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Polycystic ovary syndrome: An overview
Reviews in Gynaecological Practice 5 (2005) 115–122 www.elsevier.com/locate/rigp
Gynaecological endocrinology
Polycystic ovary syndrome: An overview Abdulmalik U. Bako *, Sharon Morad 1, William A. Atiomo 2 Department of Obstetrics and Gynaecology, School of Human Development, University of Nottingham, Queen’s Medical Centre, University Hospital, Derby Road, Nottingham NG7 2UH, UK Received 10 February 2005; accepted 18 April 2005 Available online 23 May 2005
Abstract Polycystic ovary syndrome (PCOS) is a heterogeneous condition that represents a continuous spectrum from asymptomatic women with polycystic ovaries demonstrated on ultrasound through to those with the classic features of infertility, obesity and hyperandrogenaemia. It is now generally believed to be a metabolic and endocrine condition secondary to relative insulin resistance and compensatory hyperinsulinaemia. Hyperinsulinaemia is thought to cause abnormal ovarian androgen metabolism and altered ovarian gonadotrophin response resulting in anovulation, oligoamenorrhoea and features of hyperandrogenism. Logically, therapeutic strategies aimed at correcting the insulin resistance (weight loss and insulin sensitisers) would in theory make more sense than symptom relief. The potential increased risks of cardiovascular disease and non-insulin-dependent diabetes mellitus would also be obviated. In practice, however, several gaps exist in our current knowledge of the pathophysiology of PCOS with resulting challenges in strategies that aim primarily to correct insulin resistance. This article discusses the current understanding and management of polycystic ovary syndrome. Novel future research directions are suggested. # 2005 Elsevier B.V. All rights reserved. Keywords: Polycystic ovary syndrome; Insulin resistance; Clomifene; Metformin
1. Introduction Polycystic ovary syndrome (PCOS) is a heterogeneous disorder of unknown aetiology affecting 5–10% of women of reproductive age [1]. It is a disorder that affects the reproductive, endocrine and metabolic systems, and it is the most common cause of anovulatory infertility. Its exact cause is unknown; however, there are several theories about its pathophysiology. In the last decade, the insulin resistance hypothesis has gathered several converts [2]. It is thought that relative insulin resistance results in chronic hyperinsulinaemia which gives rise to abnormal ovarian androgen metabolism, impaired follicle growth and altered gonadotrophin response [3]. This article argues that several gaps in our understanding of the links between the insulin resistance * Corresponding author. Tel.: +44 1159249924. E-mail addresses: [email protected] (A.U. Bako), [email protected] (S. Morad), [email protected] (W.A. Atiomo). 1 Tel. +44 1159249924. 2 Tel. +44 1159249924x43500/43572. 1471-7697/$ – see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.rigp.2005.04.001
hypothesis and clinical features, diagnosis, pathophysiology and treatment outcome call for research strategies which look beyond insulin resistance in a search for a better understanding of PCOS. Novel molecular biology techniques that allow the simultaneous study of several genes and proteins (mRNA micro arrays and proteomics) expressed in various target tissues of interest in a discovery-driven approach now offer this opportunity. The currently accepted definition, epidemiology and pathophysiology of PCOS are first discussed followed by the clinical features and long-term health risks. Although possible future research directions are discussed in the concluding segments of this article, the overall emphasis is on the current clinical management of PCOS.
2. Clinical diagnosis It is interesting to note that despite the wide acceptance of the insulin resistance hypothesis in PCOS, it does not feature in past and current diagnostic criteria. Traditionally, there
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were two schools of thought on the ideal diagnostic criteria for PCOS. The European school of thought held that PCOS encompassed the presence of polycystic ovaries on ultrasound and one or more of the signs and symptoms of raised concentrations of serum androgen and chronic anovulation in the absence of pituitary and adrenal disease [4]. On the other hand, the North American School of Thought diagnosed PCOS where a combination of hyperandrogenism and menstrual/ovulatory dysfunction, in the absence of non-classic adrenal hyperplasia were present. There was no need to identify the presence of polycystic ovaries by ultrasonography [2]. This disparity resulted in challenges in research and clinical management, as the findings of clinical research studies carried out in either Europe or America were not necessarily applicable to a local population, if the research originated in a continent where different diagnostic criteria were used for PCOS. More recently, in an attempt to resolve this conflict, a joint consensus meeting of the American Society for Reproductive Medicine and the European Society of Human Reproduction an Embryology (ASRM/ESHRE) refined the definition of PCOS [5]. It agreed that PCOS was primarily a condition of ovarian dysfunction and that in the absence of other aetiologies (such as prolactinoma, congenital adrenal hyperplasia or an androgen-secreting tumour) two or more of the following criteria established PCOS. These included: oligo- and/or anovulation, clinical and/or biochemical signs of hyperandrogenism and at least one polycystic ovary on ultrasound (Table 1). The morphology of polycystic ovary was redefined as the presence of an ovary with 12 or more follicles measuring 2–9 mm in diameter and/or an increased ovarian volume (>10 ml3) [5]. This ASRM/ESHRE consensus definition is currently accepted as the ideal definition of PCOS. The key advantages are its ability to standardise definitions used in research studies of the epidemiology, pathophysiology and treatment of PCOS.
3. Epidemiology The true prevalence of PCOS is not known because of the pre-existing debates about the precise diagnostic criteria. Variations in the quoted prevalence are largely due to different populations and diagnostic criteria used in the studies. This is again complicated by the absence of measures of insulin resistance in most studies on the epidemiology of PCOS. Hospital-based studies have reported the prevalence of ultrasonic appearance of polycystic ovaries to range from 45 to 92% [6–8]. However, community-based studies have reported the incidence of polycystic ovaries to be 17–22% [4,9–11]. The quoted prevalence in these studies should be taken with caution because in some of the studies full biochemical and clinical assessment were not performed and hospital data do not reflect the picture in the larger population. Wijeyaratne et al. [12] reported that the prevalence of PCOS may be higher in South Asian immigrants to the UK and Rodin et al. [13] found the prevalence of PCOS among the South Asian immigrants in Britain to be 52% with majority of them (49.1%) presenting with menstrual abnormality. The lack of an absolute correlation between insulin resistance and ultrasound evidence of PCOS supports our argument for delving beyond insulin resistance in the aetiology of PCOS.
4. Pathophysiology A variety of theories/systems have been implicated in the pathophysiology of PCOS. These include aberrations of the hypothalamo–pituitary–ovarian axis, intra-ovarian growth factors, fetal programming and more recently insulin resistance and its metabolic consequences including the metabolic syndrome X. The increased prevalence of symptoms of PCOS amongst family members of affected women also suggests a genetic link. However, how these
Table 1 Ultrasound, endocrine and biochemical investigations in PCOS Investigation
Normal rangea
Comment
Pelvic ultrasound
Assess ovarian morphology
Refer to ASRM/ESHRE definition
LH FSH
2–10 iu/l 2–8 iu/l
Measured on days 1–3 of a menstrual bleed or randomly if amenorrhoeic
Oestradiol Testosterone
0.5–3.5 nmol/l
SHBG FAI (T 100/SHBG) Prolactin Thyroid stimulating hormone Fasting insulin Oral glucose tolerance test (OGTT) a
16–119 nmol/l <5 0.5–5 iu/l <500 mu/l <30 mu/l
Range may vary depending on laboratory.
