 mIU/L warrants a repeat and then further investigation if still elevated. CT or MRI of the pituitary fossa may be used to exclude a hypothalamic tumour, a non‐functioning pituitary tumour compressing the hypothalamus or a prolactinoma. Serum prolactin concentrations greater than 5000 mIU/L are usually associated with a macroprolactinoma, which by definition is greater than 1 cm in diameter. Serum measurements of estradiol are of limited value as they vary considerably, even in a patient with amenorrhoea. If the patient is well oestrogenized, the endometrium will be clearly seen on an ultrasound scan and should be shed on progestogen withdrawal. Serum gonadotrophin measurements help to distinguish between cases of hypothalamic or pituitary failure and gonadal failure. Elevated gonadotrophin concentrations indicate a failure of negative feedback as a result of primary or premature ovarian insufficiency (POI, formerly known as premature ovarian failure). A serum follicle‐stimulating hormone (FSH) concentration of greater than 15 IU/L that is not associated with a preovulatory luteinizing hormone (LH) surge suggests impending ovarian failure. FSH levels of greater than 40 IU/L are suggestive of irreversible ovarian failure. The exact values vary according to individual assays, and so local reference levels should be checked. It is also important to assess serum gonadotrophin levels at baseline (during the first 3 days of a menstrual period). In patients with oligomenorrhoea/amenorrhoea, it may be necessary to perform two or more random measurements, although combining an endocrine assessment with an ultrasound scan on the same day aids the diagnosis. An elevated LH concentration, when associated with a raised FSH concentration, is indicative of ovarian failure. However, if LH is elevated alone (and is not attributable to the preovulatory LH surge), this suggests PCOS. This may be confirmed by a pelvic ultrasound scan. Rarely, an elevated LH in a phenotypic female may be due to androgen insensitivity syndrome, although this condition presents with primary amenorrhoea. Inhibin B is thought to be the ovarian hormone with the greatest influence on pituitary secretion of FSH. Previously, it was thought that serum concentrations of inhibin B might provide better quantification of ovarian reserve than serum FSH concentrations; however, the assay is no longer being used. Anti‐Müllerian hormone (AMH) is best known as a product of the testes during fetal development that suppresses the development of Müllerian structures. AMH is also produced by the pre‐antral and antral follicles and appears to be a more stable predictor of the ovarian follicle pool as it does not fluctuate through the menstrual cycle. Indeed, it has been reported that higher AMH concentrations are associated with increased numbers of mature oocytes, embryos and clinical pregnancies during in vitro fertilization (IVF) treatment. Assays for AMH are now available for routine use and it is this hormone that currently offers the greatest promise for future assessment of ovarian reserve and function. The number of antral follicles in the ovary, as assessed by pelvic ultrasound, also correlates well with ovarian reserve and serum AMH levels. Indeed, it is the number of small antral follicles, 2–6 mm in diameter, that declines significantly with age while there is little change in the larger follicles of 7–10 mm, which is still below the size at which growing follicles have been recruited. Failure at the level of the hypothalamus or pituitary is reflected by abnormally low levels of serum gonadotrophin concentrations, and gives rise to hypogonadotrophic hypogonadism. Kallmann’s syndrome is the clinical finding of anosmia and/or colour blindness associated with hypogonadotrophic hypogonadism, usually a cause of primary amenorrhoea. CT or MRI should be performed if indicated. Women with POI (under the age of 40 years) may have a chromosomal abnormality, for example Turner’s syndrome (45X or 46XX/45X mosaic) or other sex chromosome mosaicisms. A number of genes have also been associated with familial POI, but have not been assessed in routine clinical practice. An autoantibody screen should also be undertaken in women with POI, although it can be difficult to detect anti‐ovarian antibodies and many will have evidence of other autoantibodies (e.g. thyroid), which then indicates the need for further surveillance. A history of a recent endometrial curettage or endometritis in a patient with normal genitalia and normal endocrinology, but with absent or only a small withdrawal bleed following a progestogen challenge, is suggestive of Asherman’s syndrome. An ultrasound scan and/or a hysterosalpingogram (HSG) may be helpful and hysteroscopy will confirm the diagnosis (Fig. 47.2). Fig. 47.2 Conventional X‐ray hysterosalpingogram demonstrating Asherman’s syndrome, with