The Polycystic Ovary Syndrome: Guidance for Healthcare Professionals
The Polycystic Ovary Syndrome (PCOS) – Information for patients
The Polycystic Ovary Syndrome: Guidance for Healthcare Professionals
The polycystic ovary syndrome (PCOS) is the commonest endocrine disturbance affecting women. The polycystic ovary syndrome (PCOS) is a heterogeneous condition whose pathophysiology appears to be multifactorial and polygenic. The definition of the syndrome has been much debated. Key features include menstrual cycle disturbance, hyperandrogenism and obesity. There are many extra-ovarian aspects to the pathophysiology of PCOS yet ovarian dysfunction is central.1 At a recent consensus meeting a refined definition of the PCOS was agreed: namely the presence of two out of the following three criteria: 1) Oligo- and/or anovulation; 2) Hyperandrogenism (clinical and/or biochemical); 3) Polycystic ovaries, with the exclusion of other aetiologies (The Rotterdam ESHRE/ASRM PCOS consensus workshop group, 2004).2 The morphology of the polycystic ovary, has been redefined as an ovary with 12 or more follicles measuring 2-9 mm in diameter and/or increased ovarian volume (>10 cm3).3
It has long been recognised that the presence of enlarged ovaries with multiple small cysts (2-8 mm) and a hypervascularized, androgen-secreting stroma are associated with signs of androgen excess (hirsutism, alopecia, acne), obesity and menstrual cycle disturbance (oligomenorrhoea or amenorrhoea). There is considerable heterogeneity of symptoms and signs amongst women with PCOS4 and for an individual these may change over time. The PCOS is familial5 and various aspects of the syndrome may be differentially inherited. Polycystic ovaries can exist without clinical signs of the syndrome, which may then become expressed over time - especially for example with a gain in weight.
There are a number of interlinking factors that affect expression of PCOS. A gain in weight is associated with a worsening of symptoms whilst weight loss will ameliorate the endocrine and metabolic profile and symptomatology.6 Normal ovarian function relies upon the selection of a follicle, which responds to an appropriate signal (follicle stimulating hormone) in order to grow, become 'dominant' and ovulate. This mechanism is disturbed in women with PCOS, resulting in multiple small cysts, most of which contain potentially viable oocytes but within dysfunctional follicles.
Elevated serum concentrations of insulin are more common in both lean and obese women with PCOS than weight-matched controls. Indeed it is hyperinsulinaemia that appears to be the key to the pathogenesis of the syndrome7 as insulin stimulates androgen secretion by the ovarian stroma and appears to affect the normal development of ovarian follicles, both by the adverse effects of androgens on follicular growth and possibly also by suppressing apoptosis and permitting the survival of follicles otherwise destined to disappear. The prevalence of diabetes in obese women with PCOS is at least 11% and so a measurement of impaired glucose tolerance is important and long term screening advisable.
Insulin resistance is defined as a diminution in the biological responses to a given level of insulin. In the presence of an adequate pancreatic reserve, normal circulating glucose levels are maintained at higher serum insulin concentrations. There have been a large number of studies demonstrating the presence of insulin resistance and corresponding hyperinsulinaemia in both obese and non-obese women with PCOS. Obese women with PCOS have consistently been shown to be insulin resistant to a greater degree than their weight-matched controls. It appears that obesity and PCOS appear to have a synergistic effect on the degree and severity of the insulin resistance and subsequent hyperinsulinaemia in this group of women. Insulin resistance correlates both with inter-menstrual interval and with hyperandrogenaemia - in other words the greater the degree of menstrual disturbance or androgen excess the greater the metabolic disturbance .
Exercise and weight-loss have so far been the most physiological way to improve insulin sensitivity, and improve the metabolic abnormalities associated with the syndrome. In women with PCOS it has been demonstrated that even relatively modest weight loss improves the hormonal profile and improvement in the reproductive outcome for all forms of fertility treatment. Since the association between insulin resistance and BMI is stronger in obese women with PCOS, than in weight-matched controls, the benefits of weight loss should be even greater in these women than in women without PCOS.
• Hyperandrogenism (hirsutism, acne, alopecia)
• Menstrual disturbance
• Asymptomatic, with polycystic ovaries on ultrasound scan
Possible late sequelae
• Type 2, Diabetes mellitus
• Cardiovascular disease
• Endometrial carcinoma
Raised androgens (testosterone and androstenedione)
Raised luteinising hormone (LH) in 40%, normal follicle stimulating hormone (FSH)
RaisedFasting insulin (not routinely measured; insulin resistance assessed by GTT)
Supressed sex hormone binding globulin (SHBG), results in elevated “free androgen index”
Normal or elevated oestradiol, oestrone
Normal or elevated Prolactin
Normal or elevated Anti-Mullerian hormone (AMH)
(may vary with local laboratory assays)
|Pelvic ultrasound||To assess ovarian morphology and endometrial thickness||Transabdominal scan satisfactory in women who are not sexually active.|
|Testosterone (T)||0.5 – 3.5 nmol/l||It is unnecessary to measure other androgens unless total testosterone is > 5 nmol/l, in which case referral is indicated.|
|Sex hormone binding globulin (SHBG)||16 – 119 nmol/l|
|Free androgen index:
T x 100 / SHBG
|< 5||Insulin suppresses SHBG, resulting in a high FAI in the presence of a normal total T|
|Oestradiol||measurement is unhelpful to diagnosis||Oestrogenisation may be confirmed by endometrial assessment.|
|Luteinising hormone (LH)||2 – 10 IU/L||FSH and LH best measured during days 1-3 of a menstrual bleed. If oligo-/ amenorrhoeic then random samples are taken.|
|Follicle stimulating hormone (FSH)||2 – 8 IU/L|
thyroid function, TSH
|< 500 mU/L
0.5 – 5 IU/L
|Measure if oligo-/ amenorrhoeic|
|Fasting insulin (not routinely measured; insulin resistance assessed by GTT)||< 30 mU/L||Additional points|
Women who are obese, and also many slim women with PCOS, will have insulin resistance and elevated serum concentrations of insulin (usually < 30 mU/L fasting). We suggest that a 75 gram oral glucose tolerance test (GTT) be performed in women with PCOS and a BMI > 30 kg/m2, with an assessment of the fasting and two hour glucose concentration. It has been suggested that South Asian women should have an assessment of glucose tolerance if their BMI is greater than 25 kg/m2 because of the greater risk of insulin resistance at a lower BMI than seen in the Caucasian population.