Measurement unhelpful and would not affect management Suspect congenital adrenal hyperplasia or an androgen-secreting tumour and refer if total testosterone is >5 nmol/l Insulin suppresses SHBG Value raised with normal testosterone and low SHBG Assay level if oligo- or amenorrhoeic Assay level if oligo- or amenorrhoeic Not measured in routine clinical practice Seventy-five grams of OGTT to assess insulin resistance. Refer to diabetic clinic if abnormal and arrange annual fasting blood glucose if impaired
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systems interact to result in the PCOS phenotype is still uncertain [14]. Insulin resistance is the main hypothesis that appears to be fast gathering pace as the single unifying hypothesis in PCOS. However, the fact that it is thought to be present in 30–60% of women with PCOS and not all of them raises more questions than it answers and supports our argument for novel research directions. The mechanisms of insulin resistance in PCOS are also uncertain. It has been postulated that genetic abnormalities in the regulation of insulin receptor phosphorylation result in an increased insulin-independent serine phosphorylation and decreased insulin-dependent tyrosine phosphorylation leading to decrease insulin sensitivity [1] and compensatory hyperinsulinaemia. It is thought that compensatory hyperinsulinaemia augments the stimulatory action of LH on theca cell androgen biosynthesis through upregulation of genes encoding steroidogenic enzymes [15]. It has also been postulated that hyperinsulinaemia acts on the hypothalamus and pituitary leading to increase LH concentration and on the ovarian stromal cells resulting in increase free circulating androgens and a decrease in sex hormone binding globulin (SHBG) [15]. Hyperinsulinaemia also leads to imbalance in the production of insulin-like growth factor binding protein-1 resulting in abnormal local steriodogenesis. Insulin resistance may also lead to direct stimulation of an ovarian protease inhibitor (plasminogen activator inhibitor-1 (PAI-1)) resulting in limitation of follicular growth. The absence of a direct link between the ovarian and metabolic phenotype of PCOS however calls for a look beyond insulin resistance.
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heavy and sometimes erratic bleeding as the endometrium breaks down. 5.2. Infertility Infertility is the presenting complaint in 40% of women with PCOS and it is due to anovulation. The exact mechanism underlying the association between infertility and PCOS remains unknown. It was thought that the subfertility could be due to the presence of high LH and androgen levels. It was suggested that high LH level in the follicular phase of the menstrual cycle caused a premature resumption of meiosis with the consequent release of a ‘premature oocyte’ [20]. However, it would appear that several factors interact to form part of the vicious cycle of abnormal steriodogenesis, folliculogenesis, abnormal oocyte maturation, decrease endometrial receptivity and early pregnancy loss [21]. 5.3. Androgen excess (hirsutism and acne) Androgen excess presents as hirsutism, which is terminal hair of male pattern distribution (facial hair: upper lip, chin, side burn, chest, upper and upper abdomen, upper and lower back, upper arm, thigh and buttock). Rapid onset of hirsutism and signs of virilism should be investigated to rule out adult onset congenital adrenal hyperplasia and malignancy. The degree of hirsutism can be evaluated by using the modified Ferriman and Galway score before commencing therapy and for monitoring response. 5.4. Obesity
5. Clinical presentation The principal features of PCOS include menstrual irregularities, anovulatory infertility, androgen excess (hirsutism, acne and temporal balding) and obesity [4,16]. Some patients with PCOS are asymptomatic and for some individuals signs and symptoms may change over time [17]. The heterogeneity of the features of women with PCOS which varies from a mild disorder affecting the reproductive, endocrine and metabolic systems to a severe disturbance suggests that insulin resistance is not the single unifying hypothesis. Several factors affect the expression of PCOS, for example, weight gain is associated with worsening of symptoms and signs while an improvement in the clinical features of the syndrome is seen with weight loss [18,19]. 5.1. Menstrual irregularity Menstrual irregularity (oligo- or amenorrhoea) is the most common reason for gynaecological presentation. PCOS women with amenorrhoea are not oestrogen deficient. Indeed, the endometrium of oligoamenorrhoeic women with PCOS is under continuous exposure to oestrogen until the endometrial growth outstrips its blood supply. This results in
Ten to 65% of women with PCOS are obese (BMI greater than 30 kg/m2). Central obesity with increased waist–hip ratio (WHR) (normal WHR: 0.82–0.85) is a common finding amongst obese women with PCOS [22]. It is thought that obesity exacerbates the underlying insulin resistance in patients with PCOS. However, the fact that insulin resistance may be present in non-obese women with PCOS raises further questions about the interrelationships between obesity and insulin resistance.
6. Treatment Although insulin resistance is thought to underpin PCOS, treatment is still largely directed at presenting symptoms rather than the correction of the underlying cause/pathophysiology. Apart from the treatment of anovulatory infertility where a systematic review has demonstrated a clear improvement in ovulation rates with metformin, the lack of clear evidence of the use of insulinsensitising agents in the treatment of hirsutism, obesity and acne raises questions about the validity of insulin resistance hypothesis.