intrauterine synechiae. There is no flow of contrast through the right tube, although thickening of the cornual end of the tube suggests the possibility of tubal spasm. There is flow to the end of the left fallopian tube, although no free spill into the peritoneal cavity. This raises the possibility of sacculated adhesions around the fimbrial end of the tube. Source: Balen AH. Infertility in Practice, 4th edn. London: Informa Healthcare, 2014. Reproduced with permission of CRC Press. Measurement of bone mineral density (BMD) is indicated in amenorrhoeic women who are oestrogen deficient. Measurements of density are made in the lumbar spine and femoral neck. The vertebral bone is more sensitive to oestrogen deficiency and vertebral fractures tend to occur in a younger age group (50–60 years) than fractures at the femoral neck (70+ years). However, it should be noted that crush fractures can spuriously increase the measured BMD. An X‐ray of the dorsolumbar spine is therefore often complementary, particularly in patients who have lost height. Amenorrhoea may also have long‐term metabolic and physical consequences. In women with PCOS and prolonged amenorrhoea, there is a risk of endometrial hyperplasia and adenocarcinoma. If on resumption of menstruation there is a history of persistent intermenstrual bleeding, or on ultrasound there is a postmenstrual endometrial thickness of greater than 10 mm, an endometrial biopsy is indicated. Serum cholesterol measurements are important because of the association of an increased risk of heart disease in women with POI. Women with PCOS, although not oestrogen deficient, may have a subnormal ratio of high‐density lipoprotein (HDL) to total cholesterol. This is as a consequence of the hypersecretion of insulin that occurs in many women with PCOS. Women who are obese, and also many slim women with PCOS, may have insulin resistance and elevated serum concentrations of insulin (usually <30 mIU/L fasting, although not measured in clinical practice). A 75‐g oral glucose tolerance test should be performed in women with PCOS and a BMI above 30 kg/m2, with an assessment of the fasting and 2‐hour glucose concentration (Table 47.3). It has been suggested that South Asian women should have an assessment of glucose tolerance if their BMI is greater than 25 kg/m2 because of the greater risk of insulin resistance at a lower BMI than seen in the white population. Table 47.3 Definitions of glucose tolerance after a 75‐g glucose tolerance test. PCOS is a heterogeneous collection of signs and symptoms that form a spectrum of disorders, with mild presentation in some but severe disturbance of reproductive, endocrine and metabolic function in others. The pathophysiology of PCOS appears to be multifactorial and polygenic. The definition of the syndrome has been much debated. Key features include menstrual cycle disturbance, hyperandrogenism and obesity. There are many extra‐ovarian aspects to the pathophysiology of PCOS, yet ovarian dysfunction is central. The joint ESHRE/ASRM (European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine) consensus defined PCOS as requiring the presence of two of the following three criteria: The consensus meeting that provided this definition was held in Rotterdam and so the ESHRE/ASRM criteria are often known as the Rotterdam criteria [2]. Other aetiologies of hyperandrogenism and menstrual cycle disturbance should be excluded by appropriate investigations, as described in this chapter. The morphology of the polycystic ovary has been redefined as an ovary with 12 or more follicles measuring 2–9 mm in diameter and/or increased ovarian volume (>10 cm3) [3]. The use of higher resolution ultrasound than was available at the time of the Rotterdam meeting has led some to suggest that more follicles (19 or even 25) should define the polycystic ovary, but no consensus has been reached [4]. There is considerable heterogeneity of symptoms and signs among women with PCOS and for an individual these may change over time [1,2] (Table 47.4). PCOS may be familial, and various aspects of the syndrome may be differentially inherited. Polycystic ovaries can exist without clinical signs of the syndrome, which may then become expressed in certain circumstances. There are a number of factors that affect expression of PCOS, for example a gain in weight is associated with a worsening of symptoms while weight loss may ameliorate the endocrine and metabolic profile and symptomatology. Table 47.4 Signs and symptoms of polycystic ovary syndrome. FSH, follicle‐stimulating hormone; GTT, glucose tolerance test; LH, luteinizing hormone; SHBG, sex hormone‐binding globulin. Genetic studies have identified a link between PCOS and disordered insulin metabolism, and indicate that the syndrome may be the presentation of a complex genetic trait disorder. The features of obesity, hyperinsulinaemia and