Definitions of glucose tolerance after a 75 g glucose tolerance test (GTT)
|Diabetes Mellitus||Impaired Glucose Tolerance (IGT)||Impaired Fasting Glycaemia|
|Fasting glucose (mmol/l)||> 7.0||< 7.0||> 6.1 and < 7.0|
|2 hour glucose (mmol/l)||> 11.1||> 7.8, < 11.1||< 7.8|
|Action||Refer Diabetic Clinic||Dietary advice. Check fasting glucose annually||Dietary advice. Check fasting glucose annually|
The clinical management of a women with PCOS should be focused on her individual problems. However, the symptoms typically associated with the condition have also been shown to lead to a significant reduction in health-related quality of life (HRQoL)8. HRQoL is a multi-dimensional, dynamic concept that encompasses physical, psychological, and social aspects that are associated with a particular disease or its treatment 9,10. Therefore any management of the woman with PCOS needs to consider and understand the negative impact this condition may have upon these psycho-social parameters. For example, although the management of hirsutism may be considered as a purely cosmetic issue, excessive facial hair has been shown to be one of the major causes of marked psychological stress in women with PCOS11, often caused by the embarrassment about the excessive hair growth. Infertility and weight issues have also been found to affect other social and psychological parameters. Infertility can cause tensions within the family, altered self-perception, and problems at work12,13.
Whilst obesity worsens the symptoms, the metabolic scenario conspires against weight loss and many women experience frustration in attempts to lose weight and suffer from low-esteem and poor body image. Diet and physical activity are key to symptom control. Initial reports of the use of insulin-sensitising agents (eg, metformin)7,14 were encouraging and suggested an improvement in biochemistry and symptoms, although large RCTs have recently suggested no real improvement with metformin. Ovulation induction has traditionally involved the use of clomiphene citrate and then gonadotrophin therapy or laparoscopic ovarian surgery in those who are clomiphene resistant. Patients with PCOS are not oestrogen deficient and those with amenorrhoea are at risk not of osteoporosis but rather of endometrial hyperplasia or adenocarcinoma (due to the unopposed actions of oestrogen in the absence of progesterone released after ovulation). Cycle control and regular withdrawal bleeding is achieved with the oral contraceptive pill, which has the additional beneficial effect of suppressing serum testosterone concentrations and hence improving hirsutism and acne. Dianette and Yasmin, containing the anti-androgens cyproterone acetate and drosperinone respectively, are usually recommended15. However, if contraception is not required, trial of cycle control with metformin may be preferable, particularly in obese women with metabolic problems14.
Obesity worsens both symptomatology and the endocrine profile and so obese women (BMI>30kg/m2) should therefore be encouraged to lose weight. Weight loss improves the endocrine profile, the likelihood of ovulation and a healthy pregnancy. Much has been written about diet and PCOS. The right diet for an individual is one that is practical, sustainable and compatible with her lifestyle. It is sensible to reduce glycaemic load by lowering sugar content in favour of more complex carbohydrates and to avoid fatty foods. Meal replacement therapy or low calorie diets may be appropriate: it is often helpful to refer to a dietitian, if available. An increase in physical activity is essential, preferably as part of the daily routine. 30 minutes per day of brisk exercise is encouraged to maintain health, but to lose weight, or sustain weight loss, 60 to 90 minutes per day is advised. Concurrent behavioural therapy improves the chances of success of any method of weight loss.
Anti-obesity drugs may help with weight loss and both orlistat16 and sibutramine17 have been shown in small studies to be effective in PCOS. Orlistat is a pancreatic lipase inhibitor which prevents absorption of around 30% of dietary fat, whereas sibutramine is a centrally acting serotonin and noradrenaline reuptake inhibitor, which enhances satiety. Both agents can also improve insulin sensitivity and are currently licensed for individuals with a BMI of >30 kg/m2 or lower if comorbidities such as Type 2 diabetes are present. Both agents have been shown to improve insulin resistance, lipid profile and glycaemic control and orlistat has been shown to reduce blood pressure and testosterone. Orlistat and sibutramine are increasingly being used in Primary Care as an adjunct to diet and lifestyle advice; both require monitoring for efficacy and sibutramine for possible increases in blood pressure. New agents in development for obesity, such as rimonobant, may also have a role to play in PCOS. Metformin can also improve insulin resistance and may aid some women with weight loss, although this has not been confirmed by randomised trials. The combination of Metformin and an anti obesity agent may be an ideal combination and clinical trials to formally evaluate this approach are required. Metformin therapy is discussed in greater detail below.