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6.1. Infertility Ovulation induction strategies in general include: weight reduction, medical treatment (anti-oestrogens—mainly clomifene citrate, tamoxifen and gonadotrophin therapy) and surgical treatment. 6.1.1. Clomifene Clomifene citrate (50–100 mg) taken on days 2–6 of a natural or induced menstrual bleed can be used to induce ovulation. Overall, clomifene citrate is successful in about 80% of anovulatory women, however, pregnancy occurs in about half of them [18]. Its effectiveness is reduced in obese women with PCOS. A therapeutic daily dose over 100 mg may cause thickening of cervical mucous and has not been found to be beneficial. Administration of clomifene citrate should be monitored using ultrasound scanning to assess follicular development in order to reduce the risk of multiple pregnancies (10–16%). 6.1.2. Metformin The insulin resistance hypothesis in PCOS has provided the rationale for the use of insulin-sensitising agents (such as metformin to improve the reproductive and metabolic abnormalities in non-diabetic women with PCOS [23,24]. Metformin has been shown to improve insulin sensitivity, reduce LH, PAI-1 and testosterone levels (total and free) which are thought to impair folliculogenesis. Follicle stimulating hormone and SHBG levels are also increased [25]. In a meta-analysis of 13 randomised controlled trials (involving 310 women), Lord et al. [24] showed that metformin was effective in achieving ovulation in women with PCOS when compared with placebo, metformin and clomifene were similarly effective when compared to clomifene citrate alone. It has therefore been argued that there could be a place for the use of metformin as a first-line agent in ovulation induction in obese and non-obese women with anovulatory infertility due to PCOS [26]. However, the UK’s National Institute for Clinical Excellence (NICE) [27] recommendation is that metformin can be used as an adjunct to clomifene in women who failed to respond to clomifene alone. Before commencing metformin therapy in anovulatory women with PCOS, it is good practice to offer appropriate advice on weight loss including diet, life style and exercise. Baseline investigations (full blood count, fasting lipids, oral glucose tolerance test, renal and liver function tests) should be performed before commencing treatment because metformin can cause lactic acidosis in mild renal impairment. These investigations should also be repeated yearly whilst the patient is on metformin. Because of the theoretical risk of hypoglycaemia (due to metformin), patient should be counselled about the symptoms of hypoglycaemia and advised to stop treatment if it is suspected. Metformin is currently not licensed for use in pregnancy and it is recommended that it should be discontinued once
pregnancy is confirmed; however, there is no evidence of fetal teratogenicity. Indeed, metformin has been used in pregnant women with type 2 diabetes mellitus without increase in major fetal abnormality when compared with controls of untreated pregnant women with type 2 diabetes mellitus [28]. Where clomifene and or metformin treatment do not result in ovulation, the second-line options include either gonadotrophins therapy or surgery. 6.1.3. Gonadotrophins Medical treatment with parenteral gonadotrophins (pure FSH or human menopausal gonadotrophins) can be employed in patients resistant to anti-oestrogens. However, gonadotrophins have been shown to be associated with an increased incidence of multiple pregnancy and ovarian hyperstimulation syndrome (OHSS) because of the recruitment of multiple follicles [14,29]. Follicular development should be closely monitored with ultrasound to minimise these risks. Successful treatment with gonadotrophins has been shown in PCOS women with obesity and insulin resistance [30], however, serum IGF levels have not been shown to be a useful predictor of gonadotrophin response prior to in vitro fertilisation [31]. The central role of insulin resistance hypothesis is again contested. 6.1.4. Surgery Laparoscopic ovarian drilling using electrodiathermy is currently an alternative second-line option in the treatment of women with PCOS who have failed to respond to medical treatment [14,18,29]. It is associated with considerably lower multiple pregnancy rates compared to gonadotrophins and no case of ovarian hyperstimulation was reported in a trial by Farquhar et al. [32]. An argument could be made for its consideration before gonadotrophins; however, the associated hazards of surgery should be considered. In a cohort study of up to 20 years, Gjonnaess [33] showed that there was persistence in ovulation and normalisation of serum androgens and SHBG following laparoscopic ovarian electrocautery in over 60% of the patients treated. The suggested mechanism of action of ovarian drilling is that the destruction of the androgenproducing stroma of the ovaries with electrocautery leads to a reduction in serum androgen levels, thereby decreasing the amount of substrate available for peripheral aromatisation to oestrogens. It has been postulated that this will restore the feedback mechanism to the hypothalamus–pituitary axis, allowing appropriate gonadotrophin stimulation for follicular development and ovulation [34]. Laparoscopic ovarian drilling does not however change insulin responses to OGTT again questioning the central role of insulin resistance in PCOS [35]. Laparoscopic ovarian drilling using diathermy is potentially associated with periovarian adhesions [36] and theoretically could lead to premature ovarian failure [29] due to over destruction of ovarian stroma; however, there is no clear evidence that this is the case.
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6.2. Obesity
6.4. Hirsutism and hyperandrogenism
PCOS patients who are obese (BMI > 30 kg/m2) should be encouraged to lose weight because obesity is associated with worse endocrine and biochemical features of PCOS. Weight loss enhances insulin sensitivity and improves the endocrine profile and the chances of ovulation, and achieving viable and healthy pregnancy [18,37]. Traditionally, a low-fat and high-carbohydrate diet in conjunction with moderate regular exercise is thought to aid weight loss. The emphasis should be on reducing central adiposity and improving the WHR. In clinical practice, weight loss in women with PCOS can be challenging as postprandial thermogenesis is reduced. There is evidence that group counselling incorporated with exercise and education may facilitate long-term behavioural change of obese women with PCOS [38,39]. Patients with PCOS need encouragement to achieve a behavioural change. In general, weight management ideally requires a multidisciplinary approach involving the dietician, psychologist and the clinician. Anti-obesity drug, such as Orlistat (Xenical1), could be used on a short-term basis in order to encourage longer term general life style modification [3]. There is currently no evidence that metformin on its own leads to weight loss in obese women with PCOS independent of conventional diet and exercise, despite its effect on insulin metabolism and its side effects of nausea, vomiting and diarrhoea.
Modalities of physical treatment of hirsutism include shaving, waxing and bleaching, electrolysis, and laser and photothermolysis. Electrolysis is expensive and can be painful; it should be performed by a trained expert. Shaving can be time-consuming and all physical methods do not guarantee permanent cure, so patients should be counselled appropriately because re-growth of hair is not uncommon and indeed scarring may occur. Repeated laser and photothermolysis tend to produce a near permanent result because hair follicles in the early growing phase are destroyed during treatment [18]. The rate of hair growth and therefore progression of hirsutism can be reduced by anti-androgens, such as cyproterone-acetate, spironolactone, ketoconazole, dutasteride and finasteride. Co-cyprindiol (Dianette1, Schering Health) is often used in the first instance. Dianette (containing cyproterone acetate 2 mg and ethinyloestradiol 35 mcg) is taken cyclically and its effect on hair growth may not be evident in the first 3–6 months. The addition of a higher dose of cyproterone acetate (50–100 mg) in the first 10 days of every cycle was not found to be beneficial [39]. Liver function should be evaluated before commencing cyproterone acetate and regularly afterwards (after 6 months then annually). It is contraindicated in patients with hepatic disease, history of venous thrombo embolism and youths less than 18 years (may arrest bone maturation). Treatment should be withdrawn once hirsutism has completely resolved. It is important that an effective contraception is used because anti-androgens can cross the placenta and affect the sexual development of the male fetus. Anti-androgens are not appropriate if pregnancy is desired. Dutasteride and finasteride are specific inhibitors of five alpha reductase but contraindicated in women and adolescents. Spironolactone (a weak diuretic) may be used in women in whom Dianette1 is unsuitable. It may be taken daily in a dose of 25–100 mg. Spironolactone may cause hyponatraemia, hyperkalaemia and hepatotoxity, so liver function and serum electrolytes should be checked regularly. Finally, in the context of the insulin resistance hypothesis, hirsutism and acne should improve when insulin resistance is ameliorated. In support of this hypothesis, a Cochrane review of two trials involving 24 subjects found metformin to be significantly effective compared to placebo on reported hirsutism score [41]. On the other hand, some studies have failed to find an improvement in hirsutism with 6 months metformin use [42]. Larger definitive studies are however awaited.