hyperandrogenaemia, which are commonly seen in PCOS, are also known to be factors that confer an increased risk of cardiovascular disease and non‐insulin‐dependent diabetes mellitus (NIDDM) [5]. There are studies indicating that women with PCOS have an increased risk for these diseases, which pose long‐term risks for health, and this evidence has prompted debate as to the need for screening women for PCOS [5] (Fig. 47.3). Fig. 47.3 (a) Transabdominal ultrasound scan of a normal ovary. (b) Transabdominal ultrasound scan of a polycystic ovary. (c) Transvaginal ultrasound scan of a polycystic ovary. (d) Transabdominal ultrasound scan of a multicystic ovary. (e) MRI of a pelvis, demonstrating two polycystic ovaries (closed arrows) and a hyperplastic endometrium (open arrow). Source: Balen AH. Infertility in Practice, 4th edn. London: Informa Healthcare, 2014. Reproduced with permission of CRC Press. Polycystic ovaries are commonly detected by ultrasound or other forms of pelvic imaging, with estimates of the prevalence in the general population being in the order of 20–33% [6]. Although the ultrasound criteria for the diagnosis of polycystic ovaries have not, until now, been universally agreed, the characteristic features are accepted as being an increase in the number of follicles and the amount of stroma compared with normal ovaries, resulting in an increase in ovarian volume. The ‘cysts’ are not cysts in the sense that they do contain oocytes and indeed are follicles whose development has been arrested. The actual number of cysts may be of less relevance than the volume of ovarian stroma or of the ovary itself, which has been shown to closely correlate with serum testosterone concentrations. Polycystic ovary syndrome has long been noted to have a familial component. Genetic analysis has been hampered by the lack of a universal definition for PCOS. Most of the criteria used for diagnosing PCOS are continuous traits, such as degree of hirsutism, level of circulating androgens, extent of menstrual irregularity, and ovarian volume and morphology. To perform genetic analyses, these continuous variables have to be transformed into nominal variables. Family studies have revealed that about 50% of first‐degree relatives have PCOS, suggesting a dominant mode of inheritance [2,5]. Commonly, first‐degree male relatives appear more likely to have the metabolic syndrome [7]. Further discussion of this complex area is beyond the scope of this chapter and much research is being performed to provide a more detailed account of the various genetic abnormalities that may be involved in the pathogenesis of PCOS. Hypersecretion of androgens by the stromal theca cells of the polycystic ovary leads to the cardinal clinical manifestation of the syndrome, hyperandrogenism, and is also one of the mechanisms whereby follicular growth is inhibited with the resultant excess of immature follicles. Hypersecretion of LH by the pituitary – a result of both disordered ovarian–pituitary feedback and exaggerated pulses of gonadotrophin‐releasing hormone (GnRH) from the hypothalamus – stimulates testosterone secretion by the ovary. Furthermore, insulin is a potent stimulus for androgen secretion by the ovary, which, by way of a different receptor for insulin, does not exhibit insulin resistance. Insulin therefore amplifies the effect of LH, and additionally magnifies the degree of hyperandrogenism by suppressing liver production of the main carrier protein, SHBG, thus elevating the free androgen index. It is a combination of genetic abnormalities combined with environmental factors, such as nutrition and body weight, which then affect expression of the syndrome. The highest reported prevalence of PCOS has been 52% among South Asian immigrants in Britain, of whom 49.1% had menstrual irregularity [8]. Rodin et al. [8] demonstrated that South Asian women with PCOS had a comparable degree of insulin resistance to controls with established type 2 diabetes mellitus. Insulin resistance and hyperinsulinaemia are common antecedents of type 2 diabetes, with a high prevalence in South Asian people. Type 2 diabetes also has a familial basis, inherited as a complex genetic trait that interacts with environmental factors, chiefly nutrition, commencing during fetal life. We have found that South Asian people with anovulatory PCOS have greater insulin resistance and more severe symptoms of the syndrome than anovulatory white people with PCOS [9]. Furthermore, we have found that women from South Asia living in the UK appear to express symptoms at an earlier age than their white British counterparts [10]. Obesity and metabolic abnormalities are recognized risk factors for the development of ischaemic heart disease in the general population, and these are also recognized features of PCOS. The question is whether women with PCOS are at an increased risk of ischaemic