Assessment and management of polycystic ovary syndrome: Summary of an evidence-based guideline

In the paper

“One high-quality RCT (level II) with a low risk of bias using letrozole versus placebo in PCOS with CCR, found letrozole better for ovulation rates ( P =0.006) but similar for pregnancy rate and live birth rate per patient. 243”

What the sources say

• Supported

  The trial reports six ovulations with letrozole versus none with placebo (P=0.006) in women with PCOS and clomiphene resistance. It reports one pregnancy and live birth in the letrozole arm and none in the placebo arm; thus, 'similar' means no demonstrated difference in those outcomes, not identical rates. The methods describe randomization, allocation concealment, and blinding, consistent with the citing paper's low-risk-of-bias characterization. (LLM, conf=0.89)

  cites [243] source

In the paper

“Studies examining the reproductive effects of metformin in PCOS suggest benefits but are limited by study design. 223”

What the sources say

• Not checked yetcites [223] source

In the paper

“Metformin regimens in PCOS are not well standardised in research or clinical practice, with doses varying between 500 and 2550 mg per day and both standard and slowrelease preparations available. 209”

What the sources say

• Not checked yetcites [209] source

In the paper

“The rates of twin and triplet pregnancy with clomiphene citrate are 5%-7% and 0.3%, respectively.”

What the sources say

• Not checked yetcites [219] source

In the paper

“Gonadotrophins appear to be as effective as laparoscopic ovarian surgery”

In the paper

“One high-quality RCT (level II) with low risk of bias found 10 days of letrozole better than 5 days for pregnancy rate per cycle ( P =0.03), with no differences in ovulation rate per patient and miscarriage rate per pregnancy among women with CCR PCOS. 246”

What the sources say

• Not checked yetcites [246] source

In the paper

“Mechanisms underpinning hormonal changes and resumption of ovulation remain poorly understood.”

In the paper

“One high-quality systematic review of RCTs (level I) with low risk of bias compared laparoscopic ovarian surgery to gonadotrophins with no differences for live birth rate, pregnancy and ovulation rate per patient and miscarriage rate per pregnancy, but laparoscopic ovarian surgery had fewer multiple pregnancies. 255”

What the sources say

• Not checked yetcites [255]

In the paper

“The mechanisms of action, comparative effectiveness and the long-term risks of laparoscopic ovarian surgery in infertile women with PCOS still remain unclear”

In the paper

“One high-quality RCT (level II) with a low risk of bias found that clomiphene citrate plus metformin was better than laparoscopic ovarian surgery for ovulation rate per cycle ( P =0.02), but there was no difference for live birth rate, pregnancy rate per cycle and miscarriage rate per pregnancy. 256”

What the sources say

• Not checked yetcites [256] source

In the paper

“There is little research addressing the long-term complications of laparoscopic ovarian surgery.”

In the paper

“Laparoscopic ovarian surgery, when compared with other second-line treatments, is equally effective as gonadotrophins, with fewer multiple pregnancies.”

In the paper

“A recent meta-analysis of bariatric surgery in general populations reports weight loss of 38.5 kg or 56% excess weight loss and resolution of DM2 in 78% of patients with DM2. 266”

What the sources say

• Not checked yetcites [266] source

In the paper

“There was insufficient evidence to support or refute the use of laparoscopic ovarian surgery over either metformin or clomiphene citrate alone, or clomiphene citrate plus metformin, for multiple pregnancies, 257,260 and there was insufficient evidence to support or refute the use of laparoscopic ovarian surgery over any intervention for adverse effects and QoL.”

What the sources say

• Not checked yetcites [257] source
• Not checked yetcites [260] source

In the paper

“Generally in PCOS, there is a paucity of evidence and the evidence that is available is of poor quality”

In the paper

“PCOS has potential for major metabolic consequences, including obesity and related type 2 diabetes mellitus (DM2) as well as cardiovascular disease (CVD)”

What the sources say

• Not checked yetcites [2] source
• Not checked yetcites [3] source

In the paper

“being more common among those who are overweight or of Indigenous background.”

What the sources say

• Not checked yetcites [1] source

In the paper

“Polycystic ovary syndrome (PCOS) has recently been shown to affect a striking 12%-21% of Australian reproductive-age women”

What the sources say

• Not checked yetcites [1] source

In the paper

“Indigenous women appear to have a higher prevalence and severity of PCOS.”