The easiest way to control the menstrual cycle is the use of a low dose combined oral contraceptive preparation. This will result in an artificial cycle and regular shedding of the endometrium. An alternative is a progestogen (such as medroxyprogesterone acetate [Provera] or dydrogesterone [Duphaston]) for 12 days every 1-3 months to induce a withdrawal bleed. It is also important once again to encourage weight loss. As women with PCOS are thought to be at increased risk of cardiovascular disease a “lipid friendly” combined contraceptive pill should be used. Metformin is an alternative agent which could be tried if contraception is not required, although again there is little evidence for its benefit from randomised trials. An alternative means of providing endometrial protection is the use of a progestogen secreting Mirena intrauterine sustem (IUS).
In women with anovulatory cycles the action of oestradiol on the endometrium is unopposed because of the lack of cyclical progesterone secretion. This may result in episodes of irregular uterine bleeding, and in the long term endometrial hyperplasia and even endometrial cancer. An ultrasound assessment of endometrial thickness provides a bioassay for oestradiol production by the ovaries and conversion of androgens in the peripheral fat. If the endometrium is thicker than 15mm a withdrawal bleed should be induced and if the endometrium fails to shed then endometrial sampling is required to exclude endometrial hyperplasia or malignancy. The only young women to get endometrial carcinoma (<35 years), which otherwise has a mean age of occurrence of 61 years in the U.K., are those with anovulation secondary to PCOS or oestrogen-secreting tumours.
Ovulation can be induced with the anti-oestrogens, clomiphene citrate (50-100 mg) or tamoxifen (20-40mg), days 2-6 of a natural or artificially induced bleed. Whilst clomiphene is successful in inducing ovulation in over 80% of women, pregnancy only occurs in about 40%. Clomiphene citrate should only be prescribed in a setting where ultrasound monitoring is available (and performed) in order to minimise the 10% risk of multiple pregnancy and to ensure that ovulation is taking place18. A daily dose of more than 100 mg rarely confers any benefit. Once an ovulatory dose has been reached, the cumulative conception rate continues to increase for up to ten to twelve cycles19. Clomiphene is only licensed for six months use in the U.K.,20 and so we would advise careful counselling of patients if clomiphene citrate therapy is continued beyond six months.
The therapeutic options for patients with anovulatory infertility who are resistant to anti-oestrogens are either parenteral gonadotrophin therapy or laparoscopic ovarian diathermy. Because the polycystic ovary is very sensitive to stimulation by exogenous hormones, it is very important to start with very low doses of gonadotrophins and follicular development must be carefully monitored by ultrasound scans. The advent of transvaginal ultrasonography has enabled the multiple pregnancy rate to be reduced to approximately 7% because of its higher resolution and clearer view of the developing follicles. Cumulative conception and livebirth rates after 6 months may be 62% and 54%, respectively, and after 12 months 73% and 62%, respectively21. Close monitoring should enable treatment to be suspended if three or more mature follicles develop, as the risk of multiple pregnancy obviously increases.
Women with the polycystic ovary syndrome are also at increased risk of developing the ovarian hyperstimulation syndrome (OHSS). This occurs if too many follicles (>10mm) are stimulated and results in abdominal distension, discomfort, nausea, vomiting and sometimes difficulty breathing. The mechanism for OHSS is thought to be secondary to activation of the ovarian renin-angiotensin pathway and excessive secretion of vascular epidermal growth factor (VEGF). The ascites, pleural and pericardial effusions exacerbate this serious condition and the resultant haemoconcentration can lead to thromboembolism. The situation worsens if a pregnancy has resulted from the treatment as hCG from the placenta further stimulates the ovaries. Hospitalisation is sometimes necessary in order for intravenous fluids and heparin to be given to prevent dehydration and thromboembolism. Although the OHSS is rare it is potentially fatal and should be avoidable with appropriate monitoring of gonadotrophin therapy.
Ovarian diathermy is free of the risks of multiple pregnancy and ovarian hyperstimulation and does not require intensive ultrasound monitoring. Laparoscopic ovarian diathermy has taken the place of wedge resection of the ovaries (which resulted in extensive peri-ovarian and tubal adhesions), and it appears to be as effective as routine gonadotrophin therapy in the treatment of clomiphene-insensitive PCOS, although time to pregnancy is a little slower22.
The bioavailability of testosterone is affected by the serum concentration of sex hormone-binding globulin (SHBG). High levels of insulin lower the production of SHBG and so increase the free fraction of androgen. Elevated serum androgen concentrations stimulate peripheral androgen receptors, resulting in an increase in 5-alpha reductase activity directly increasing the conversion of testosterone to the more potent metabolite, dihydrotestosterone. Symptoms of hyperandrogenism include hirsutism and acne, which are both distressing conditions. Hirsutism is characterised by terminal hair growth in a male pattern of distribution, including chin, upper lip, chest, upper and lower back, upper and lower abdomen, upper arm, thigh and buttocks. A standardised scoring system, such as the modified Ferriman and Gallwey score should be used to evaluate the degree of hirsutism before and during treatments.