heart disease, and whether this will occur at an earlier age than women with normal ovaries. The basis for the idea that women with PCOS are at a 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 is defined as a diminution in the biological responses to a given level of insulin. In the presence of an adequate pancreatic reserve, normal circulating glucose levels are maintained at higher serum insulin concentrations. In the general population, cardiovascular risk factors include insulin resistance, obesity, glucose intolerance, hypertension and dyslipidaemia. There have been a large number of studies demonstrating the presence of insulin resistance and corresponding hyperinsulinaemia in both obese and non‐obese women with PCOS [5]. Obese women with PCOS have consistently been shown to be more insulin resistant than weight‐matched controls. It appears that obesity and PCOS have an additive effect on the degree and severity of the insulin resistance and subsequent hyperinsulinaemia in this group of women. The insulin resistance causes compensatory hypersecretion of insulin, particularly in response to glucose, so euglycaemia is usually maintained at the expense of hyperinsulinaemia. Insulin resistance is restricted to the extrasplanchnic actions of insulin on glucose dispersal. The liver is not affected (hence the fall in SHBG and HDL), neither is the ovary (hence the menstrual problems and hypersecretion of androgens) nor the skin, hence the development of acanthosis nigricans. Women with PCOS who are oligomenorrhoeic are more likely to be insulin resistant than those with regular cycles, irrespective of their BMI, with the intermenstrual interval correlating with the degree of insulin resistance [5]. Women with PCOS have a greater truncal abdominal fat distribution as demonstrated by a higher waist to hip ratio. The central distribution of fat is independent of BMI and associated with higher plasma insulin and triglyceride concentrations and reduced HDL cholesterol concentrations. From a practical point of view, if the measurement of waist circumference is greater than 80 cm, there will be excess visceral fat and an increased risk of metabolic problems. Thus, there is evidence that insulin resistance, central obesity and hyperandrogenaemia have an adverse effect on lipid metabolism, yet these are surrogate risk factors for cardiovascular disease. Significantly, Pierpoint et al. [11] reported the mortality rate in 1028 women diagnosed as having PCOS between 1930 and 1979. All the women were older than 45 years and 770 women had been treated by wedge resection of the ovaries. A total of 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 ischaemic heart disease. There were six deaths from diabetes as an underlying or contributory cause compared with the expected 1.7 deaths. The standard mortality rate both overall and for cardiovascular disease was not higher in the women with PCOS than 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% CI 1.5–8.4). Thus, despite surrogate markers for cardiovascular disease, no increased rate of death from cardiovascular disease could be demonstrated in this study [5,11]. The majority of studies that have identified the risk factors of obesity and insulin resistance in women with PCOS have investigated adult populations, commonly including women who have presented to specialist endocrine or reproductive clinics. However, PCOS has been identified in much younger populations [6], in which women with increasing symptoms of PCOS were found to be more insulin resistant. These data emphasize the need for long‐term prospective studies of young women with PCOS in order to clarify the natural history and to determine which women will be at risk of diabetes and cardiovascular disease later in life. A study of women with PCOS and a mean age of 39 years followed over a period of 6 years found that 9% of those with normal glucose tolerance developed impaired glucose tolerance (IGT) and 8% developed NIDDM [12], while 54% of women with IGT at the start of the study had NIDDM at follow‐up. The risks of disease progression, not surprisingly, were greatest in those who were overweight. Whilst PCOS may evolve during adolescence, many of the symptoms (e.g. menstrual irregularity and acne) occur commonly in normal adolescent girls and so it is generally considered unwise to make the diagnosis until more than 2 years after menarche [5]. Endometrial adenocarcinoma is the second most common female genital malignancy, but only 4% of cases occur in women aged under 40 years. 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. Women with endometrial carcinoma have had fewer births than controls, and it has also been demonstrated that infertility per se increases the risk [5]. Hypertension and type 2 diabetes mellitus have long been linked to endometrial cancer – conditions that are now known also to be associated with PCOS. However, the true risk of endometrial carcinoma in women with clearly defined PCOS is difficult to ascertain [5]. Endometrial hyperplasia may be a precursor to adenocarcinoma, although the rate of progression is difficult to predict. 