- Email: [email protected]
Polycystic ovary syndrome
SEX HORMONES
Polycystic ovary syndrome
What’s new?
Stephen Franks C
Following the ESHRE/ASRM consensus meeting, new recommendations for diagnostic criteria have been proposed, acknowledging that the spectrum of presentation of PCOS includes women with hyperandrogenism and regular menses
C
Recent data indicate an abnormality of early follicle development in the polycystic ovary, suggesting an intrinsic abnormality of ovarian function which may contribute to the mechanism of anovulation
C
Clomiphene remains the first choice of treatment for anovulatory infertility. Addition of metformin is not helpful
C
Metabolic abnormalities are becoming an increasingly important feature of PCOS as the population becomes more obese. There are many reports of the efficacy of metformin in the management of metabolic and endocrine abnormalities, but its therapeutic importance remains unclear
Abstract Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women. It typically presents with symptoms of anovulation, associated with clinical and/or biochemical evidence of androgen excess. The spectrum of presentation, however, includes women with hyperandrogenism who have regular periods. As well as being the most common cause of anovulatory infertility it is now recognized as a major risk factor for development of type 2 diabetes. The aetiology of PCOS remains unclear, but both genetic and environmental factors are involved. Typical biochemical features are raised serum concentrations of testosterone and elevation of serum luteinizing hormone (LH), particularly in anovulatory women. The diagnosis is made primarily on clinical criteria. The finding of raised testosterone and/or LH complements the clinical diagnosis. In obese women an oral glucose tolerance test should be undertaken to detect impaired glucose tolerance. Management of PCOS includes treatment of infertility, menstrual regulation in those who do not desire pregnancy and treatment of associated symptoms of hyperandrogenism. Another important aspect of management is the introduction of diet and lifestyle changes in overweight and obese women with PCOS to improve fertility but also in prevention of the possible long-term consequences of the metabolic disturbance characteristic of anovulatory women with PCOS.
view of these findings, the diagnostic criteria for PCOS were revised at a consensus conference jointly sponsored by the European Society for Human Reproduction and Embryology (ESHRE) and the American Society of Reproductive Medicine (ASRM) in Rotterdam, The Netherlands in 2003 (Table 1).4 The diagnosis now requires the presence of at least two of the following features: polycystic ovaries oligo-ovulation or anovulation clinical and/or biochemical evidence of androgen excess. In all recently published series characterized by the Rotterdam definition of PCOS, the largest subgroup is nevertheless that defined by the National Institutes of Health (NIH) criteria, i.e. women with oligo- or anovulation together with clinical or biochemical evidence of androgen excess. The subclassification also has implications for predicting a risk of metabolic abnormalities (as outlined below).
Keywords anovulation; impaired glucose tolerance; insulin resistance; ovary; type 2 diabetes
Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder in women. It typically presents with symptoms of anovulation (amenorrhoea, oligomenorrhoea or irregular cycles) associated with clinical and/or biochemical evidence of androgen excess (hirsutism, acne or alopecia). It is by far the most common cause of anovulatory infertility but is now recognized to be a major risk factor for development of type 2 diabetes.1,2 Until recently, the most widely accepted clinical definition of PCOS was the association of hyperandrogenism with chronic anovulation in women without specific underlying disease of the adrenal or pituitary gland.3 Early descriptions of the syndrome were based on ovarian morphology, but this was not considered an essential requirement for the diagnosis. However, recent application of modern, high-resolution diagnostic ultrasonography has again tipped the balance towards a more morphologically based diagnosis. It is now recognized that the spectrum of presentation of PCOS includes both women with hirsutism and regular cycles, and non-hirsute women with anovulation. In
Aetiology The aetiology of PCOS remains unclear, but both genetic and environmental (particularly nutritional) factors are involved. It is clear that the ovary is the principal source of the excess androgens, suggesting that it represents a primary ovarian disorder. This is supported by recent data that indicate that there is an abnormality of the earliest (gonadotrophin-independent) stages of ovarian follicle development5e7 and this abnormality may contribute to the mechanism of anovulation.8 PCOS is a familial disorder with evidence of heritability of endocrine and metabolic indices, but its genetic basis remains uncertain.9,10 It is likely to be a complex trait in which more than one, and perhaps several, genes are involved.11e18
Metabolic disorder in polycystic ovary syndrome PCOS is now known to be associated with a characteristic metabolic disorder comprising hyperinsulinaemia, insulin resistance (Figure 1) and dyslipidaemia. There is an interaction
Stephen Franks MD FRCP FMedSci is Professor of Reproductive Endocrinology at Imperial College Faculty of Medicine, St Mary’s and the Hammersmith Hospitals, London, UK. Competing interests: none declared.