Treatment options include cosmetic and medical therapies. As drug therapies may take six to nine months or longer before any improvement of hirsutism is perceived physical treatments including electrolysis, waxing and bleaching may be helpful whilst waiting for medical treatments to work. For many years the most ‘permanent’ physical treatment for unwanted hair has been electrolysis. It is time-consuming, painful and expensive and should be performed by an expert practitioner. Regrowth is not uncommon and there is no really permanent cosmetic treatment but the last few years have seen much development in the use of laser and photothermolysis techniques. There are many different types of laser in production and each requires evaluation of dose intensity, effectiveness and safety. The technique is promising, being faster and more effective than shaving, waxing or chemical depilation. Repeated treatments are required for a near permanent effect because only hair follicles in the growing phase are obliterated at each treatment. Hair growth occurs in three cycles so six to nine months of regular treatments are typical. Patients should be appropriately selected (dark hair on fair skin is best), and warned that complete hair removal cannot be guaranteed and some scarring may occur. At present it is not widely available and is still an expensive option.
Vaniqa (eflornithine) has been recently developed as a topical treatment for hirsutism. It works by inhibiting the enzyme ornithine decarboxylase in hair follicles and may be a useful therapy for those who wish to avoid hormonal treatments but may also be used in conjunction with hormonal therapy. Vaniqa may cause some thinning of the skin and so high factor sun block is recommended when exposed to the sun.
Medical regimens should stop further progression of hirsutism and decrease the rate of hair growth. Therapy for acne should aim to lower sebum excretion, alter follicular cell desquamation, reduce propionibacteria and reduce inflammation.
If using anti-androgen therapy, adequate contraception is important in women of reproductive age as transplacental passage of anti-androgens may disturb the genital development of a male fetus.
The best pharmacological treatment of proven effectiveness is a combination of the synthetic progestogen cyproterone acetate, which is anti-gonadotrophic and anti-androgenic, with ethinyl oestradiol. Dianette contains ethinyloestradiol (35mcg) in combination with cyproterone (2 mg).23 Dianette is licenced for moderate to severe hirsutism and severe acne. The antiandrogen effect reduces sebum excretion in 2-3 months and results in clinical improvement in acne in 4-6 months.
Oestrogens lower circulating androgens by a combination of a slight inhibition of gonadotrophin secretion and by an increase in hepatic production of sex hormone binding globulin (SHBG) resulting in lower free testosterone. Cyproterone acetate can rarely cause liver damage and liver function should be checked regularly (after 6 months and then annually). There was thought to be an increased risk of thrombo-embolism and so once symptom control has been achieved and sustained over 3-4 months, it has been recommended to switch to a lower dose COCP. The data overall, however, is reassuring and if a patient prefers to remain on Dianette she may do so long term with appropriate monitoring.
Spironolactone is a weak diuretic with anti-androgenic properties and may be used in women with either hirsutism and/or acne in whom the COCP is contra-indicated at a daily dose of 25 – 100 mg24. Drosperinone is a derivative of spironolactone and contained in the new COCP, Yasmin, which also appears affective for women with PCOS. Other anti-androgens such as ketoconazole, finasteride and flutamide have been tried, but are not widely used in the U.K. for the treatment of hirsutism in women due to their adverse side effects. Furthermore they are no more effective than cyproterone acetate.
Topical anti-acne agents can be safely and successfully combined with systemic anti-androgen therapy in an attempt to target as many aetiological factors as possible. However, these topical treatments alone have little effect on sebum production so are not generally successful when utilised alone in acne associated with PCOS. Topical retinoids impact on the microcomedo which is the precursor to non-inflammatory and inflammatory acne lesions. They also have direct comedolytic and anti-inflammatory activity. These agents are useful adjuvant therapies in combination with anti-androgen treatments and can be used as maintenance treatment after discontinuation of systemic therapy. Topical antimicrobials (Benzoyl peroxide / antibiotics) have good anti-inflammatory activity and should help to reduce inflammatory lesions when used alongside anti-androgen treatment.
Oral isotretinoin, a hospital only prescribed medication, is the single systemic therapy that targets the four main aetiological factors implicated in acne. However, it is currently only licensed for severe acne not responding to alternative therapies. A recent European Directive concerning isotretinoin has enforced a strict Pregnancy Prevention Programme due to the high risk of teratogenecity with this drug. COCPs can be used safely alongside oral isotretinoin and are recommended by the European Directive. Although clinical clearance of acne lesions with oral isotretinoin is very likely, relapse rates post therapy are higher than average when acne is associated with PCOS.
A number of pharmacological agents have been used to amplify the physiological effect of weight loss, notably metformin. This biguanide inhibits the production of hepatic glucose and enhances the sensitivity of peripheral tissue to insulin, thereby decreasing insulin secretion. It has been shown that metformin may ameliorate hyperandrogenism in women with PCOS and can restore menstrual cyclicity in some cases. Not all authors agree with these findings particularly if there is no concurrent weight loss14. The insulin-sensitizing agent troglitazone also improves the metabolic and reproductive abnormalities in PCOS although this product was withdrawn because of hepatotoxicity and whilst newer insulin sensitising agents, such as rosigliazone and pioglitazone are also helpful they should probably not yet be used in the context of infertility.