What the sources say

• Not checked yetcites [1] source
• Not checked yetcites [12]

In the paper

“It also has significant mental health and psychological impact, impairing quality of life (QoL).”

What the sources say

• Not checked yetcites [4] source
• Not checked yetcites [5] source

In the paper

“PCOS has significant and diverse implications, including reproductive (hyperandrogenism, hirsutism, anovulation, infertility), metabolic (insulin resistance [IR], impaired glucose tolerance, DM2, adverse cardiovascular risk profiles) and psychological features (increased anxiety and depression and worsened QoL).”

What the sources say

• Not checked yetcites [9] source

In the paper

“fertility issues most prominent among women in their 20s and 30s”

What the sources say

• Not checked yetcites [11] source

In the paper

“It is estimated that 70% of Australian women with PCOS remain undiagnosed”

What the sources say

• Not checked yetcites [1] source

In the paper

“The role of ultrasound remains controversial for adolescents, among whom a polycystic appearance of the ovaries is very common, potentially leading to overdiagnosis; 16”

What the sources say

• Not checked yetcites [16] source

In the paper

“challenges to feminine identity and body image due to obesity, acne, excess hair, infertility and long-term health-related concerns compromise QoL and adversely affect mood and psychological wellbeing.”

What the sources say

• Not checked yetcites [5] source
• Not checked yetcites [23] source

In the paper

“Women with PCOS present with psychological, 5,23 reproductive 24 and metabolic implications.”

What the sources say

• Not checked yetcites [5] source
• Not checked yetcites [23] source
• Not checked yetcites [24] source

In the paper

“With a higher prevalence and greater severity of depression and anxiety, low self-esteem, negative body image, and psychosexual dysfunction, 5,25”

What the sources say

• Not checked yetcites [5] source
• Not checked yetcites [25] source

In the paper

“Diagnosis of PCOS is now largely based on the Rotterdam criteria, 14 which are inclusive of the original National Institutes of Health (NIH) criteria 15 and require two of three key features: oligo- or anovulation, clinical and/or biochemical hyperandrogenism and polycystic ovaries on ultrasound (Figure 2).”

What the sources say

• Not checked yetcites [14] source
• Not checked yetcites [15]

In the paper

“PCOS phenotypes vary widely depending on life stage, genotype, ethnicity and environmental factors, including lifestyle and body weight.”

In the paper

“Indeed, the adverse impact of obesity on fertility, exacerbated by delay in childbearing, is resulting in a significant social, health and economic burden in Australia. 35”

What the sources say

• Not checked yetcites [35] source

In the paper

“Women with PCOS are therefore a population at high risk of developing DM2 and CVD.”

In the paper

“Obesity has a specific impact on women's reproductive health, increasing the prevalence and severity of PCOS, infertility, pregnancy complications, gestational diabetes and fetal pregnancy complications, with substantial and escalating economic costs. 33,34”

What the sources say

• Not checked yetcites [33] source
• Not checked yetcites [34] source

In the paper

“Women with PCOS also have an increased prevalence of metabolic syndrome (associated with an increased risk for DM2 and CVD), 28”

What the sources say

• Not checked yetcites [28] source

In the paper

“individual risk factors for CVD and clinical signs of atherosclerosis, 29,30”

What the sources say

• Not checked yetcites [29] source
• Not checked yetcites [30] source

In the paper

“Obesity is now the primary cause of chronic disease among Australian women, with adverse outcomes including DM2 and CVD. 31”

What the sources say

• Not checked yetcites [31]

In the paper

“Cardiovascular risk factors are increased and CVD appears more prevalent among women with PCOS despite inadequate long-term studies to appropriately address this question. 22”

What the sources say

• Not checked yetcites [22] source

In the paper

“There are limited clinical guidelines and no evidence-based guidelines, either in Australia or internationally, for assessment or management of women with PCOS; rather, PCOS is briefly mentioned within guidelines for the management of obesity and DM2. 45,54”

What the sources say

• Not checked yetcites [45]
• Not checked yetcites [54]

In the paper

“The recommendations in this guideline are strengthened by the use of rigorous methodology for evidence review and guideline development, including use of: study designs least susceptible to bias; a-priori criteria for inclusion and appraisal of studies; extraction of study data; and meta-analysis where appropriate.”