MEDICINE 37:9
441
Ó 2009 Elsevier Ltd. All rights reserved.
SEX HORMONES
These findings have significant implications for long-term health. It is estimated that 15e40% of obese young women with PCOS have impaired glucose tolerance or frank type 2 diabetes mellitus. In older women with a history of PCOS, the risk of developing type 2 diabetes is estimated to be two- to sixfold greater than in a matched reference population. Epidemiological studies are in broad agreement with these figures, suggesting a doubling of risk independent of obesity, and a three- to fourfold increase in risk in obese women with PCOS. As in subjects without PCOS, a family history of diabetes, previous gestational diabetes and, of course, impaired glucose tolerance are all additional factors that can amplify the risk. These women also appear to be at increased risk of cardiovascular disease, but there is little direct information regarding cardiovascular morbidity in these patients.
Diagnostic criteria for polycystic ovary syndrome US National Institutes of Health, 1990
C C
European Society for Human Reproduction and Embryology/ American Society of Reproductive Medicine, Rotterdam, 2003
Chronic anovulation Clinical and/or biochemical signs of hyperandrogenism
C C
C
Oligo-ovulation and/or anovulation Clinical and/or biochemical signs of hyperandrogenism Polycystic ovaries
The NIH definition3 requires both criteria to make the diagnosis; the ESHRE/ ASRM diagnostic criteria4 require at least two. In both definitions, the diagnosis assumes exclusion of other diagnoses that may replicate the symptoms of polycystic ovary syndrome (e.g. non-classical congenital adrenal hyperplasia caused by 21-hydroxylase deficiency).
Investigations Serum concentrations of testosterone and other androgens are raised in PCOS. Hypersecretion of luteinizing hormone (LH) d in the presence of a normal value of follicle-stimulating hormone (FSH) d is common, particularly in anovulatory women, and is a specific but not very sensitive index of the syndrome; many patients with all of the other clinical and biochemical features of PCOS have normal LH levels. The diagnosis is made primarily on clinical and ultrasonographic criteria (Figure 2). The finding of raised testosterone and/or LH merely complements the clinical diagnosis. Nevertheless, it is important to measure serum testosterone in hirsute women because greatly increased levels (>5 nmol/litre, i.e. more than twice the upper limit of the normal range in most laboratories) are an indication for further investigation. More serious causes of hirsutism (e.g. Cushing’s syndrome, adrenal or ovarian tumours) are rare but may masquerade as PCOS (polycystic ovaries are commonly found on ultrasonography in these conditions) and measurement of serum testosterone is a useful screening procedure. A short history of hirsutism or rapid worsening of hyperandrogenic symptoms should alert the physician to the likelihood of one of these less common, but more serious, causes. In contrast to patients with other causes of amenorrhoea, amenorrhoeic women with PCOS are not oestrogen-deficient; their serum oestradiol levels tend to be in the normal, early to mid-follicular phase range.
Table 1
between the effect of PCOS and that of obesity, such that the metabolic abnormalities in women with PCOS are amplified to a greater degree by obesity than in weight-matched controls. The metabolic abnormalities appear to be a particular feature of those with the classical syndrome (hyperandrogenism and anovulation), whereas equally hyperandrogenaemic women with polycystic ovaries but regular menses (and those with anovulation without androgen excess) tend to exhibit normal insulin secretion and action.14
HOMA-IR according to PCOS phenotype PCO + anov + androgen PCO + androgen PCO + anov
Investigation of metabolic abnormalities Fasting plasma glucose estimation in overweight and obese women with PCOS (body mass index (BMI) >25 kg/m2) will identify those with previously undiagnosed type 2 diabetes, but is not useful for uncovering impaired glucose tolerance (IGT). The proceedings of the Rotterdam consensus meeting suggest that, in obese women (BMI >30 kg/m2), an oral glucose tolerance test should be undertaken to detect IGT and a fasting lipid profile determined. All obese patients with PCOS must be considered at risk of type 2 diabetes and should be offered dietary advice (see below). The BMI threshold for metabolic testing in women with PCOS may need to be adjusted (downwards) for populations at increased risk of insulin resistance (e.g. south Asian women) and it has been suggested that waist circumference is a better index of risk than BMI.