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 [5]. Indeed, we consider it important that women with PCOS shed their endometrium at least every 3 months. For those with oligomenorrhoea/amenorrhoea who do not wish to use cyclical hormone therapy, we recommend an ultrasound scan to measure endometrial thickness and morphology every 6–12 months (depending on menstrual history). An endometrial thickness greater 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 Mirena® (Bayer Pharma, Newbury, UK). 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 [5]. Pierpoint et al. [11] assessed mortality from the national registry of deaths and standardized mortality rate (SMR) calculated for patients with PCOS compared with the normal population. The average follow‐up period was 30 years. The SMR for all neoplasms was 0.91 (95% CI 0.60–1.32) and 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. 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 notion that is by no means proven. Women with PCOS who are oligo‐ovulatory/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 raise the risk of a woman with PCOS to that of a woman with normal ovulation. However, the polycystic ovary 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. There are a few studies which have addressed the possibility of an association between polycystic ovaries and ovarian cancer. The results are conflicting and the ability to generalize is limited owing to problems with the study designs [5]. In the large UK study by Pierpoint et al. [11], the SMR for ovarian cancer was 0.39 (95% CI 0.01–2.17). The clinical management of a women with PCOS should be focused on her individual problems. Obesity worsens both symptomatology and the endocrine profile and obese women (BMI >30 kg/m2) should therefore be encouraged to lose weight. Weight loss improves the endocrine profile, the likelihood of ovulation and a healthy pregnancy. Much has been written about diet and PCOS. The right diet for an individual is one that is practical, sustainable and compatible with her lifestyle. It is sensible to keep carbohydrate content down and to avoid fatty foods. It is often helpful to refer to a dietitian. Bariatric surgery (either gastric banding or gastric bypass procedures) are also very effective for women with a BMI over 35 kg/m2, although it is inadvisable to conceive immediately after surgery until metabolism has stabilized after the initial rapid loss of weight [13]. Amenorrhoeic women with PCOS are not oestrogen deficient and are not at risk of osteoporosis. Indeed, they are oestrogen replete and at risk of endometrial hyperplasia (see section on endometrial cancer). The easiest way to control the menstrual cycle is the use of a low‐dose combined oral contraceptive preparation. This will result in an artificial cycle and regular shedding of the endometrium. An alternative is a progestogen such as medroxyprogesterone acetate (Provera) for 12 days every 1–3 months to induce a withdrawal bleed, or the continuous provision of progesterone into the uterine cavity by Mirena. It is important once again to encourage weight loss. The bioavailability of testosterone is affected by the serum concentration of SHBG. High levels of insulin lower the production of SHBG and so increase the free fraction of androgen. Elevated serum androgen concentrations stimulate peripheral androgen receptors, resulting in an increase in 5α‐reductase activity, directly increasing the conversion of testosterone to the more potent metabolite dihydrotestosterone. Women with PCOS do not become virilized (i.e. they do not develop deepening of the voice, increased muscle mass, breast atrophy or clitoromegaly). A total testosterone level greater than 5 nmol/L or rapid onset of signs of hyperandrogenism requires further investigation. Late‐onset CAH is not common in the UK but is more prevalent in certain ethnic groups (e.g. Mediterranean, South American and some Jewish populations). Hirsutism is characterized by terminal hair growth in a male pattern of distribution, including the 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–Gallwey score, may be used to evaluate the degree of hirsutism before and during treatments (Fig. 47.4). Many women attend having already tried cosmetic techniques and so it may be difficult to obtain a baseline assessment. Fig. 47.4 The Ferriman–Gallwey Hirsutism Scoring System. The chart is used both to provide an initial score, with a scale of 0–3 at each of 12 points, depending on severity, and for the monitoring of progress with therapy. Source: Balen AH. Infertility in Practice, 4th edn. London: Informa Healthcare, 2014. Reproduced with permission of CRC Press. 