There has been much publicity about the use of metformin. Metformin does not appear induce weight loss, although coincident weight loss will of course provide additional benefit. Indeed in Leeds we have performed the largest RCT to look at metformin versus placebo and found no benefit from metformin over 6 months with regard to either menstrual control or other symptoms.27 Those who improved were women who lost weight whether on metformin or placebo. Two large RCTs have also demonstrated no benefit from metformin when combined with clomiphene citrate.28,29 Therefore metformin does not appear to hold the promise that was initially presumed and we recommend its use only in those with impaired glucose tolerance of type 2 diabetes.
In summary, the PCOS is a heterogeneous, familial condition.
• Ovarian dysfunction leads to the main signs and symptoms
• The ovary is influenced by external factors in particular the gonadotrophins, insulin and other growth factors, which are dependent upon both genetic and environmental influences.
• There are long term risks of developing diabetes and possibly cardiovascular disease.
• Therapy to date has been symptomatic but by our improved understanding of the pathogenesis treatment options are becoming available that strike more at the heart of the syndrome.
• PCOS is the commonest endocrine disorder in women (prevalence 15-20%).
• PCOS is a heterogeneous condition. Diagnosis is made by the ultrasound detection of polycystic ovaries or one or more of a combination of symptoms and signs (hyperandrogenism [acne, hirsutism, alopecia], obesity, menstrual cycle disturbance [oligo/ amenorrhoea]) and biochemical abnormalities (hypersecretion of testosterone, luteinizing hormone and insulin).
• Management is symptom orientated.
• If obese, weight loss should be encouraged to improve symptoms, reproductive function and long term health. A glucose tolerance test should be performed if the BMI is > 30 kg/m2 (or > 25 kg/m2 if from South Asia).
• Menstrual cycle control is achieved by cyclical oral contraceptives, progestogens or a Mirena intrauterine system can be used to protect the endometrium.
• Ovulation induction may be difficult and require progression through various treatments which should be monitored carefully to prevent multiple pregnancy.
• Hyperandrogenism is usually managed with the COCPs Dianette or Yasmin. Alternatives include spironolactone. Flutamide and finasteride are not routinely prescribed because of potential adverse effects. Reliable contraception is required with anti-androgen therapy.
• Insulin sensitizing agents (e.g. metformin) appear to be of limited, if any, benefit.
Indications for referral to specialist clinic
• Serum testosterone > 5 nmol/l (to exclude other causes of androgen excess, e.g. tumours, late onset congenital adrenal hyperplasia, Cushings syndrome)
• Rapid onset hirsutism (to exclude androgen secreting tumours)
• Glucose intolerance / diabetes
• Amenorrhoea of more than 6 months – for pelvic ultrasound scan to exclude endometrial hyperplasia
• Refractory symptoms
1. Balen AH. The pathogenesis of polycystic ovary syndrome: the enigma unravels. Lancet 1999; 354: 966-7.
2. The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Authors: Fauser B, Tarlatzis B, Chang J, Azziz R, Legro R, Dewailly D, Franks S, Balen AH, Bouchard P, Dahlgren E, Devoto, Diamanti E, Dunaif A, Filicori M, Homburg R, Ibanez L, Laven J, Magoffin D, Nestler J, Norman R, Pasquali R, Pugeat M, Strauss J, Tan SL, Taylor A, Wild R, Wild S. Human Reproduction 2004; 19: 41-47.
3. Balen AH, Laven JSE, Tan SL, Dewailly D. Ultrasound Assessment of the Polycystic Ovary: International Consensus Definitions. Human Reproduction Update 2003; 9: 505-514.
4. Balen AH, Conway GS, Kaltsas G, Techatraisak K, Manning PJ, West C, Jacobs HS. Polycystic ovary syndrome: The spectrum of the disorder in 1741 patients. Human Reprod 1995; 10:2705-2712
5. Franks S, Gharani N, Waterworth D, Batty S, White D, Williamson R, McCarthy M. The genetic basis of polycystic ovary syndrome. Hum Reprod 1997; 12: 2641-2648.
6. Clark AM, Ledger W, Galletly C, Tomlinson L, Blaney F, Wang X, and Norman RJ: Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Human Reprod 1995; 10: 2705-2712
7. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanisms and implication for pathogenesis. Endocrine Review 1997; 18: 774-800.
8. Jones GL, Benes K, Clark TL, Denham R, Holder MG, Haynes TJ, Mulgrew NC, Shepherd KE, Wilkinson VH, Singh M, Balen A, Lashen H, Ledger WL (2004) The Polycystic Ovary Syndrome Health-Related Quality of Life Questionnaire (PCOSQ): a Validation. Human Reproduction. 19: 317- 377
9. Colwell H, Mathias SD, Pasta DJ, Henning JM, Steege JF (1998) A health-related quality of life instrument for symptomatic patients with endometriosis: a validation study. Am. J. Obstet. Gynecol. 179, 47-55
10. Naughton MJ, McBee WI (1997) Health –related quality of life after hysterectomy. Clin. Obstet.Gynecol. 40, 947-57
11. Sonino N, Fava GA, Mani L, Belluardo P, Boscaro M (1993) Quality of life of hirsute women. Postgrad. Med. J. 69, 186-9
12. Paulson JD, Haarman BS, Salerno RL, Asmar P (1988) An investigation of the relationship between emotional maladjustment and infertility. Fertil. Steril. 49, 258-62
13. Downey J, Yingling S, McKinney M, Husami M, Jewelewicz R, Maidman J (1989) Mood disorders, psychiatric symptoms and distress in women presenting for infertility evaluation. Fertil. Steril. 52, 425-32