Control
0.0
0.2
0.4
0.6
0.8
1.0
2
3
HOMA-IR Figure 1 Homeostasis model assessment of insulin resistance (HOMA-IR), an index of insulin resistance, in subgroups of women. with PCOS, as defined by the ESHRE/ASRM Rotterdam criteria. The subgroups are PCO with anovulation and androgen excess (PCO þ anov þ androgen, n ¼ 191), PCO with androgen excess and regular menses (PCO þ androgen, n ¼ 76) and PCO with anovulation but no hyperandrogenism (PCO þ anov, n ¼ 42). Values are geometric mean (SD). Insulin resistance is present only in the group with both anovulation and androgen excess; the other groups have values similar to those in control women (n ¼ 76). Adapted from Barber et al, 2007.14
MEDICINE 37:9
442
Ó 2009 Elsevier Ltd. All rights reserved.
SEX HORMONES
In overweight women with PCOS, weight reduction alone may result in spontaneous ovulation and it is recommended that diet and lifestyle changes should be the first-choice treatment in overweight and obese women with PCOS.15 Although initial studies suggested that metformin (see below) improved ovulation rates in women with PCOS when give alone or together with clomiphene,17 data emerging from two recent large, prospective, double-blind, randomized control trials have shown no benefit of metformin alone or in combination with clomiphene.15,18,19 Menstrual regulation Menstrual regulation may be indicated in those who do not wish to conceive. Many patients suffer occasional distressing episodes of prolonged and/or heavy vaginal bleeding. Even in patients without menstrual symptoms, treatment may be advisable because of the long-term risks of unopposed oestrogen (endometrial hyperplasia and cancer). A low-dose combined oral contraceptive (containing ethinylestradiol, 20e35 mg) may be the most convenient form of treatment, although cyclical progestogen is a reasonable alternative, particularly in women who do not need the pill for contraceptive purposes. Hirsutism and acne Management of hirsutism usually involves cosmetic treatment to remove unwanted hair and, in more severe cases, anti-androgen therapy. The most commonly used anti-androgen is cyproterone acetate. This also has progestogenic activity and can be combined with ethinylestradiol to provide cycle control in addition to management of hyperandrogenic symptoms. This treatment is equally effective for the treatment of acne, although other options such as antibiotics and retinoic acid derivatives may be considered. Despite earlier concerns, there is no evidence that co-cypridiol is more likely to cause thrombo-embolic events than other thirdgeneration oral contraceptives.20 Eflornithine is a recently available topical treatment for facial hirsutism. It is an ornithine decarboxylase inhibitor, and acts by slowing the rate of hair growth.
Ultrasound images of a normal ovary a and polycystic ovary b, showing typical increase in follicle number and stromal area in PCO. Images courtesy of Judith M Adams. Figure 2
Management Management of PCOS includes: treatment of infertility menstrual regulation in those who do not desire pregnancy treatment of associated symptoms of hyperandrogenism prevention of the possible long-term consequences of the metabolic disturbance characteristic of anovulatory women with PCOS.
Metabolic abnormalities Treatment that reduces plasma insulin and insulin resistance is likely to be beneficial for both metabolic and reproductive reasons. It has been shown that calorie restriction in obese women with PCOS improves insulin sensitivity and glucose tolerance, and leads to resumption of spontaneous ovulatory cycles and normal fertility in many cases. Such improvements can be achieved with a reduction of as little as 5% of initial weight. Is there any place for metformin in the management of PCOS? Metformin is of course well established in the management of type 2 diabetes. Results of the Diabetes Prevention Program have shown that metformin, whilst less effective than diet and lifestyle modification, is nevertherless useful in reducing the rate of conversion from IGT to frank diabetes.21 Whilst there have been no such studies specifically in women with PCOS, it seems logical therefore to consider metformin in women with PCOS and IGT, particularly in those struggling with dietary measures. Insulin-sensitizing drugs may also have a role in reducing the risk of diabetes and (perhaps) improving ovarian function. The
Induction of ovulation Induction of ovulation can be accomplished in 75e80% of women with PCOS by the use of anti-oestrogens, typically clomiphene citrate. Management of clomiphene-resistant patients is difficult. Recently, surgical procedures such as laparoscopic ovarian diathermy have become more popular. Success rates are difficult to assess, given the variation in selection criteria used for the reported studies, and there is a risk of causing intra-abdominal adhesions, which are a further cause of infertility. The treatment of choice in clomiphene non-responders is low-dose FSH,15 with careful ultrasonographic monitoring of the ovarian response. In the author’s centre, use of low-dose FSH has been successful in maintaining the multiple pregnancy rate (3% in the author’s centre) at a minimum. Recent data from a randomized control trial suggest that laparoscopic ovarian diathermy may be as effective as low-dose FSH in inducing ovulation, but adjunctive therapy with clomiphene and/or FSH was also required after surgery in about two-thirds of cases.16
MEDICINE 37:9
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Ó 2009 Elsevier Ltd. All rights reserved.