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 while waiting for medical treatments to work. Electrolysis 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. Laser and photothermolysis techniques are more expensive but may have a longer duration of effect. Comparative studies, however, have not been performed. Repeated treatments are required for a near‐permanent effect because only 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. The topical use of eflornithine may be effective. 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. Eflornithine may cause some thinning of the skin and so high‐factor sun block is recommended when exposed to the sun. Medical regimens should stop further progression of hirsutism and decrease the rate of hair growth. Adequate contraception is important in women of reproductive age as transplacental passage of anti‐androgens may disturb the genital development of a male fetus. First‐line therapy has traditionally been the preparation Dianette, which contains ethinylestradiol (30 µg) in combination with cyproterone acetate (2 mg). The addition of higher doses of the synthetic progestogen cyproterone acetate (50–100 mg) do not appear to confer additional benefit. The effect on acne and seborrhoea is usually evident within a couple of months. Cyproterone acetate can rarely be associated with liver damage, and liver function should be checked after 6 months and then annually. Once symptom control has been obtained, it is advisable to switch to a combined oral contraceptive pill containing a lower dose of ethinylestradiol because of concerns about the increased risk of thromboembolism with Dianette [5]. In women in whom the combined oral contraceptive pill is contraindicated, spironolactone, a weak diuretic with anti‐androgenic properties, may be used at a daily dose of 25–100 mg. Drospirenone is a derivative of spironolactone and is contained in the combined oral contraceptive pill Yasmin, which may also be beneficial for women with PCOS. Other anti‐androgens such as ketoconazole, finasteride and flutamide have been tried, but are not widely used in the UK for the treatment of hirsutism in women owing to their adverse side effects. Furthermore, they are no more effective than cyproterone acetate [5]. Various factors influence ovarian function, and fertility is adversely affected by an individual being overweight or having elevated serum concentrations of LH. Strategies to induce ovulation include weight loss, oral antioestrogens (principally clomifene citrate or tamoxifen), parenteral gonadotrophin therapy and laparoscopic ovarian surgery. Clomifene is the traditional first‐line therapy and can be continued for 6–12 cycles of treatment if the patient is ovulating with normal endocrinology. Aromatase inhibitors, such as letrozole, may also stimulate ovulation and appear to be associated with a lower risk of multiple pregnancy; however, they are not currently licensed for the treatment of infertility. For those who do not ovulate, the options include daily injections of either recombinant FSH, human menopausal gonadotrophins (hMGs, which contain both FSH and LH activity) or laparoscopic ovarian diathermy [14]. Women with PCOS are at risk of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy, and so ovulation induction has to be carefully monitored with serial ultrasound scans. Improvements in lifestyle, with a combination of exercise and diet to achieve weight reduction, are important for improving the prospects of both spontaneous and drug‐induced ovulation. In addition, overweight women with PCOS are at increased risk of obstetric complications, gestational diabetes mellitus and pre‐eclampsia, and their fetuses are at increased risk of congenital malformations and miscarriage [15]. Ovulation can be induced with the antioestrogen clomifene citrate (50–100 mg) taken from days 2–6 of a natural or artificially induced bleed. While clomifene is successful in inducing ovulation in over 80% of women, pregnancy only occurs in about 40%. Clomifene citrate should only be prescribed in a setting where ultrasound monitoring is available (and performed) in order to minimize the 10% risk of multiple pregnancy and to ensure that ovulation is taking place [14]. A daily dose of more than 100 mg rarely confers any benefit and can cause thickening of the cervical mucus, which can impede passage of sperm through the cervix. Once an ovulatory dose has been reached, the cumulative conception rate continues to increase for up to 10–12 cycles [14]. The therapeutic options for patients with anovulatory infertility who are resistant to antioestrogens are either parenteral gonadotrophin therapy or laparoscopic ovarian diathermy. Because the polycystic ovary is very sensitive to stimulation by exogenous hormones, it