14. Lord JM, Flight IHK, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. British Medical Journal 2003; 327: 951-5.
15. Cussons AJ, Stuckley BG, Walsh JP, Burke V, Norman RJ (2005) Polycystic ovarian syndrome: marked differences between endocrinologists and gynaecologists in diagnosis and management. Clin. Endocrinol (Oxf). Mar; 62(3)289-95
16. Jayagopal V, Kilpatrick ES, Holding S, Jennings PE and Atkin SL. Orlistat is as Beneficial as Metformin in the Treatemnt of Polycystic Ovarian Syndrome. Journal of Clinical Endocrinology and Metabolism Vol. 90, No.2, 729-733
17. Sabuncu T, Harma M, Harma M, Nazligul Y, Kilic F. Sibutramine has a positive effect on clinical and metabolic parameters in obese patients with Polycystic Ovary Syndrome. Fertil Steril. 2003 Nov;80(5):1199-204
18. Guidelines on the initial investigation and management of infertility. RCOG Press, London 1998 and NICE Guidelines 2004.
19. Kousta E, White DM, Franks S: Modern use of clomiphene citrate in induction of ovulation. Human Reprod Update 1997; 3: 359-365.
20. Balen AH & Jacobs. Infertility in Practice, Third Edition, Informa Press, 2008.
21. Balen AH, Braat DDM, West C, Patel A, Jacobs HS: Cumulative conception and live birth rates after the treatment of anovulatory infertility. An analysis of of the safety and efficacy of ovulation induction in 200 patients. Human Reproduction, 1994 9: 1563-1570.
22. Bayram N, van Wely M, Kaaijk EM, Bossuyt PMM, van der Veen F. Using an electrocautery strategy or recombinant FSH to induce ovulation in polycystic ovary syndrome: randomised controlled trial. BMJ 2004; 328: 192-195.
23. 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.
24. Thiboutot D, Chen WC. Update and future of hormonal therapy in acne. Dermatology 2003 206:57-67.
25. Jannsen OE, Mehlmauer N, Hahn S, Offner AH, Gartner B. High prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome. Eur J Endocrinol. 2004 Mar; 150(3): 363-9
26. Ghosh S, Kabir SN, Pakrashi A, Chatterjee S, Chakravarty B. Suclinical hypothyroidism: a determinant of polycystic ovary syndrome. Horm Res 1993; 39:61-6
27. Tang T, Glanville J, Barthh J, Hayden c, Balen AH. Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomised, placebo-controlled, double-blind multicentre study. Hum Reprod 2006; 21: 80–89
28. Moll E et al. 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
29. Legro RS et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007; 356: 551–566
Clinical Management of Polycystic Ovary Syndrome. Balen AH – Editor-in-chief, with co-editors: G. Conway, R. Homburg, R. Legro. Taylor & Francis, London & New York, 2005.
Current Management of Polycystic Ovary Syndrome. Edited by Adam Balen, Steve Franks, Roy Homburg and Sean Kehoe. Proceedings of 59th RCOG Study Group, RCOG Press, London 2010.
Last Updated December 2010
The polycystic ovary syndrome (PCOS) is the commonest hormonal disturbance to affect women. The main problems that women with PCOS experience are menstrual cycle disturbances (irregular or absent periods), difficulty in controlling body weight and skin problems (acne and unwanted hair growth on the face or body). Not all women with PCOS experience all of the symptoms and furthermore a woman’s problems may change over time. In particular if an individual becomes overweight then her problems are likely to worsen.
About 30% of women have polycystic ovaries, although a smaller proportion will have symptoms of the polycystic ovary syndrome – perhaps 15-20% of women. The problem therefore is extremely common, although many women have relatively mild symptoms.
What are polycystic ovaries ?
Women have two ovaries which are situated in the pelvis alongside the uterus (womb). The ovaries have two main functions: the release of eggs and the production of hormones. The ovaries contain thousands of eggs which are present from birth. Each egg is surrounded by a group of cells which develop into a small fluid filled blister/cyst, or follicle. If a woman is having regular periods and is ovulating one of these follicles grows to about 20mm diameter and then releases its egg, which then passes into one of the fallopian tubes. It is in the fallopian tube that fertilisation occurs and the fertilised egg (embryo) then travels into the uterus where it implants into the lining of the uterus (endometrium) and grows as a pregnancy. If fertilisation does not occur, the endometrium comes away as a menstrual period about 14 days after ovulation.
The second main function of the ovary is the production of hormones. Hormones are substances that are released into the blood stream and circulate around the body influencing other organs. The hormones from the ovary influence many parts of the body, in particular the uterus and breasts. There are many hormones that are released from the ovary and they fall into three main groups: oestrogens, androgens and progestogens. Women make all of these hormones, but sometimes in different proportions. Testosterone is the main androgen hormone, made by the ovaries of all women. Oestrogen is made out of testosterone and helps the lining of the womb (endometrium) to grow.
Polycystic ovaries contain many small follicles which each contain an egg and have started to grow but do not reach a mature size and instead remain at a size of about 2-9 mm in diameter. A polycystic ovary usually contains at least twelve of these small follicles or cysts. The ovaries are also slightly enlarged and their central hormone producing tissue (stroma) is also thickened. The diagnosis is best made by an ultrasound scan which visualises the ovaries and the small cysts within them. Sometimes blood tests show characteristic changes in hormone levels, although these changes are not universal and can vary considerably between different women.