6.3. Menstrual abnormality The risk of prolonged oestrogen stimulation of the endometrium in PCOS, which may lead to erratic heavy bleeding, and the risk of developing endometrial hyperplasia and carcinoma is the rational for inducing regular withdrawal bleeds in these women [40]. The low-dose combined oral contraceptive pills (COCP) can be administered to induce regular menstrual cycles. There is, however, no clear evidence of the effectiveness of COCP on the primary prevention of endometrial carcinoma in amenorrhoeic women with PCOS. Similarly, the effectiveness of contraceptive pills taken back to back every 3 months is unknown. The COCP is relatively contraindicated in obesity and there is theoretical concern over the effect of COCP on insulin resistance [3]. Regular endometrial withdrawal bleeding can also be induced by the administration of medroxyprogesterone acetate or dydrogesterone taken cyclically for 12 days every 1–3 months. Persistently thick endometrium on transvaginal ultrasound should be investigated by endometrial biopsy and/or hysteroscopy [23] and there may be a role for annual screening with transvaginal ultrasound scans in women with PCOS over the age of 40 years. The association between the resumption of ovulation and regular menstruation and metformin treatment suggests that there may also be a role for metformin use in primary prevention of endometrial hyperplasia/cancer. Definitive studies are however required.
7. Long-term health implications of PCOS There appears to be clear evidence that hyperinsulinaemia in PCOS is associated with late development of impaired glucose tolerance and type 2 diabetes [43]. The
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risk of developing type 2 diabetes is increased in obese and non-obese women with PCOS. It is therefore good practice for healthcare professionals responsible for the care of women with PCOS to screen them for diabetes annually. Although, it is recognised that hyperinsulinaemia, hyperandrogenism and obesity (features of PCOS) are cardiovascular risk factors. There is evidence that mortality amongst women with PCOS from cardiovascular disease is not significantly higher, although the long-term risk of developing atherosclerotic disease, hypertension and myocardial infarction is greater [44,45]. Women with PCOS should be offered annual fasting cholesterol, lipids and triglycerides [23]. Prolonged exposure to premenopausal level of oestrogen can lead to endometrial hyperplasia and carcinoma [46,47] although the risk has not been clearly defined. There may also be an association between unopposed oestrogen stimulation in PCOS and breast cancer, however there is no evidence to support this hypothesis [46]. In the only study so far on mortality in women with PCOS, Pierpoint et al. [48] found no significant increase in breast cancer deaths among women with documented PCOS.
8. Areas for future research There is a clear need for further studies to explore the aetiology of PCOS since insulin resistance is not present in all cases of PCOS. Given the complexity of PCOS, a discovery-based approach that aims to identify all the possible genes and proteins expressed differently in women with PCOS should now make it possible to advance our understanding of PCOS. The use of novel techniques, such as mRNA micro arrays and proteomics, would facilitate discovery-based research in PCOS. In theory computational analysis of the large datasets created and data exploration with artificial neural networks should provide simple algorithms, which would shed more insight into the complexity of PCOS. There are needs for other types of researches. Some of these should include clinical trials to assess the true efficacy of insulin-sensitising medication with live birth rate as a primary outcome, the role of metformin in menstrual regulation and primary prevention of non-insulin-dependent diabetes in teenagers and studies comparing laparoscopic ovarian drilling with metformin and laparoscopic ovarian drilling in women who have failed to ovulate with clomifene.
9. Conclusion This article reviewed the current definition, epidemiology, pathophysiology, clinical management and longer term health risks of PCOS. Although it is proposed that insulin resistance appears to be the key metabolic defect in the aetiology of PCOS, it does not fully explain the aetiology of the complex
syndrome. Current treatment strategies which have evolved from symptom control to treating the underlying pathology of insulin resistance with insulin-sensitising agents, such as metformin, general lifestyle modification (exercise and improved diet) are however welcome. Future research that delves beyond insulin resistance is required. Novel molecular biology techniques that encourage a discovery-based approach were suggested in this article. These include the combination of mRNA micro arrays, proteomics and computational analysis to obtain further insight into PCOS from the analysis of the complex data sets generated. New leads may then be generated which should lead to focussed hypothesis-driven research of new pathways or systems which provide a clearer picture of PCOS than is currently the case with the insulin resistance hypothesis.
Practice points: New international consensus criteria for the diagnosis of PCOS Assessment of obesity: BMI, WHR Individualisation of investigation, management and follow-up Biochemistry and endocrinology: early follicular phase LH, FSH, free testosterone, free androgen index (FAI), SHBG, prolactin Ovulation induction can be effectively induced by metformin in both obese and non-obese patients with PCOS Weight loss programme Metformin should not be used as a weight reduction agent, but should be used in conjunction with general life style modification, such as increased exercise and improved diet Screening for diabetes and long-term risks of endometrial cancer should be considered Follow-up: regular review of BMI, blood pressure, fasting blood sugar and cholesterol, endometrial assessment (TVS) in oligoamenorrhoiec women above 40 years Research agenda: Understanding the pathophysiology of PCOS using discovery-based approaches, such as the application of genomics, proteomics and bioinformatics Effect of metformin on pregnancy and live birth rates Evidence for the safety of long-term use of metformin Evidence for the medical treatment of menstrual abnormality in PCOS
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[22] Rebuffe-Scrive M, Cullerg G, Lundberg PA, et al. Anthropometric variables and metabolism in polycystic ovarian disease. Horm Metab Res 1989;21:391–7. [23] Royal College of Obstetricians and Gynaecologists. Long-term consequence of polycystic ovary syndrome. Guideline no. 33, London: RCOG; 2003. [24] Lord JM, Flight IHK, Norman RJ. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome. The cochrane database of systematic reviews, issue 2; 2003. [25] Moghetti P, Castello R, Negri C, et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebocontrolled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab 2000;85:139–46. [26] Sinha A, Atiomo W. The role of metformin in the treatment of infertile women with polycystic ovary syndrome. TOG 2004;6: 145–51. [27] NICE 2004. Infertility. Technology appraisal guidance no. 22. Available at http://www.nice.org.uk/page.aspx?o=15724, last accessed January 2004. [28] Coetzee EJ, Jackson WP. Oral hypoglycaemic in the first trimester and fetal outcome. S Afr Med J 1984;65:635–7. [29] Farquhar C, Vandekerckhove P, Lilford R. Laparoscopic ‘‘drilling’’ by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome. The cochrane database of systematic reviews, issue 1; 2004. [30] Mulders AG, Laven JS, Eijkemans MJ, Hughes EG, Fauser BC. Patient predictors for outcome of gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility: a metaanalysis. Hum Reprod Updat 2003;9(5):429–49. [31] Keay SD, Liversedge NH, Akande VA, Mathur RS, Jenkins JM. Serum IGF-1 concentrations following pituitary desensitisation do not predict the ovarian response to gonodotrophin stimulation prior to IVF. Hum Reprod 2003;8(9):797–801. [32] Farquhar CM, Williamson K, Gudex G, Johnson N, Garland J, Sadler L. A randomised controlled trial of laparoscopic ovarian diathermy versus gonadotrophin therapy for women for women with clomiphene resistant polycystic ovarian syndrome. Fertil Steril 2001;78(2): 404–11. [33] Gjonnaess H. Late endocrine effect of ovarian electrocautery in women with polycystic ovary syndrome. Fertil Steril 1998;69:697– 701. [34] Felemban A, Tan SL, Tulandi T. Laparoscopic treatment of polycystic ovaries with insulated needle cautery: a reappraisal. Fertil Steril 2000;73:266–9. [35] Tulandi T, Saleh A, Morris D, Jacobs HS, Payne NN, Tan SL. Effects of laparoscopic ovarian drilling on serum vascular endothelial growth factor and on insulin responses to the oral glucose tolerance test in women with polycystic ovary syndrome. Fertil Steril 2000;74(3): 585–8. [36] Greenblatt E, Casper R. Adhesion formation after laparoscopic ovarian cautery for polycystic ovarian syndrome: lack of correlation with pregnancy rate. Fertil Steril 1993;60:766–70. [37] Clark AM, Thornley B, Tomlinson L, et al. Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Hum Reprod 1998;13:1502–5. [38] Ayyad C, Andersen T. Long-term efficacy of dietary treatment of obesity: a systematic review of studies published between 1931 and 1999. Obes Rev 2000;1:113–9. [39] Moran L, Norman RJ. Understanding and managing disturbances in insulin metabolism and body weight in women with polycystic ovary syndrome. In: Arulkumaran S, editor. Clin Obstet Gynaecol 2004;18(5):719–736. [40] Hickey M, Higham J, Fraser IS. Progestogens versus oestrogens and progestogens for irregular uterine bleeding associated with anovulation. The cochrane database of systematic reviews, issue 1; 2000.