SEX HORMONES
12 Franks S. Genetic and environmental origins of obesity relevant to reproduction. Reprod Biomed Online 2006; 12: 526e31. 13 Urbanek M. The genetics of the polycystic ovary syndrome. Nat Clin Pract Endocrinol Metab 2007; 3: 103e11. 14 Barber TM, Wass JA, McCarthy MI, Franks S. Metabolic characteristics of women with polycystic ovaries and oligo-amenorrhoea but normal androgen levels: implications for the management of polycystic ovary syndrome. Clin Endocrinol 2007; 66: 513e17. 15 ESHRE/ASRM1. Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod 2008; 23: 462e77. 16 Bayram N, van Wely M, Kaaijk EM, Bossuyt PM, van der Veen F. Using an electrocautery strategy or recombinant follicle stimulating hormone to induce ovulation in polycystic ovary syndrome: randomised controlled trial. BMJ 2004; 328: 192. 17 Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003; 327: 951e3. 18 Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ 2006; 332: 1485. 19 Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007; 356: 551e66. 20 Franks S, Layton A, Glasier A. Cyproterone acetate/ethinyl estradiol for acne and hirsutism: time to revise prescribing policy. Hum Reprod 2008; 23: 231e2. 21 Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393e403.
thiazolidinediones are a relatively new class of such drugs, which have been introduced primarily for the control of type 2 diabetes. In a large, randomized, multi-centre study troglitazone was shown to improve insulin sensitivity and menstrual cyclicity in obese women with PCOS. However, this drug has been withdrawn because of serious side effects, and although there are newer, apparently safer, preparations available, there are concerns about the wisdom of administering thiazolidinediones in women of reproductive age. A
REFERENCES 1 Franks S. Polycystic ovary syndrome. N Engl J Med 1995; 333: 853e61. 2 Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005; 352: 1223e36. 3 Zawadzki J, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine FP, Merriam GR, eds. Polycystic ovary syndrome. Oxford: Blackwell, 1992. 4 Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19: 41e7. 5 Webber LJ, Stubbs S, Stark J, et al. Formation and early development of follicles in the polycystic ovary. Lancet 2003; 362(9389): 1017e21. 6 Maciel GA, Baracat EC, Benda JA, et al. Stockpiling of transitional and classic primary follicles in ovaries of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2004; 89: 5321e7. 7 Stubbs SA, Stark J, Dilworth SM, Franks S, Hardy K. Abnormal preantral folliculogenesis in polycystic ovaries is associated with increased granulosa cell division. J Clin Endocrinol Metab 2007; 92: 4418e26. 8 Franks S, Stark J, Hardy K. Follicle dynamics and anovulation in polycystic ovary syndrome. Hum Reprod Update 2008; 14: 367e78. 9 Legro RS, Bentley-Lewis R, Driscoll D, Wang SC, Dunaif A. Insulin resistance in the sisters of women with polycystic ovary syndrome: association with hyperandrogenemia rather than menstrual irregularity. J Clin Endocrinol Metab 2002; 87: 2128e33. 10 Franks S, Webber LJ, Goh M, et al. Ovarian morphology is a marker of heritable biochemical traits in sisters with polycystic ovaries. J Clin Endocrinol Metab 2008; 93: 3396e402. 11 Franks S, McCarthy M. Genetics of ovarian disorders: polycystic ovary syndrome. Rev Endocr Metab Disord 2004; 5: 69e76.
MEDICINE 37:9
FURTHER READING Adashi EY, Rock JA, Rosenwaks Z, eds. Reproductive endocrinology, surgery and technology. New York: Raven, 1996. Dunaif A, Givens JR, Haseltine FP, Merriam GR, eds. Polycystic ovary syndrome. Oxford: Blackwell, 1992. Ehrmann D. Polycystic ovary syndrome. N Engl J Med 2005; 352: 1223e36. Franks S. Assessment and management of anovulatory infertility in polycystic ovary syndrome. Endocrinol Metab Clin North Am 2003; 32: 639e51. Franks S. Polycystic ovary syndrome. N Engl J Med 1995; 333: 853e61.