The ultrasound picture is not always clear and some women with the polycystic ovary syndrome may have an ultrasound scan that does not demonstrate polycystic ovaries. The syndrome is defined by the presence of at least two out of the following three:
1) Signs or symptoms of high androgens (unwanted facial or bodily hair, loss of hair from the head, acne or an elevated blood level of testosterone) – after other causes for this have been excluded,
2) Irregular or absent menstrual periods – after other causes for this have been excluded,
3) Polycystic ovaries on ultrasound scan
Women with polycystic ovary syndrome may have the following hormonal disturbances:
Elevated levels of:
• Testosterone: an ovarian androgen hormone that influences hair growth;
• Oestrogen: an ovarian hormone that stimulates growth of the womb lining (endometrium);
• Luteinising hormone (LH, a pituitary hormone which influences hormone production by the ovaries and is important for normal ovulation);
• Insulin (a hormone that is principally involved in utilisation of energy from food), which when elevated may stimulate the ovary to over-produce testosterone and prevent the follicles from growing normally to release eggs and hence cause the ovary to become polycystic. Indeed it is high levels of insulin that is thought to be one of the main problems for women with polycystic ovary syndrome. Insulin becomes more elevated in women who are overweight.
There are many other subtle hormonal abnormalities that affect ovarian function and influence the menstrual cycle, fertility, bodily hair growth, body weight and general health.
Standard blood tests include measurements of:
The following hormones: testosterone, luteinising hormone (LH), follicle stimulating hormone (FSH), thyroid hormones, prolactin. Sex hormone binding globulin (SHBG) – the protein that carries testosterone around the blood is also sometimes, but not always, measured. Recently a test of anti-Mullerian hormone (AMH) has been found to correlate well with the presence of polycystic ovaries.
Glucose tolerance test – a sugary drink is given first thing in the morning on an empty stomach and blood taken at the time of the drink and then again after 2 hours. This helps to see how well the body handles sugar in food and is a screening test for diabetes. In essence it helps to assess the action of insulin.
Cholesterol levels (best done first thing in the morning before anything is eaten or drunk).
An ultrasound scan of the pelvis allows visualization of the ovaries and also the womb – it is important also to measure the thickness of the womb lining (endometrium).
It is now thought that having polycystic ovaries may run in families and there is evidence of a genetic cause. Some women may have polycystic ovaries and never have symptoms - or for that matter never know that they have polycystic ovaries. In fact, it appears that between 20 – 33% of women in the U.K. have polycystic ovaries, of whom perhaps three-quarters have symptoms of the polycystic ovary syndrome – often these symptoms are mild. There are racial differences, with women from Southern Asia, for example having a higher rate of PCOS and disturbed insulin metabolism than European Caucasian women.
Ovaries do not suddenly become polycystic, but women who have polycystic ovaries may develop symptoms at any time, for reasons that are not always clear. A gain in body weight is often the precipitating cause for the development of symptoms. The appearance of polycystic ovaries does not disappear although symptoms may improve, either naturally or as a result of therapy.
It appears that one of the fundamental problems is with over production of insulin due to inefficient handling of energy from food. Whilst the extra insulin is working hard, but ineffectively, to turn food into energy it fails and gets turned into fat. The high levels of insulin have other effects in the body – including stimulating the ovaries to over produce androgens (mainly testosterone), preventing normal ovulation and also longer term effects on the circulation (leading to high cholesterol levels and an increased risk of cardiovascular disease: heart attack and stroke). There is also an increased risk of diabetes occurring in later life.
The balance of hormones is affected by body weight and being overweight can greatly upset this balance and make the above symptoms worse. Some women with polycystic ovaries only develop symptoms if they put on weight. Being overweight (obesity) is commonly associated with the polycystic ovary syndrome and this increases the risk of heart disease and high blood pressure in later life. Many clinics now measure cholesterol levels and if they are abnormal dietary advice is given. A high fibre, low fat and low sugar diet at a young age, together with regular exercise, may help to reduce problems such as high blood pressure and heart attacks when older. Smoking cigarettes seriously worsens the risk of developing these problems. Another problem sometimes seen in later life is "late onset diabetes" in which the body is unable to use sugar efficiently. If this occurs it is then necessary to reduce the dietary intake of carbohydrates and sometimes to take oral medication. The risk of both cardiovascular disease and diabetes can be reduced by keeping to the correct weight for your height.
The small cysts in the ovaries do not get larger, in fact they eventually disappear and are replaced by new cysts. Unless they develop into a mature follicle that will ovulate when it is about 20mm in diameter, the cysts are on average 5mm and no greater than 9mm. These are not the type of ovarian cyst that require surgical removal, as such cysts are 50mm or larger. The cysts of the polycystic ovary do not cause ovarian cancer.
Women with infrequent or absent periods are at risk of excessive growth of the lining of the womb (endometrium). It is important that the endometrium is shed on a regular basis to prevent this from happening for if the endometrium becomes too thick it may sometimes develop into cancer of the womb (endometrial carcinoma). The endometrium can be seen on an ultrasound scan and if it appears too thick, or irregular, a dilatation and curretage (D & C) operation is advised in order to examine the endometrium under a microscope.