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[41] Barth JH, Cherry CA, Wojnarowska F, Dawber RPR. Cyproterone acetate for severe hirsutism: results of a double-blind dose-ranging study. Clin Endocrinol 1991;35:5–10. [42] Lord JM, Flight IHK, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003;327: 951–6. [43] Kriplani A, Agarwal N. Effects of metformin on clinical and biochemical parameters in polycystic ovary syndrome. J Reprod Med 2004;49(5):361–7. [44] Wild RA. Long-term health consequences of PCOS. Hum Reprod Updat 2002;8:231–41.
[45] Talbot E, Guzick D, Clerici A, Berga S, Detre K, Weimer K, et al. Coronary heart disease risk factors in women with polycystic ovary syndrome. Arterioscler Thromb Vasc Biol 1995;15:821–6. [46] Coulam CB, Annegers JF, Kranz JS. Chronic anovulaton syndrome and associated neoplasia. Obstet Gynecol 1983;61:403–7. [47] Cheung AP. Ultrasound and menstrual history in predicting endometrial hyperplasia in polycystic ovary syndrome. Obstet Gynecol 2001;98:325–31. [48] Pierpoint T, McKeigue PM, Isaacs AJ, Wild SH, Jacobs HS. Mortality of women with polycystic ovary syndrome at long-term follow-up. J Clin Epidemiol 1998;51:581–6.
Gynaecological endocrinology
Polycystic ovary syndrome: An overview Abdulmalik U. Bako *, Sharon Morad 1, William A. Atiomo 2 Department of Obstetrics and Gynaecology, School of Human Development, University of Nottingham, Queen’s Medical Centre, University Hospital, Derby Road, Nottingham NG7 2UH, UK Received 10 February 2005; accepted 18 April 2005 Available online 23 May 2005
Abstract Polycystic ovary syndrome (PCOS) is a heterogeneous condition that represents a continuous spectrum from asymptomatic women with polycystic ovaries demonstrated on ultrasound through to those with the classic features of infertility, obesity and hyperandrogenaemia. It is now generally believed to be a metabolic and endocrine condition secondary to relative insulin resistance and compensatory hyperinsulinaemia. Hyperinsulinaemia is thought to cause abnormal ovarian androgen metabolism and altered ovarian gonadotrophin response resulting in anovulation, oligoamenorrhoea and features of hyperandrogenism. Logically, therapeutic strategies aimed at correcting the insulin resistance (weight loss and insulin sensitisers) would in theory make more sense than symptom relief. The potential increased risks of cardiovascular disease and non-insulin-dependent diabetes mellitus would also be obviated. In practice, however, several gaps exist in our current knowledge of the pathophysiology of PCOS with resulting challenges in strategies that aim primarily to correct insulin resistance. This article discusses the current understanding and management of polycystic ovary syndrome. Novel future research directions are suggested. # 2005 Elsevier B.V. All rights reserved. Keywords: Polycystic ovary syndrome; Insulin resistance; Clomifene; Metformin
1. Introduction Polycystic ovary syndrome (PCOS) is a heterogeneous disorder of unknown aetiology affecting 5–10% of women of reproductive age [1]. It is a disorder that affects the reproductive, endocrine and metabolic systems, and it is the most common cause of anovulatory infertility. Its exact cause is unknown; however, there are several theories about its pathophysiology. In the last decade, the insulin resistance hypothesis has gathered several converts [2]. It is thought that relative insulin resistance results in chronic hyperinsulinaemia which gives rise to abnormal ovarian androgen metabolism, impaired follicle growth and altered gonadotrophin response [3]. This article argues that several gaps in our understanding of the links between the insulin resistance * Corresponding author. Tel.: +44 1159249924. E-mail addresses: [email protected] (A.U. Bako), [email protected] (S. Morad), [email protected] (W.A. Atiomo). 1 Tel. +44 1159249924. 2 Tel. +44 1159249924x43500/43572. 1471-7697/$ – see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.rigp.2005.04.001
hypothesis and clinical features, diagnosis, pathophysiology and treatment outcome call for research strategies which look beyond insulin resistance in a search for a better understanding of PCOS. Novel molecular biology techniques that allow the simultaneous study of several genes and proteins (mRNA micro arrays and proteomics) expressed in various target tissues of interest in a discovery-driven approach now offer this opportunity. The currently accepted definition, epidemiology and pathophysiology of PCOS are first discussed followed by the clinical features and long-term health risks. Although possible future research directions are discussed in the concluding segments of this article, the overall emphasis is on the current clinical management of PCOS.
2. Clinical diagnosis It is interesting to note that despite the wide acceptance of the insulin resistance hypothesis in PCOS, it does not feature in past and current diagnostic criteria. Traditionally, there
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were two schools of thought on the ideal diagnostic criteria for PCOS. The European school of thought held that PCOS encompassed the presence of polycystic ovaries on ultrasound and one or more of the signs and symptoms of raised concentrations of serum androgen and chronic anovulation in the absence of pituitary and adrenal disease [4]. On the other hand, the North American School of Thought diagnosed PCOS where a combination of hyperandrogenism and menstrual/ovulatory dysfunction, in the absence of non-classic adrenal hyperplasia were present. There was no need to identify the presence of polycystic ovaries by ultrasonography [2]. This disparity resulted in challenges in research and clinical management, as the findings of clinical research studies carried out in either Europe or America were not necessarily applicable to a local population, if the research originated in a continent where different diagnostic criteria were used for PCOS. More recently, in an attempt to resolve this conflict, a joint consensus meeting of the American Society for Reproductive Medicine and the European Society of Human Reproduction an Embryology (ASRM/ESHRE) refined the definition of PCOS [5]. It agreed that PCOS was primarily a condition of ovarian dysfunction and that in the absence of other aetiologies (such as prolactinoma, congenital adrenal hyperplasia or an androgen-secreting tumour) two or more of the following criteria established PCOS. These included: oligo- and/or anovulation, clinical and/or biochemical signs of hyperandrogenism and at least one polycystic ovary on ultrasound (Table 1). The morphology of polycystic ovary was redefined as the presence of an ovary with 12 or more follicles measuring 2–9 mm in diameter and/or an increased ovarian volume (>10 ml3) [5]. This ASRM/ESHRE consensus definition is currently accepted as the ideal definition of PCOS. The key advantages are its ability to standardise definitions used in research studies of the epidemiology, pathophysiology and treatment of PCOS.