444
Ó 2009 Elsevier Ltd. All rights reserved.
Polycystic ovary syndrome
What’s new?
Stephen Franks C
Following the ESHRE/ASRM consensus meeting, new recommendations for diagnostic criteria have been proposed, acknowledging that the spectrum of presentation of PCOS includes women with hyperandrogenism and regular menses
C
Recent data indicate an abnormality of early follicle development in the polycystic ovary, suggesting an intrinsic abnormality of ovarian function which may contribute to the mechanism of anovulation
C
Clomiphene remains the first choice of treatment for anovulatory infertility. Addition of metformin is not helpful
C
Metabolic abnormalities are becoming an increasingly important feature of PCOS as the population becomes more obese. There are many reports of the efficacy of metformin in the management of metabolic and endocrine abnormalities, but its therapeutic importance remains unclear
Abstract Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women. It typically presents with symptoms of anovulation, associated with clinical and/or biochemical evidence of androgen excess. The spectrum of presentation, however, includes women with hyperandrogenism who have regular periods. As well as being the most common cause of anovulatory infertility it is now recognized as a major risk factor for development of type 2 diabetes. The aetiology of PCOS remains unclear, but both genetic and environmental factors are involved. Typical biochemical features are raised serum concentrations of testosterone and elevation of serum luteinizing hormone (LH), particularly in anovulatory women. The diagnosis is made primarily on clinical criteria. The finding of raised testosterone and/or LH complements the clinical diagnosis. In obese women an oral glucose tolerance test should be undertaken to detect impaired glucose tolerance. Management of PCOS includes treatment of infertility, menstrual regulation in those who do not desire pregnancy and treatment of associated symptoms of hyperandrogenism. Another important aspect of management is the introduction of diet and lifestyle changes in overweight and obese women with PCOS to improve fertility but also in prevention of the possible long-term consequences of the metabolic disturbance characteristic of anovulatory women with PCOS.
view of these findings, the diagnostic criteria for PCOS were revised at a consensus conference jointly sponsored by the European Society for Human Reproduction and Embryology (ESHRE) and the American Society of Reproductive Medicine (ASRM) in Rotterdam, The Netherlands in 2003 (Table 1).4 The diagnosis now requires the presence of at least two of the following features: polycystic ovaries oligo-ovulation or anovulation clinical and/or biochemical evidence of androgen excess. In all recently published series characterized by the Rotterdam definition of PCOS, the largest subgroup is nevertheless that defined by the National Institutes of Health (NIH) criteria, i.e. women with oligo- or anovulation together with clinical or biochemical evidence of androgen excess. The subclassification also has implications for predicting a risk of metabolic abnormalities (as outlined below).
Keywords anovulation; impaired glucose tolerance; insulin resistance; ovary; type 2 diabetes
Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder in women. It typically presents with symptoms of anovulation (amenorrhoea, oligomenorrhoea or irregular cycles) associated with clinical and/or biochemical evidence of androgen excess (hirsutism, acne or alopecia). It is by far the most common cause of anovulatory infertility but is now recognized to be a major risk factor for development of type 2 diabetes.1,2 Until recently, the most widely accepted clinical definition of PCOS was the association of hyperandrogenism with chronic anovulation in women without specific underlying disease of the adrenal or pituitary gland.3 Early descriptions of the syndrome were based on ovarian morphology, but this was not considered an essential requirement for the diagnosis. However, recent application of modern, high-resolution diagnostic ultrasonography has again tipped the balance towards a more morphologically based diagnosis. It is now recognized that the spectrum of presentation of PCOS includes both women with hirsutism and regular cycles, and non-hirsute women with anovulation. In
Aetiology The aetiology of PCOS remains unclear, but both genetic and environmental (particularly nutritional) factors are involved. It is clear that the ovary is the principal source of the excess androgens, suggesting that it represents a primary ovarian disorder. This is supported by recent data that indicate that there is an abnormality of the earliest (gonadotrophin-independent) stages of ovarian follicle development5e7 and this abnormality may contribute to the mechanism of anovulation.8 PCOS is a familial disorder with evidence of heritability of endocrine and metabolic indices, but its genetic basis remains uncertain.9,10 It is likely to be a complex trait in which more than one, and perhaps several, genes are involved.11e18
Metabolic disorder in polycystic ovary syndrome PCOS is now known to be associated with a characteristic metabolic disorder comprising hyperinsulinaemia, insulin resistance (Figure 1) and dyslipidaemia. There is an interaction
Stephen Franks MD FRCP FMedSci is Professor of Reproductive Endocrinology at Imperial College Faculty of Medicine, St Mary’s and the Hammersmith Hospitals, London, UK. Competing interests: none declared.