In the paper

“The prevalence of PCOS among Indigenous Australian women appears to be as high as 21% by the Rotterdam criteria 12 and the NIH criteria, 50 and increases with rising BMI. 12”

What the sources say

• Not checked yetcites [12]
• Not checked yetcites [50] source

In the paper

“The National Aboriginal and Torres Strait Islander Health Survey (NATSIHS) found that Indigenous Australians are 1.2 times more likely to be overweight or obese than non-Indigenous Australians, and this disparity is greatest for women. 51”

What the sources say

• Not checked yetcites [51]

In the paper

“Evidence reviews were conducted for each of the 22 identified clinical questions.”

In the paper

“Included studies were classified according to the NHMRC levels of evidence 56 and appraised using a-priori criteria according to study design, using a descriptive component approach to assign a risk of bias rating. 57”

What the sources say

• Not checked yetcites [56]
• Not checked yetcites [57]

In the paper

“The risk of metabolic complications is already high among Indigenous women, independent of PCOS; therefore, PCOS can amplify metabolic risk in these women.”

In the paper

“Public and targeted consultation on the draft guideline was conducted for 30 days commencing 5 March 2011, in accordance with the legislative requirements for approval of externally developed guidelines under Section 14A of the National Health and Medical Research Council Act 1992 (Cwlth).”

In the paper

“DM2 is the second-commonest cause of mortality and disabilityadjusted life-years (DALY) among Indigenous women. 52”

What the sources say

• Not checked yetcites [52]

In the paper

“this NHMRC-approved evidence-based guideline followed a rigorous, systematic process of development, which is briefly outlined below and in detail in the full guideline. 8”

What the sources say

• Not checked yetcites [8]

In the paper

“In a group of Indigenous women with PCOS, 30.3% were obese and 7.0% had a normal BMI. 12”

What the sources say

• Not checked yetcites [12]

In the paper

“Search strategies were developed according to a-priori selection criteria for each clinical question.”

In the paper

“For many aspects of PCOS, there is little or no evidence or the evidence is of poor quality, with other potential biases resulting from different methods for diagnosis of PCOS and differing end points.”

In the paper

“The recommendations were formulated using a considered judgement process that took into account the amount and quality of available evidence as well as its generalisability and applicability to current practice in Australia.”

In the paper

“The leading cause of burden of disease among Indigenous women in the NATSIHS was anxiety and depression, accounting for 10% of the burden. 51”

What the sources say

• Not checked yetcites [51]

In the paper

“data were extracted from included studies using a specially developed data extraction form, 57 and meta-analyses were performed where appropriate.”

What the sources say

• Not checked yetcites [57]

In the paper

“All aspects of the guideline were developed as outlined in the NHMRC standards and procedures for externally developed guidelines, 55 and accordingly, the guideline was approved by the NHMRC in July 2011.”

What the sources say

• Not checked yetcites [55]

In the paper

“The optimal methodology for testosterone measurement on which to base calculated measurements is unclear; however, Davison and colleagues have described a highly sensitive direct manual radioimmunoassay in the Australian setting that more accurately measures total testosterone than other assays, and that provides reference values for androgens by age. 58”

What the sources say

• Not checked yetcites [58] source

In the paper

“During the second year, hormonal profiles are similar to control-group adult women during both phases of the menstrual cycle, although progesterone levels remain lower. 63”

What the sources say

• Not checked yetcites [63] source

In the paper

“For diagnosis of PCOS, calculated bioavailable and free testosterone were better than androstenedione, SHBG and total testosterone levels, and the FAI was better than androstenedione and SHBG levels. 61”

What the sources say

• Not checked yetcites [61] source

In the paper

“The average adult menstrual cycle is 28 days, with a normal cycle range of 24 to 35 days. 64”

What the sources say

• Not checked yetcites [64]

In the paper

“PCOS is diagnosed based on at least two of: oligo- or anovulation, hyperandrogenism (clinical and/or biochemical) and polycystic ovaries on ultrasound after exclusion (where relevant) of other conditions such as thyroid dysfunction, congenital adrenal hyperplasia, hyperprolactinaemia, androgen-secreting tumours and Cushing syndrome (Figure 2). 14”

What the sources say

• Not checked yetcites [14] source

In the paper

“In approving the full version of the guideline, the NHMRC is satisfied that it is based on the systematic identification and synthesis of the best available scientific evidence and makes clear recommendations for health professionals practising in an Australian health care setting.”