3. Epidemiology The true prevalence of PCOS is not known because of the pre-existing debates about the precise diagnostic criteria. Variations in the quoted prevalence are largely due to different populations and diagnostic criteria used in the studies. This is again complicated by the absence of measures of insulin resistance in most studies on the epidemiology of PCOS. Hospital-based studies have reported the prevalence of ultrasonic appearance of polycystic ovaries to range from 45 to 92% [6–8]. However, community-based studies have reported the incidence of polycystic ovaries to be 17–22% [4,9–11]. The quoted prevalence in these studies should be taken with caution because in some of the studies full biochemical and clinical assessment were not performed and hospital data do not reflect the picture in the larger population. Wijeyaratne et al. [12] reported that the prevalence of PCOS may be higher in South Asian immigrants to the UK and Rodin et al. [13] found the prevalence of PCOS among the South Asian immigrants in Britain to be 52% with majority of them (49.1%) presenting with menstrual abnormality. The lack of an absolute correlation between insulin resistance and ultrasound evidence of PCOS supports our argument for delving beyond insulin resistance in the aetiology of PCOS.
4. Pathophysiology A variety of theories/systems have been implicated in the pathophysiology of PCOS. These include aberrations of the hypothalamo–pituitary–ovarian axis, intra-ovarian growth factors, fetal programming and more recently insulin resistance and its metabolic consequences including the metabolic syndrome X. The increased prevalence of symptoms of PCOS amongst family members of affected women also suggests a genetic link. However, how these
Table 1 Ultrasound, endocrine and biochemical investigations in PCOS Investigation
Normal rangea
Comment
Pelvic ultrasound
Assess ovarian morphology
Refer to ASRM/ESHRE definition
LH FSH
2–10 iu/l 2–8 iu/l
Measured on days 1–3 of a menstrual bleed or randomly if amenorrhoeic
Oestradiol Testosterone
0.5–3.5 nmol/l
SHBG FAI (T 100/SHBG) Prolactin Thyroid stimulating hormone Fasting insulin Oral glucose tolerance test (OGTT) a
16–119 nmol/l <5 0.5–5 iu/l <500 mu/l <30 mu/l
Range may vary depending on laboratory.
Measurement unhelpful and would not affect management Suspect congenital adrenal hyperplasia or an androgen-secreting tumour and refer if total testosterone is >5 nmol/l Insulin suppresses SHBG Value raised with normal testosterone and low SHBG Assay level if oligo- or amenorrhoeic Assay level if oligo- or amenorrhoeic Not measured in routine clinical practice Seventy-five grams of OGTT to assess insulin resistance. Refer to diabetic clinic if abnormal and arrange annual fasting blood glucose if impaired
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systems interact to result in the PCOS phenotype is still uncertain [14]. Insulin resistance is the main hypothesis that appears to be fast gathering pace as the single unifying hypothesis in PCOS. However, the fact that it is thought to be present in 30–60% of women with PCOS and not all of them raises more questions than it answers and supports our argument for novel research directions. The mechanisms of insulin resistance in PCOS are also uncertain. It has been postulated that genetic abnormalities in the regulation of insulin receptor phosphorylation result in an increased insulin-independent serine phosphorylation and decreased insulin-dependent tyrosine phosphorylation leading to decrease insulin sensitivity [1] and compensatory hyperinsulinaemia. It is thought that compensatory hyperinsulinaemia augments the stimulatory action of LH on theca cell androgen biosynthesis through upregulation of genes encoding steroidogenic enzymes [15]. It has also been postulated that hyperinsulinaemia acts on the hypothalamus and pituitary leading to increase LH concentration and on the ovarian stromal cells resulting in increase free circulating androgens and a decrease in sex hormone binding globulin (SHBG) [15]. Hyperinsulinaemia also leads to imbalance in the production of insulin-like growth factor binding protein-1 resulting in abnormal local steriodogenesis. Insulin resistance may also lead to direct stimulation of an ovarian protease inhibitor (plasminogen activator inhibitor-1 (PAI-1)) resulting in limitation of follicular growth. The absence of a direct link between the ovarian and metabolic phenotype of PCOS however calls for a look beyond insulin resistance.
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heavy and sometimes erratic bleeding as the endometrium breaks down. 5.2. Infertility Infertility is the presenting complaint in 40% of women with PCOS and it is due to anovulation. The exact mechanism underlying the association between infertility and PCOS remains unknown. It was thought that the subfertility could be due to the presence of high LH and androgen levels. It was suggested that high LH level in the follicular phase of the menstrual cycle caused a premature resumption of meiosis with the consequent release of a ‘premature oocyte’ [20]. However, it would appear that several factors interact to form part of the vicious cycle of abnormal steriodogenesis, folliculogenesis, abnormal oocyte maturation, decrease endometrial receptivity and early pregnancy loss [21]. 5.3. Androgen excess (hirsutism and acne) Androgen excess presents as hirsutism, which is terminal hair of male pattern distribution (facial hair: upper lip, chin, side burn, chest, upper and upper abdomen, upper and lower back, upper arm, thigh and buttock). Rapid onset of hirsutism and signs of virilism should be investigated to rule out adult onset congenital adrenal hyperplasia and malignancy. The degree of hirsutism can be evaluated by using the modified Ferriman and Galway score before commencing therapy and for monitoring response. 5.4. Obesity
5. Clinical presentation The principal features of PCOS include menstrual irregularities, anovulatory infertility, androgen excess (hirsutism, acne and temporal balding) and obesity [4,16]. Some patients with PCOS are asymptomatic and for some individuals signs and symptoms may change over time [17]. The heterogeneity of the features of women with PCOS which varies from a mild disorder affecting the reproductive, endocrine and metabolic systems to a severe disturbance suggests that insulin resistance is not the single unifying hypothesis. Several factors affect the expression of PCOS, for example, weight gain is associated with worsening of symptoms and signs while an improvement in the clinical features of the syndrome is seen with weight loss [18,19]. 5.1. Menstrual irregularity Menstrual irregularity (oligo- or amenorrhoea) is the most common reason for gynaecological presentation. PCOS women with amenorrhoea are not oestrogen deficient. Indeed, the endometrium of oligoamenorrhoeic women with PCOS is under continuous exposure to oestrogen until the endometrial growth outstrips its blood supply. This results in
Ten to 65% of women with PCOS are obese (BMI greater than 30 kg/m2). Central obesity with increased waist–hip ratio (WHR) (normal WHR: 0.82–0.85) is a common finding amongst obese women with PCOS [22]. It is thought that obesity exacerbates the underlying insulin resistance in patients with PCOS. However, the fact that insulin resistance may be present in non-obese women with PCOS raises further questions about the interrelationships between obesity and insulin resistance.