MEDICINE 37:9
441
Ó 2009 Elsevier Ltd. All rights reserved.
SEX HORMONES
These findings have significant implications for long-term health. It is estimated that 15e40% of obese young women with PCOS have impaired glucose tolerance or frank type 2 diabetes mellitus. In older women with a history of PCOS, the risk of developing type 2 diabetes is estimated to be two- to sixfold greater than in a matched reference population. Epidemiological studies are in broad agreement with these figures, suggesting a doubling of risk independent of obesity, and a three- to fourfold increase in risk in obese women with PCOS. As in subjects without PCOS, a family history of diabetes, previous gestational diabetes and, of course, impaired glucose tolerance are all additional factors that can amplify the risk. These women also appear to be at increased risk of cardiovascular disease, but there is little direct information regarding cardiovascular morbidity in these patients.
Diagnostic criteria for polycystic ovary syndrome US National Institutes of Health, 1990
C C
European Society for Human Reproduction and Embryology/ American Society of Reproductive Medicine, Rotterdam, 2003
Chronic anovulation Clinical and/or biochemical signs of hyperandrogenism
C C
C
Oligo-ovulation and/or anovulation Clinical and/or biochemical signs of hyperandrogenism Polycystic ovaries
The NIH definition3 requires both criteria to make the diagnosis; the ESHRE/ ASRM diagnostic criteria4 require at least two. In both definitions, the diagnosis assumes exclusion of other diagnoses that may replicate the symptoms of polycystic ovary syndrome (e.g. non-classical congenital adrenal hyperplasia caused by 21-hydroxylase deficiency).
Investigations Serum concentrations of testosterone and other androgens are raised in PCOS. Hypersecretion of luteinizing hormone (LH) d in the presence of a normal value of follicle-stimulating hormone (FSH) d is common, particularly in anovulatory women, and is a specific but not very sensitive index of the syndrome; many patients with all of the other clinical and biochemical features of PCOS have normal LH levels. The diagnosis is made primarily on clinical and ultrasonographic criteria (Figure 2). The finding of raised testosterone and/or LH merely complements the clinical diagnosis. Nevertheless, it is important to measure serum testosterone in hirsute women because greatly increased levels (>5 nmol/litre, i.e. more than twice the upper limit of the normal range in most laboratories) are an indication for further investigation. More serious causes of hirsutism (e.g. Cushing’s syndrome, adrenal or ovarian tumours) are rare but may masquerade as PCOS (polycystic ovaries are commonly found on ultrasonography in these conditions) and measurement of serum testosterone is a useful screening procedure. A short history of hirsutism or rapid worsening of hyperandrogenic symptoms should alert the physician to the likelihood of one of these less common, but more serious, causes. In contrast to patients with other causes of amenorrhoea, amenorrhoeic women with PCOS are not oestrogen-deficient; their serum oestradiol levels tend to be in the normal, early to mid-follicular phase range.
Table 1
between the effect of PCOS and that of obesity, such that the metabolic abnormalities in women with PCOS are amplified to a greater degree by obesity than in weight-matched controls. The metabolic abnormalities appear to be a particular feature of those with the classical syndrome (hyperandrogenism and anovulation), whereas equally hyperandrogenaemic women with polycystic ovaries but regular menses (and those with anovulation without androgen excess) tend to exhibit normal insulin secretion and action.14
HOMA-IR according to PCOS phenotype PCO + anov + androgen PCO + androgen PCO + anov
Investigation of metabolic abnormalities Fasting plasma glucose estimation in overweight and obese women with PCOS (body mass index (BMI) >25 kg/m2) will identify those with previously undiagnosed type 2 diabetes, but is not useful for uncovering impaired glucose tolerance (IGT). The proceedings of the Rotterdam consensus meeting suggest that, in obese women (BMI >30 kg/m2), an oral glucose tolerance test should be undertaken to detect IGT and a fasting lipid profile determined. All obese patients with PCOS must be considered at risk of type 2 diabetes and should be offered dietary advice (see below). The BMI threshold for metabolic testing in women with PCOS may need to be adjusted (downwards) for populations at increased risk of insulin resistance (e.g. south Asian women) and it has been suggested that waist circumference is a better index of risk than BMI.