is extremely important to start with very low doses of gonadotrophins and follicular development must be carefully monitored by ultrasound scans. The advent of transvaginal ultrasonography has enabled the multiple pregnancy rate to be reduced to less than 5% because of its higher resolution and clearer view of the developing follicles. Cumulative conception and live‐birth rates after 6 months may be 62% and 54%, respectively, and after 12 months 73% and 62%, respectively [16] (Fig. 47.5). Close monitoring should enable treatment to be suspended if more than two mature follicles develop, as the risk of multiple pregnancy increases (Fig. 47.6). Fig. 47.5 Cumulative conception rates (CCR) over successive cycles in normal women (closed square) and after ovulation induction in 103 women with anovulatory PCOS (open circle), 77 women with hypogonadotrophic hypogonadism (closed circle) and 20 patients with weight‐related amenorrhoea (open square). While patients with weight‐related amenorrhoea conceive readily after ovulation induction, we now believe that their management should be weight gain before conception (see text). Source: Balen AH, Braat DDM, West C, Patel A, Jacobs HS. Cumulative conception and live birth rates after the treatment of anovulatory infertility. Hum Reprod 1994;9:1563–1570. Reproduced with permission of Oxford University Press. Fig. 47.6 (a) Transvaginal ultrasound scan of unifollicular development in a polycystic ovary and (b) an overstimulated polycystic ovary. Source: Balen AH. Infertility in Practice, 4th edn. London: Informa Healthcare, 2014. Reproduced with permission of CRC Press. Women with PCOS are also at increased risk of developing OHSS. This occurs if too many follicles (>10 mm) are stimulated and results in abdominal distension, discomfort, nausea, vomiting and sometimes difficulty in breathing. The mechanism for OHSS is thought to be secondary to activation of the ovarian renin–angiotensin pathway and excessive secretion of vascular epidermal growth factor (VEGF). The ascites and pleural and pericardial effusions exacerbate this serious condition and the resultant haemoconcentration can lead to thromboembolism. The situation worsens if a pregnancy has resulted from the treatment as human chorionic gonadotrophin from the placenta further stimulates the ovaries. Hospitalization is sometimes necessary in order for intravenous fluids and heparin to be given to prevent dehydration and thromboembolism. Although OHSS is rare, it is potentially fatal and should be avoidable with appropriate monitoring of gonadotrophin therapy. Ovarian diathermy is free of the risks of multiple pregnancy and OHSS and does not require intensive ultrasound monitoring. Laparoscopic ovarian diathermy has taken the place of wedge resection of the ovaries (which resulted in extensive periovarian and tubal adhesions) and carries a reduced risk of multiple pregnancy compared with gonadotrophin therapy in the treatment of clomifene‐insensitive PCOS. Pregnancy rates are higher with 6 months of gonadotrophin therapy compared with 6 months after laparoscopic ovarian diathermy [17]. A number of pharmacological agents have been used to amplify the physiological effect of weight loss, notably metformin. This biguanide inhibits the production of hepatic glucose and enhances the sensitivity of peripheral tissue to insulin, thereby decreasing insulin secretion. It has been shown that metformin may ameliorate hyperandrogenism and abnormalities of gonadotrophin secretion in some women with PCOS, and therefore it was suggested that it might restore menstrual cyclicity and fertility. The insulin‐sensitizing agent troglitazone also appeared to significantly improve the metabolic and reproductive abnormalities in PCOS, although it was withdrawn because of reports of deaths from hepatotoxicity, and other thiazolidinediones such as rosiglitazone and pyoglitazone are not advocated for women trying to conceive. Most of the initial studies of metformin in the management of PCOS were observational. Metformin appears to be less effective in those who are significantly obese (BMI >35 kg/m2). The largest appropriately powered, prospective, randomized, double‐blind, placebo‐controlled study set out to evaluate the combined effects of lifestyle modification and metformin in 143 obese anovulatory women with a mean BMI of 38 kg/m2 [18]. All subjects had an individualized assessment by a dietitian in order to set a realistic goal that could be sustained with an average reduction of energy intake of 500 kcal/day. As a result, both the metformin‐treated and placebo groups managed to lose weight, but the amount of weight reduction did not differ between the two groups. An increase in menstrual cyclicity was observed in those who lost weight but again did not differ between the two arms of the study, reinforcing the key role of weight reduction.