In the paper

“Between the ages of 2 and 9 years, the size and morphology of the ovaries are relatively stable, with the volume of each ovary being less than 2 cm 3 ; however, from around 9 years of age onward, the ovaries undergo progressive increases in size. 70”

What the sources say

• Not checked yetcites [70] source

In the paper

“Of girls who begin menses at before 12 years of age, between 12 and 13 years, and after 13 years of age, 50% of cycles are ovulatory by 1 year, 3 years, and 4.5 years, respectively. 69”

What the sources say

• Not checked yetcites [69] source

In the paper

“Original NIH criteria based on ovulatory disturbance and hyperandrogenism may be the optimal way to diagnose PCOS in adolescents.”

In the paper

“Elements of a successful collaboration include 'a willingness to collaborate, trust in each other, mutual respect and communication'. 74”

What the sources say

• Not checked yetcites [74] source

In the paper

“Successful collaboration also relies on adequate systems and organisational supports. 75”

What the sources say

• Not checked yetcites [75] source

In the paper

“The number of large antral follicles and ovarian size reaches its maximum around the time of menarche 71,72”

What the sources say

• Not checked yetcites [71] source
• Not checked yetcites [72] source

In the paper

“One level III3 case-control study with moderate risk of bias 73 was identified by our search to answer the question, and was deemed insufficient evidence on which to base a recommendation.”

What the sources say

• Not checked yetcites [73] source

In the paper

“There is a high prevalence of polycystic ovaries among adolescents, and normal reference ranges for this age group have not been developed or validated.”

In the paper

“In PCOS, other novel CVD risk factors, premature cardiovascular dysfunction and subclinical CVD 29,30,83 have been noted and are related to IR and obesity. 84-89”

What the sources say

• Not checked yetcites [29] source
• Not checked yetcites [30] source
• Not checked yetcites [83] source
• Not checked yetcites [84] source
• Not checked yetcites [85] source
• Not checked yetcites [86] source
• Not checked yetcites [87] source
• Not checked yetcites [88] source
• Not checked yetcites [89] source

In the paper

“Women with PCOS often have increased cardiovascular risk factors (hyperinsulinaemia, dyslipidaemia, hypertension) and increased prevalence of metabolic syndrome 81”

What the sources say

• Not checked yetcites [81] source

In the paper

“Women with PCOS have increased Finnish Diabetes Risk Scores as well as increased risk of gestational diabetes, 24 prediabetes and DM2 11,103 - independent of, but exacerbated by, obesity.”

What the sources say

• Not checked yetcites [24] source
• Not checked yetcites [11] source
• Not checked yetcites [103] source

In the paper

“Earlier-onset hyperglycaemia and rapid progression to DM2 is also reported in PCOS. 104,105”

What the sources say

• Not checked yetcites [104] source
• Not checked yetcites [105] source

In the paper

“IR is a key aetiological feature in PCOS, worsening the reproductive and metabolic features, type 2 diabetes and CVD risk. 30,99,100”

What the sources say

• Not checked yetcites [30] source
• Not checked yetcites [99] source
• Not checked yetcites [100] source

In the paper

“In contrast, Shaw and colleagues examined a subset of postmen-pausal women from the Women's Ischemia Syndrome Evaluation study who had displayed clinical features consistent with PCOS and confirmed increased cardiovascular events and deaths. 22”

What the sources say

• Not checked yetcites [22] source

In the paper

“We did not identify high-quality PCOS-specific evidence to answer the question, hence a clinical consensus recommendation was made based on clinical expertise, an international position statement on CVD risk assessment in PCOS 78 and on national guidelines on absolute CVD risk assessment, 46 management of obesity, 54 lipids 77,79 and hypertension 80 for the general population.”

What the sources say

• Not checked yetcites [78] source
• Not checked yetcites [46]
• Not checked yetcites [54]

In the paper

“We identified one low-quality systematic review (level I) with high risk of bias; 108 however, this was deemed insufficient evidence on which to base the recommendation.”

What the sources say

• Not checked yetcites [108] source

In the paper

“Body image is generally poor in women, yet negative body image is more prevalent among women with PCOS and affects thoughts and feelings about health and appearance, QoL, mood and physical fitness. 114,115”

What the sources say

• Not checked yetcites [114] source
• Not checked yetcites [115]

In the paper

“Screening may uncover undiagnosed mood disorders with resource implications including increasing consultation duration.”

In the paper

“The significantly increased risk of DM2 in PCOS represents a major health and economic burden.”