Control
0.0
0.2
0.4
0.6
0.8
1.0
2
3
HOMA-IR Figure 1 Homeostasis model assessment of insulin resistance (HOMA-IR), an index of insulin resistance, in subgroups of women. with PCOS, as defined by the ESHRE/ASRM Rotterdam criteria. The subgroups are PCO with anovulation and androgen excess (PCO þ anov þ androgen, n ¼ 191), PCO with androgen excess and regular menses (PCO þ androgen, n ¼ 76) and PCO with anovulation but no hyperandrogenism (PCO þ anov, n ¼ 42). Values are geometric mean (SD). Insulin resistance is present only in the group with both anovulation and androgen excess; the other groups have values similar to those in control women (n ¼ 76). Adapted from Barber et al, 2007.14
MEDICINE 37:9
442
Ó 2009 Elsevier Ltd. All rights reserved.
SEX HORMONES
In overweight women with PCOS, weight reduction alone may result in spontaneous ovulation and it is recommended that diet and lifestyle changes should be the first-choice treatment in overweight and obese women with PCOS.15 Although initial studies suggested that metformin (see below) improved ovulation rates in women with PCOS when give alone or together with clomiphene,17 data emerging from two recent large, prospective, double-blind, randomized control trials have shown no benefit of metformin alone or in combination with clomiphene.15,18,19 Menstrual regulation Menstrual regulation may be indicated in those who do not wish to conceive. Many patients suffer occasional distressing episodes of prolonged and/or heavy vaginal bleeding. Even in patients without menstrual symptoms, treatment may be advisable because of the long-term risks of unopposed oestrogen (endometrial hyperplasia and cancer). A low-dose combined oral contraceptive (containing ethinylestradiol, 20e35 mg) may be the most convenient form of treatment, although cyclical progestogen is a reasonable alternative, particularly in women who do not need the pill for contraceptive purposes. Hirsutism and acne Management of hirsutism usually involves cosmetic treatment to remove unwanted hair and, in more severe cases, anti-androgen therapy. The most commonly used anti-androgen is cyproterone acetate. This also has progestogenic activity and can be combined with ethinylestradiol to provide cycle control in addition to management of hyperandrogenic symptoms. This treatment is equally effective for the treatment of acne, although other options such as antibiotics and retinoic acid derivatives may be considered. Despite earlier concerns, there is no evidence that co-cypridiol is more likely to cause thrombo-embolic events than other thirdgeneration oral contraceptives.20 Eflornithine is a recently available topical treatment for facial hirsutism. It is an ornithine decarboxylase inhibitor, and acts by slowing the rate of hair growth.
Ultrasound images of a normal ovary a and polycystic ovary b, showing typical increase in follicle number and stromal area in PCO. Images courtesy of Judith M Adams. Figure 2
Management Management of PCOS includes: treatment of infertility menstrual regulation in those who do not desire pregnancy treatment of associated symptoms of hyperandrogenism prevention of the possible long-term consequences of the metabolic disturbance characteristic of anovulatory women with PCOS.
Metabolic abnormalities Treatment that reduces plasma insulin and insulin resistance is likely to be beneficial for both metabolic and reproductive reasons. It has been shown that calorie restriction in obese women with PCOS improves insulin sensitivity and glucose tolerance, and leads to resumption of spontaneous ovulatory cycles and normal fertility in many cases. Such improvements can be achieved with a reduction of as little as 5% of initial weight. Is there any place for metformin in the management of PCOS? Metformin is of course well established in the management of type 2 diabetes. Results of the Diabetes Prevention Program have shown that metformin, whilst less effective than diet and lifestyle modification, is nevertherless useful in reducing the rate of conversion from IGT to frank diabetes.21 Whilst there have been no such studies specifically in women with PCOS, it seems logical therefore to consider metformin in women with PCOS and IGT, particularly in those struggling with dietary measures. Insulin-sensitizing drugs may also have a role in reducing the risk of diabetes and (perhaps) improving ovarian function. The
Induction of ovulation Induction of ovulation can be accomplished in 75e80% of women with PCOS by the use of anti-oestrogens, typically clomiphene citrate. Management of clomiphene-resistant patients is difficult. Recently, surgical procedures such as laparoscopic ovarian diathermy have become more popular. Success rates are difficult to assess, given the variation in selection criteria used for the reported studies, and there is a risk of causing intra-abdominal adhesions, which are a further cause of infertility. The treatment of choice in clomiphene non-responders is low-dose FSH,15 with careful ultrasonographic monitoring of the ovarian response. In the author’s centre, use of low-dose FSH has been successful in maintaining the multiple pregnancy rate (3% in the author’s centre) at a minimum. Recent data from a randomized control trial suggest that laparoscopic ovarian diathermy may be as effective as low-dose FSH in inducing ovulation, but adjunctive therapy with clomiphene and/or FSH was also required after surgery in about two-thirds of cases.16
MEDICINE 37:9
443
Ó 2009 Elsevier Ltd. All rights reserved.