1. Menstrual irregularities.
Irregular and unpredictable periods can be unpleasant and a nuisance as well as suggesting irregular ovulation and the risk of endometrial thickening. If pregnancy is not desired the easiest approach is the use of a low dose combined oral contraceptive (that is a contraceptive pill). This will result in an artificial cycle and regular shedding of the endometrium. Some women cannot take the pill and require alternative hormonal therapy to induce regular periods, such as a progestogen for 5-10 days every 1-3 months, depending upon an individual’s requirements. We believe that it is important to have a period at least once every 3 – 4 months to prevent abnormal thickening of the womb lining. An alternative is to use a progesterone secreting coil (Mirena Intrauterine System) which releases the hormone progesterone into the womb, thereby protecting it and also often resulting in reduced or absent menstrual bleeding.
If ovulation occurs erratically it will take longer than average to get pregnant and if ovulation is not occurring it is not possible to conceive without treatment. If the menstrual cycle is irregular it is necessary to take steps to make it regular in order to achieve monthly ovulation and hence a better chance of conception. There are a number of treatments that are used to stimulate regular ovulation. The fertility clinic at the Leeds General Infirmary is at the forefront of research in this area.
First it is necessary to check that the fallopian tubes are open and that your partner’s sperm count is normal. The first drug to try is usually a tablet called clomifene citrate (Clomid), which induces ovulation in about 75% of women of whom perhaps 50-60% can expect to get pregnant after 6 months’ therapy. If clomifene does not work the alternatives include daily hormone injections of a drug that contains follicle stimulating hormone (FSH) or alternatively an operation performed by laparoscopic (“key hole”) surgery in which the ovaries are cauterized (called ovarian diathermy or “drilling”) – both will induce ovulation in about 80% of women.
Women who are overweight have a reduced chance of conception, whether naturally or with assistance and an increased risk of miscarriage and other pregnancy related complications. Weight loss is important before starting fertility therapy and this is best achieved by a strict diet and exercise programme.
Treatments to induce ovulation must be monitored by ultrasound observation of the developing follicle in the ovary. This requires attending the fertility clinic on a regular basis in order to prevent the main side effect, which is multiple pregnancy. The aim of the treatment is to induce the release of only one egg. Another risk of treatment is the ovarian hyperstimulation syndrome (OHSS), when the ovaries respond over-sensitively and can make the individual very unwell.
Metformin is a drug that has been used for many years for the treatment of diabetes. It helps the body use insulin more efficiently and therefore it was thought that it might help to correct one of the fundamental abnormalities of the syndrome, thereby improving ovarian function. Large studies however have failed to demonstrate any clear benefit from the use of metformin and so we only recommend it for women with a proven problem with high glucose levels.
3. Skin problems.
If androgen (testosterone) levels are high the skin may be affected. Acne (spots) may occur on the face, chest or back. Sometimes there is also unwanted hair growth on the face, chest, abdomen, arms and legs. These problems may be confined to small areas of the body, but sometimes they are more prominent, especially in women with darker hair or skin, simply because the unwanted hair is more noticeable than in fairer people. A less common problem is thinning of hair on the head, although if this occurs it is rarely serious. Being overweight probably causes the worst problems for women with the polycystic ovary syndrome as obesity aggravates imbalances of the hormones that control ovulation and that affect the skin and hair growth.
The contraceptive pill Dianette contains cyproterone acetate (an anti-androgen) and is an effective therapy for acne and unwanted hair growth. Spironolactone is another effective preparation, particularly for older women who may also have high blood pressure (for whom the contraceptive pill may not be allowable). There is a new contraceptive pill, Yasmin, which appears to combine the best qualities of Dianette and Spironolactone and has also shown to be effective with few side effects.
Physical treatments such as electrolysis and waxing may be helpful whilst waiting for the above medical treatments to work, as the drug therapies may take 6-9 months or longer before any benefit is perceived. However electrolysis and waxing are expensive and should only be performed by properly trained therapists as scarring can result from unskilled treatment. Recently laser therapy has proven effective, particularly for women with dark hair and fair skin. Shaving can help some women and does not make hair grow back faster.
There is a new topical preparation, Vaniqa (Eflornithine) which appears to be very useful in helping reduce unwanted bodily hair. Vaniqa may cause some thinning of the skin and so high factor sun block is recommended if you are in the sun.
Being overweight worsens the symptoms of PCOS. It can be very hard to lose weight and there isn’t a simple solution. Having PCOS does not make you gain weight but women with PCOS find it easy to put on weight as their metabolism works inefficiently to deal with food. Regular physical exercise (at least 20-30 minutes of hard exercise 5-7 days per week) will increase the body’s metabolism and significantly improve the ability to lose weight and improve long term health.
Much has been written about diet and PCOS. The right diet for an individual is one that is practical, sustainable and compatible with your lifestyle. It is sensible to keep carbohydrate content down and to avoid fatty foods. It is often helpful to sit down with a dietician to work out the best diet for you. A number of drugs are available that may help with weight loss. These can be prescribed by general practitioners and their use must be closely monitored. Sometimes surgery to either reduce the size of the stomach or place a band around the stomach (bariatric surgery, gastric banding) may be helpful for those who find it very difficult to lose weight.
In Leeds we are performing a lot of research into various aspects of PCOS in order to increase our understanding of the condition and also improve the treatments of the different problems, from obesity, androgen excess and infertility to the long term problems.
Verity is the UK national support organisation for women with PCOS. We know that it is very tempting to read information on the Web – some is excellent, some can be misleading. We recommend that you use the Verity website to get reliable source of information and support. www.verity-pcos.org.uk
Last updated: December 2010