In the paper

“Prevalence of anxiety among women with PCOS ranges from 34% 113 to 57%; 5 again, higher than in the general population (18%). 111”

What the sources say

• Not checked yetcites [113] source
• Not checked yetcites [5] source
• Not checked yetcites [111]

In the paper

“Assessment of depression and/or anxiety for women with PCOS is important, as recognition and treatment improves emotional wellbeing and QoL (Figure 6) and is likely to improve effectiveness of lifestyle intervention in PCOS.”

In the paper

“The recommendation to screen all women with PCOS and to use an OGTT will result in earlier detection of prediabetes and DM2, and will present opportunities for prevention of DM2 and its complications, through effective lifestyle intervention, as outlined below.”

In the paper

“Previous studies have noted that fasting blood glucose level alone appears to lack sensitivity in screening for prediabetes or DM2 in PCOS, with national and international groups recommending screening all women with PCOS with an OGTT. 78,107”

What the sources say

• Not checked yetcites [78] source
• Not checked yetcites [107] source

In the paper

“with high rates of associated mood disorders; 62% had major depression and 41% anxiety disorders.”

What the sources say

• Not checked yetcites [124] source

In the paper

“It is likely that improved screening practices will increase identification of disordered eating/eating disorders”

In the paper

“The prevalence of any eating disorder has been reported at 21% in PCOS, 124”

What the sources say

• Not checked yetcites [124] source

In the paper

“Australian research suggests that prevalence of diagnosable eating disorders is increasing. 118”

What the sources say

• Not checked yetcites [118] source

In the paper

“Women with PCOS also report less sexual satisfaction and lower sexual self-worth than women without PCOS”

What the sources say

• Not checked yetcites [134]

In the paper

“There is a large number of small, uncontrolled trials demonstrating that weight loss achieved through lifestyle management decreases abdominal fat, hyperandrogenism and IR and improves lipid profiles, ovulation, menstrual cyclicity, fertility, risk factors for DM2 and CVD and psychological health in women with PCOS who are overweight. 137-140”

What the sources say

• Not checked yetcites [137] source
• Not checked yetcites [138] source
• Not checked yetcites [139] source
• Not checked yetcites [140] source

In the paper

“Hence, lifestyle management is useful for targeting weight loss and prevention of weight gain, and is first-line treatment for a large proportion of women with PCOS.”

In the paper

“Overall, although exercise has benefits for women with PCOS who are overweight, the evidence is limited, inconsistent and of low quality.”

In the paper

“Pharmacological therapy i n cl u di ng clomiphene citrate, metformin and gonadotrophins are available and effective in improving fertility in women with PCOS. 208”

What the sources say

• Not checked yetcites [208]

In the paper

“There was no difference between aerobic exercise and aerobic-resistance exercise for percent of body fat, fat mass, fat-free mass, depression scores and PCOS-related QoL. 140,192”

What the sources say

• Not checked yetcites [140] source
• Not checked yetcites [192] source

In the paper

“However, this study is only published in abstract form, informing the guideline development group but not included in the evidence review.”

In the paper

“however, with small sample size and inadequate power, this cannot inform a recommendation in isolation.”

In the paper

“given the similar efficacy of lifestyle and pharmacological therapy overall, the guideline development group deemed clear benefits in using lifestyle interventions over pharmacological interventions for firstline management of infertility among women with PCOS.”

In the paper

“The evidence is generalisable to the patient population in terms of age and BMI and was completed in multiple countries; however, it may not be generalisable to Indigenous populations.”

In the paper

“Clomiphene citrate is a selective oestrogen receptor modulator with both oestrogenic and antioestrogenic properties. 216”

What the sources say

• Not checked yetcites [216] source

In the paper

“It inhibits oestradiol receptors binding in the hypothalamus and pituitary, blocking negative feedback. This hypothalamus release from negative inhibition increases gonadotrophinreleasing hormone, which in turn increases FSH and stimulates follicular growth and ovulation. 217”

What the sources say

• Not checked yetcites [217] source

In the paper

“One systematic review and one RCT were identified by our search.”

In the paper

“The evidence is generalisable to patient populations in terms of age and BMI and applicability in Australia, but may not be relevant to Indigenous populations.”

In the paper

“Metformin has been used extensively in DM2, is the most studied in PCOS, and has the most reassuring safety profile. 222”

What the sources say

• Not checked yetcites [222] source

In the paper

“Gonadotrophins are often used as second-line therapy in anovulatory PCOS women with CCR; however, there is an increased risk of multiple pregnancy and ovarian hyperstimulation syndrome. 231”

What the sources say

• Not checked yetcites [231]