SEX HORMONES
12 Franks S. Genetic and environmental origins of obesity relevant to reproduction. Reprod Biomed Online 2006; 12: 526e31. 13 Urbanek M. The genetics of the polycystic ovary syndrome. Nat Clin Pract Endocrinol Metab 2007; 3: 103e11. 14 Barber TM, Wass JA, McCarthy MI, Franks S. Metabolic characteristics of women with polycystic ovaries and oligo-amenorrhoea but normal androgen levels: implications for the management of polycystic ovary syndrome. Clin Endocrinol 2007; 66: 513e17. 15 ESHRE/ASRM1. Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod 2008; 23: 462e77. 16 Bayram N, van Wely M, Kaaijk EM, Bossuyt PM, van der Veen F. Using an electrocautery strategy or recombinant follicle stimulating hormone to induce ovulation in polycystic ovary syndrome: randomised controlled trial. BMJ 2004; 328: 192. 17 Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003; 327: 951e3. 18 Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ 2006; 332: 1485. 19 Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007; 356: 551e66. 20 Franks S, Layton A, Glasier A. Cyproterone acetate/ethinyl estradiol for acne and hirsutism: time to revise prescribing policy. Hum Reprod 2008; 23: 231e2. 21 Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393e403.
thiazolidinediones are a relatively new class of such drugs, which have been introduced primarily for the control of type 2 diabetes. In a large, randomized, multi-centre study troglitazone was shown to improve insulin sensitivity and menstrual cyclicity in obese women with PCOS. However, this drug has been withdrawn because of serious side effects, and although there are newer, apparently safer, preparations available, there are concerns about the wisdom of administering thiazolidinediones in women of reproductive age. A
REFERENCES 1 Franks S. Polycystic ovary syndrome. N Engl J Med 1995; 333: 853e61. 2 Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005; 352: 1223e36. 3 Zawadzki J, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine FP, Merriam GR, eds. Polycystic ovary syndrome. Oxford: Blackwell, 1992. 4 Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19: 41e7. 5 Webber LJ, Stubbs S, Stark J, et al. Formation and early development of follicles in the polycystic ovary. Lancet 2003; 362(9389): 1017e21. 6 Maciel GA, Baracat EC, Benda JA, et al. Stockpiling of transitional and classic primary follicles in ovaries of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2004; 89: 5321e7. 7 Stubbs SA, Stark J, Dilworth SM, Franks S, Hardy K. Abnormal preantral folliculogenesis in polycystic ovaries is associated with increased granulosa cell division. J Clin Endocrinol Metab 2007; 92: 4418e26. 8 Franks S, Stark J, Hardy K. Follicle dynamics and anovulation in polycystic ovary syndrome. Hum Reprod Update 2008; 14: 367e78. 9 Legro RS, Bentley-Lewis R, Driscoll D, Wang SC, Dunaif A. Insulin resistance in the sisters of women with polycystic ovary syndrome: association with hyperandrogenemia rather than menstrual irregularity. J Clin Endocrinol Metab 2002; 87: 2128e33. 10 Franks S, Webber LJ, Goh M, et al. Ovarian morphology is a marker of heritable biochemical traits in sisters with polycystic ovaries. J Clin Endocrinol Metab 2008; 93: 3396e402. 11 Franks S, McCarthy M. Genetics of ovarian disorders: polycystic ovary syndrome. Rev Endocr Metab Disord 2004; 5: 69e76.
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FURTHER READING Adashi EY, Rock JA, Rosenwaks Z, eds. Reproductive endocrinology, surgery and technology. New York: Raven, 1996. Dunaif A, Givens JR, Haseltine FP, Merriam GR, eds. Polycystic ovary syndrome. Oxford: Blackwell, 1992. Ehrmann D. Polycystic ovary syndrome. N Engl J Med 2005; 352: 1223e36. Franks S. Assessment and management of anovulatory infertility in polycystic ovary syndrome. Endocrinol Metab Clin North Am 2003; 32: 639e51. Franks S. Polycystic ovary syndrome. N Engl J Med 1995; 333: 853e61.
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