6. Treatment Although insulin resistance is thought to underpin PCOS, treatment is still largely directed at presenting symptoms rather than the correction of the underlying cause/pathophysiology. Apart from the treatment of anovulatory infertility where a systematic review has demonstrated a clear improvement in ovulation rates with metformin, the lack of clear evidence of the use of insulinsensitising agents in the treatment of hirsutism, obesity and acne raises questions about the validity of insulin resistance hypothesis.
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6.1. Infertility Ovulation induction strategies in general include: weight reduction, medical treatment (anti-oestrogens—mainly clomifene citrate, tamoxifen and gonadotrophin therapy) and surgical treatment. 6.1.1. Clomifene Clomifene citrate (50–100 mg) taken on days 2–6 of a natural or induced menstrual bleed can be used to induce ovulation. Overall, clomifene citrate is successful in about 80% of anovulatory women, however, pregnancy occurs in about half of them [18]. Its effectiveness is reduced in obese women with PCOS. A therapeutic daily dose over 100 mg may cause thickening of cervical mucous and has not been found to be beneficial. Administration of clomifene citrate should be monitored using ultrasound scanning to assess follicular development in order to reduce the risk of multiple pregnancies (10–16%). 6.1.2. Metformin The insulin resistance hypothesis in PCOS has provided the rationale for the use of insulin-sensitising agents (such as metformin to improve the reproductive and metabolic abnormalities in non-diabetic women with PCOS [23,24]. Metformin has been shown to improve insulin sensitivity, reduce LH, PAI-1 and testosterone levels (total and free) which are thought to impair folliculogenesis. Follicle stimulating hormone and SHBG levels are also increased [25]. In a meta-analysis of 13 randomised controlled trials (involving 310 women), Lord et al. [24] showed that metformin was effective in achieving ovulation in women with PCOS when compared with placebo, metformin and clomifene were similarly effective when compared to clomifene citrate alone. It has therefore been argued that there could be a place for the use of metformin as a first-line agent in ovulation induction in obese and non-obese women with anovulatory infertility due to PCOS [26]. However, the UK’s National Institute for Clinical Excellence (NICE) [27] recommendation is that metformin can be used as an adjunct to clomifene in women who failed to respond to clomifene alone. Before commencing metformin therapy in anovulatory women with PCOS, it is good practice to offer appropriate advice on weight loss including diet, life style and exercise. Baseline investigations (full blood count, fasting lipids, oral glucose tolerance test, renal and liver function tests) should be performed before commencing treatment because metformin can cause lactic acidosis in mild renal impairment. These investigations should also be repeated yearly whilst the patient is on metformin. Because of the theoretical risk of hypoglycaemia (due to metformin), patient should be counselled about the symptoms of hypoglycaemia and advised to stop treatment if it is suspected. Metformin is currently not licensed for use in pregnancy and it is recommended that it should be discontinued once
pregnancy is confirmed; however, there is no evidence of fetal teratogenicity. Indeed, metformin has been used in pregnant women with type 2 diabetes mellitus without increase in major fetal abnormality when compared with controls of untreated pregnant women with type 2 diabetes mellitus [28]. Where clomifene and or metformin treatment do not result in ovulation, the second-line options include either gonadotrophins therapy or surgery. 6.1.3. Gonadotrophins Medical treatment with parenteral gonadotrophins (pure FSH or human menopausal gonadotrophins) can be employed in patients resistant to anti-oestrogens. However, gonadotrophins have been shown to be associated with an increased incidence of multiple pregnancy and ovarian hyperstimulation syndrome (OHSS) because of the recruitment of multiple follicles [14,29]. Follicular development should be closely monitored with ultrasound to minimise these risks. Successful treatment with gonadotrophins has been shown in PCOS women with obesity and insulin resistance [30], however, serum IGF levels have not been shown to be a useful predictor of gonadotrophin response prior to in vitro fertilisation [31]. The central role of insulin resistance hypothesis is again contested. 6.1.4. Surgery Laparoscopic ovarian drilling using electrodiathermy is currently an alternative second-line option in the treatment of women with PCOS who have failed to respond to medical treatment [14,18,29]. It is associated with considerably lower multiple pregnancy rates compared to gonadotrophins and no case of ovarian hyperstimulation was reported in a trial by Farquhar et al. [32]. An argument could be made for its consideration before gonadotrophins; however, the associated hazards of surgery should be considered. In a cohort study of up to 20 years, Gjonnaess [33] showed that there was persistence in ovulation and normalisation of serum androgens and SHBG following laparoscopic ovarian electrocautery in over 60% of the patients treated. The suggested mechanism of action of ovarian drilling is that the destruction of the androgenproducing stroma of the ovaries with electrocautery leads to a reduction in serum androgen levels, thereby decreasing the amount of substrate available for peripheral aromatisation to oestrogens. It has been postulated that this will restore the feedback mechanism to the hypothalamus–pituitary axis, allowing appropriate gonadotrophin stimulation for follicular development and ovulation [34]. Laparoscopic ovarian drilling does not however change insulin responses to OGTT again questioning the central role of insulin resistance in PCOS [35]. Laparoscopic ovarian drilling using diathermy is potentially associated with periovarian adhesions [36] and theoretically could lead to premature ovarian failure [29] due to over destruction of ovarian stroma; however, there is no clear evidence that this is the case.
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6.2. Obesity
6.4. Hirsutism and hyperandrogenism
PCOS patients who are obese (BMI > 30 kg/m2) should be encouraged to lose weight because obesity is associated with worse endocrine and biochemical features of PCOS. Weight loss enhances insulin sensitivity and improves the endocrine profile and the chances of ovulation, and achieving viable and healthy pregnancy [18,37]. Traditionally, a low-fat and high-carbohydrate diet in conjunction with moderate regular exercise is thought to aid weight loss. The emphasis should be on reducing central adiposity and improving the WHR. In clinical practice, weight loss in women with PCOS can be challenging as postprandial thermogenesis is reduced. There is evidence that group counselling incorporated with exercise and education may facilitate long-term behavioural change of obese women with PCOS [38,39]. Patients with PCOS need encouragement to achieve a behavioural change. In general, weight management ideally requires a multidisciplinary approach involving the dietician, psychologist and the clinician. Anti-obesity drug, such as Orlistat (Xenical1), could be used on a short-term basis in order to encourage longer term general life style modification [3]. There is currently no evidence that metformin on its own leads to weight loss in obese women with PCOS independent of conventional diet and exercise, despite its effect on insulin metabolism and its side effects of nausea, vomiting and diarrhoea.