Polycystic Ovary Syndrome and Secondary Amenorrhoea
Defining polycystic ovary syndrome and secondary amenorrhoea
Examination and investigation of patients with polycystic ovary syndrome and secondary amenorrhoea
Exclude pregnancy
Examination
FSH*
1–10 IU/L (early follicular)
LH*
1–10 IU/L (early follicular)
Prolactin*
<400 mIU/L
TSH*
0.5–4.0 IU/L
Thyroxine (T4)
50–150 nmol/L
Free T4
9–22 pmol/L
Triiodothyronine (T3)
1.5–3.5 nmol/L
Free T3
4.3–8.6 pmol/L
TBG
7–17 mg/L
Testosterone (T)*
0.5–3.5 nmol/L (ranges depend on the assay being used)
SHBG
16–120 nmol/L
Free androgen index [(T × 100) ÷ SHBG]
<5
Dihydrotestosterone
0.3–1 nmol/L
Androstenedione
2–10 nmol/L
Dehydroepiandrosterone sulfate
3–10 µmol/L
Cortisol
140–700 nmol/L
8 a.m.
0–140 nmol/L
Midnight
<400 nmol/24 hours
24‐hour urinary
Estradiol
250–500 pmol/L
Estrone
400–600 pmol/L
Progesterone (mid‐luteal)
>25 nmol/L to indicate ovulation
17‐hydroxyprogesterone
1–20 nmol/L
Inhibin B
5–200 pg/mL
AMH
Values should be assessed with respect to age‐related nomograms. Low levels indicate poor ovarian reserve, normal levels suggest normal fertility and high values are often seen in women with polycystic ovaries
Uterine causes
Asherman’s syndrome
Cervical stenosis
Ovarian causes
Polycystic ovary syndrome
Premature ovarian insufficiency, formerly known as premature ovarian failure (genetic, autoimmune, infective, radiotherapy/chemotherapy)
Hypothalamic causes (hypogonadotrophic hypogonadism)
Weight loss
Exercise
Chronic illness
Psychological distress
Idiopathic
Pituitary causes
Hyperprolactinaemia
Hypopituitarism
Sheehan’s syndrome
Causes of hypothalamic/pituitary damage (hypogonadism)
Tumours (craniopharyngiomas, gliomas, germinomas, dermoid cysts)
Cranial irradiation
Head injuries
Sarcoidosis
Tuberculosis
Chronic debilitating illness
Systemic causes
Weight loss
Endocrine disorders (thyroid disease, Cushing’s syndrome, etc.)
Karyotype and other tests
Glucose tolerance
Diabetes mellitus
Impaired glucose tolerance
Impaired fasting glycaemia
Fasting glucose (mmol/L)
≥7.0
<7.0
≥6.1 and <7.0
2‐hour glucose (mmol/L)
≥11.1
≥7.8 and ≤11.1
<7.8
Polycystic ovary syndrome
Symptoms
Hyperandrogenism (acne, hirsutism, alopecia – not virilization)
Menstrual disturbance
Infertility
Obesity
Sometimes: asymptomatic, with polycystic ovaries on ultrasound scan
Serum endocrinology
↑ Fasting insulin (not routinely measured; insulin resistance or impaired glucose tolerance assessed by GTT)
↑ Androgens (testosterone and androstenedione)
↑ or normal LH, normal FSH
↓ SHBG, results in elevated free androgen index
↑ Estradiol, estrone (neither measured routinely as very wide range of values)
↑ Prolactin
Possible late sequelae
Diabetes mellitus
Dyslipidaemia
Hypertension, cardiovascular disease
Endometrial carcinoma
Genetics of polycystic ovary syndrome
Pathophysiology of polycystic ovary syndrome
Racial differences in expression of polycystic ovary syndrome
Health consequences of polycystic ovary syndrome
Polycystic ovary syndrome in younger women
Endometrial cancer
Breast cancer
Ovarian cancer
Management of polycystic ovary syndrome
Obesity
Menstrual irregularity
Hyperandrogenism and hirsutism
Infertility
Insulin‐sensitizing agents and metformin
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