Modalities of physical treatment of hirsutism include shaving, waxing and bleaching, electrolysis, and laser and photothermolysis. Electrolysis is expensive and can be painful; it should be performed by a trained expert. Shaving can be time-consuming and all physical methods do not guarantee permanent cure, so patients should be counselled appropriately because re-growth of hair is not uncommon and indeed scarring may occur. Repeated laser and photothermolysis tend to produce a near permanent result because hair follicles in the early growing phase are destroyed during treatment [18]. The rate of hair growth and therefore progression of hirsutism can be reduced by anti-androgens, such as cyproterone-acetate, spironolactone, ketoconazole, dutasteride and finasteride. Co-cyprindiol (Dianette1, Schering Health) is often used in the first instance. Dianette (containing cyproterone acetate 2 mg and ethinyloestradiol 35 mcg) is taken cyclically and its effect on hair growth may not be evident in the first 3–6 months. The addition of a higher dose of cyproterone acetate (50–100 mg) in the first 10 days of every cycle was not found to be beneficial [39]. Liver function should be evaluated before commencing cyproterone acetate and regularly afterwards (after 6 months then annually). It is contraindicated in patients with hepatic disease, history of venous thrombo embolism and youths less than 18 years (may arrest bone maturation). Treatment should be withdrawn once hirsutism has completely resolved. It is important that an effective contraception is used because anti-androgens can cross the placenta and affect the sexual development of the male fetus. Anti-androgens are not appropriate if pregnancy is desired. Dutasteride and finasteride are specific inhibitors of five alpha reductase but contraindicated in women and adolescents. Spironolactone (a weak diuretic) may be used in women in whom Dianette1 is unsuitable. It may be taken daily in a dose of 25–100 mg. Spironolactone may cause hyponatraemia, hyperkalaemia and hepatotoxity, so liver function and serum electrolytes should be checked regularly. Finally, in the context of the insulin resistance hypothesis, hirsutism and acne should improve when insulin resistance is ameliorated. In support of this hypothesis, a Cochrane review of two trials involving 24 subjects found metformin to be significantly effective compared to placebo on reported hirsutism score [41]. On the other hand, some studies have failed to find an improvement in hirsutism with 6 months metformin use [42]. Larger definitive studies are however awaited.
6.3. Menstrual abnormality The risk of prolonged oestrogen stimulation of the endometrium in PCOS, which may lead to erratic heavy bleeding, and the risk of developing endometrial hyperplasia and carcinoma is the rational for inducing regular withdrawal bleeds in these women [40]. The low-dose combined oral contraceptive pills (COCP) can be administered to induce regular menstrual cycles. There is, however, no clear evidence of the effectiveness of COCP on the primary prevention of endometrial carcinoma in amenorrhoeic women with PCOS. Similarly, the effectiveness of contraceptive pills taken back to back every 3 months is unknown. The COCP is relatively contraindicated in obesity and there is theoretical concern over the effect of COCP on insulin resistance [3]. Regular endometrial withdrawal bleeding can also be induced by the administration of medroxyprogesterone acetate or dydrogesterone taken cyclically for 12 days every 1–3 months. Persistently thick endometrium on transvaginal ultrasound should be investigated by endometrial biopsy and/or hysteroscopy [23] and there may be a role for annual screening with transvaginal ultrasound scans in women with PCOS over the age of 40 years. The association between the resumption of ovulation and regular menstruation and metformin treatment suggests that there may also be a role for metformin use in primary prevention of endometrial hyperplasia/cancer. Definitive studies are however required.
7. Long-term health implications of PCOS There appears to be clear evidence that hyperinsulinaemia in PCOS is associated with late development of impaired glucose tolerance and type 2 diabetes [43]. The
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risk of developing type 2 diabetes is increased in obese and non-obese women with PCOS. It is therefore good practice for healthcare professionals responsible for the care of women with PCOS to screen them for diabetes annually. Although, it is recognised that hyperinsulinaemia, hyperandrogenism and obesity (features of PCOS) are cardiovascular risk factors. There is evidence that mortality amongst women with PCOS from cardiovascular disease is not significantly higher, although the long-term risk of developing atherosclerotic disease, hypertension and myocardial infarction is greater [44,45]. Women with PCOS should be offered annual fasting cholesterol, lipids and triglycerides [23]. Prolonged exposure to premenopausal level of oestrogen can lead to endometrial hyperplasia and carcinoma [46,47] although the risk has not been clearly defined. There may also be an association between unopposed oestrogen stimulation in PCOS and breast cancer, however there is no evidence to support this hypothesis [46]. In the only study so far on mortality in women with PCOS, Pierpoint et al. [48] found no significant increase in breast cancer deaths among women with documented PCOS.
8. Areas for future research There is a clear need for further studies to explore the aetiology of PCOS since insulin resistance is not present in all cases of PCOS. Given the complexity of PCOS, a discovery-based approach that aims to identify all the possible genes and proteins expressed differently in women with PCOS should now make it possible to advance our understanding of PCOS. The use of novel techniques, such as mRNA micro arrays and proteomics, would facilitate discovery-based research in PCOS. In theory computational analysis of the large datasets created and data exploration with artificial neural networks should provide simple algorithms, which would shed more insight into the complexity of PCOS. There are needs for other types of researches. Some of these should include clinical trials to assess the true efficacy of insulin-sensitising medication with live birth rate as a primary outcome, the role of metformin in menstrual regulation and primary prevention of non-insulin-dependent diabetes in teenagers and studies comparing laparoscopic ovarian drilling with metformin and laparoscopic ovarian drilling in women who have failed to ovulate with clomifene.
9. Conclusion This article reviewed the current definition, epidemiology, pathophysiology, clinical management and longer term health risks of PCOS. Although it is proposed that insulin resistance appears to be the key metabolic defect in the aetiology of PCOS, it does not fully explain the aetiology of the complex
syndrome. Current treatment strategies which have evolved from symptom control to treating the underlying pathology of insulin resistance with insulin-sensitising agents, such as metformin, general lifestyle modification (exercise and improved diet) are however welcome. Future research that delves beyond insulin resistance is required. Novel molecular biology techniques that encourage a discovery-based approach were suggested in this article. These include the combination of mRNA micro arrays, proteomics and computational analysis to obtain further insight into PCOS from the analysis of the complex data sets generated. New leads may then be generated which should lead to focussed hypothesis-driven research of new pathways or systems which provide a clearer picture of PCOS than is currently the case with the insulin resistance hypothesis.
Practice points: New international consensus criteria for the diagnosis of PCOS Assessment of obesity: BMI, WHR Individualisation of investigation, management and follow-up Biochemistry and endocrinology: early follicular phase LH, FSH, free testosterone, free androgen index (FAI), SHBG, prolactin Ovulation induction can be effectively induced by metformin in both obese and non-obese patients with PCOS Weight loss programme Metformin should not be used as a weight reduction agent, but should be used in conjunction with general life style modification, such as increased exercise and improved diet Screening for diabetes and long-term risks of endometrial cancer should be considered Follow-up: regular review of BMI, blood pressure, fasting blood sugar and cholesterol, endometrial assessment (TVS) in oligoamenorrhoiec women above 40 years Research agenda: Understanding the pathophysiology of PCOS using discovery-based approaches, such as the application of genomics, proteomics and bioinformatics Effect of metformin on pregnancy and live birth rates Evidence for the safety of long-term use of metformin Evidence for the medical treatment of menstrual abnormality in PCOS
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