Evidence based guidelines for the assessment and management of fertility in PCOS


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Prof Robert Norman presented this to the Adelaide Northern Division of General Practice on 24th July 2012.

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  • 30% clinically depressed and 57% clinical anxiety, impacts on self efficacy, most especially with anxiety were under diagnosed,
  • Evidence based guidelines for the assessment and management of fertility in PCOS

    1. 1. Evidence based guidelines for the assessment and management of fertility in polycystic ovary syndromeProf Helena Teede Norman Prof Robert
    2. 2. Disclosure• Funding from MSD and Merck Serono• Employed by the University of Adelaide• Work at FertilitySA• On NHMRC Research Committee
    3. 3. Background • Prevalence of PCOS traditionally estimated at 4-8% (NIH) - Greece, Spain, USA 1,2,3 • Australian (Rotterdam) prevalence 12-18% 4 • Indigenous populations ~21% • Costs >$400 million/yr in Australia 5,6 • Major health and economic burden61) Diamanti-Kandarakis et al JCEM 1999 2) Knochenhauer ES et al JCEM 1998, 3) Asuncion M et al JCEM2000, 4) March et al Human Reprod 2010 6 5) Azziz et al JCEM 2005, 6) Teede et al MJA 2007
    4. 4. Perspective is everything
    5. 5. Clinical perspectives on PCOS Endocrinologist Gynaecologist Menstrual problems 70% 47% <0.001 Androgenisation 81% 59% <0.001 Obesity 11% 8% NS PCO ultrasound 14% 61% <0.001 Increased LH:FSH 24% 47% <0.001 Insulin resistance 6% 11% NSCussons et al (350 gynaecologists, 350 endocrinologists) Cussons et al 2007 : Survey of Australian gynaecologists and endocrinologists
    6. 6. Laboratory perspectives on PCOS Endocrinologist Gynaecologist LH,FSH 91% 94% NS Estradiol 64% 56% NS Testosterone 99% 92% NS 17OHP 70% 46% <0.001 DHEAS 80% 58% <0.001 Glucose 89% 79% 0.02 Lipids 67% 34% <0.001 Ovarian ultrasound 44% 91% <0.001Cussons et al Cussons et al 2007
    7. 7. Types of PCOS Hyperandrogenism, normal cycles, PCO ultrasound Hyperandrogenism, oligo- anovulation, PCO ultrasound (NIH)Normal androgens 16%oligo-anovulation, PCO 17% 61% 7% Hyperandrogenism, oligo- anovulation, normal ultrasound N= 380 (NIH) Prevalence of PCO around 20% Prevalence of PCOS 12-17% Prevalence in Indigenous women 21%
    8. 8. A changing paradigm in PCOSHuman Reproduction 27:14-24 (2012)
    9. 9. Diagnosis Rotterdam diagnostic criteria requires two of: 1. Oligo- or anovulation; 2. Clinical and/or biochemical signs of hyperandrogenism; 3. Polycystic ovaries; and exclusion of other aetiologies such as hypothydoidism,Rotterdam hyperprolactinemia, congenital adrenal hyperplasia, androgen- secreting tumours and Cushing’s syndrome. NIH diagnostic criteria requires: 1. Oligo- or anovulation; and 2. Clinical and/or biochemical signs of hyperandrogenism; NIH and exclusion of other aetiologies such as congenital adrenal hyperplasia, androgen-secreting tumours and Cushing’s syndrome. Teede et al MJA 2011
    10. 10. PCOS: Complex clinical syndromeNorman et al Lancet 2007
    11. 11. PCOS– lifelong consequences Peripuberty Adolescence In utero Aging Adulthood PCOS Metabolic syndromeGrowth issues Early pubertyLong-term health Precocious puberty Reproductive disorders Metabolic
    12. 12. Psychological features Anxiety & depression Poor Eating body disorders image Psychosexual dysfunctionTeede et al MJA 2011, Deeks et al Fertil Steril 2010
    13. 13. Gaps in clinical PCOS guidance• No accessible evidence-based guidelines (EBG) internationally, no Australian EBG• Current information often opinion based or included as small part of broader guidelines (Obesity and type II diabetes)• Recent position statements by international bodies (AEPCOS Society) on diagnosis, glucose intolerance, CVD risk and lifestyle treatment, but no evidence based rigorously developed guidelines
    14. 14. Evidence based practice is integration Patient of best research evidence Clinical preferencejudgment with clinical expertise Evidence and patient values from research Sackett et al. 2000. Evidence based medicine. How to practice and teach EBM. Second edition. Churchill Livingstone. London Evidence Based Practice
    15. 15. PCOS Australian Alliance
    16. 16. International /NHMRC grading A Body of evidence can be trusted to guide practice. B Body of evidence can be trusted to guide practice in most situations. Body of evidence provides some support for recommendation but care C should be taken in its application. Body of evidence is weak and recommendation must be applied with D caution.Classifications where NHMRC grading cannot be applied: In the absence of evidence, a clinical consensus recommendation has been CR made by the guideline development group. Evidence not sought. A practice point has been made by the guideline PP development group where important issues arose from discussion of evidence based or clinical consensus recommendations.
    17. 17. Proposed Infertility treatments for PCOS 1. Ovulation induction• Lifestyle intervention including diet• Clomiphene citrate• Laparoscopic drilling• Aromatase inhibitors• Gastric banding2. IVF/ICSI
    18. 18. Obesity• Prevalence of obesity is increasing and has an important bearing on the phenotype of PCOS (level B)• Higher BMI related to greater prevalence of menstrual irregularity, hyperandrogenaemia and hirsutism (level B)• Increased BMI and visceral adiposity associated with greater insulin resistance (level B)• Lifestyle management results in weight loss and improves surrogate markers of metabolic disease/syndrome (level B)Human Reproduction 27:14-24 (2012)
    19. 19. IR and metabolic syndrome• PCOS associated metabolic disorders major predictors of prediabetes, diabetes and metabolic syndrome (level B)• Patient with metabolic syndrome are an important subset of women with PCOS (level B)• Not all PCOS has similar metabolic risk. Hyperandrogenaemia and oligoamenorrhoea pose the worst risk (level B)• It is critical to stratify women for metabolic risk in PCOS. It would be helpful to have a new name for this subset (GPP)Human Reproduction 27:14-24 (2012)
    20. 20. Type 2 diabetes and PCOS • PCOS is a major risk factor for IGT and T2D (level A) • Obesity is an exacerbating factor (level B) • Obesity predicts further T2D (level B) • Screening for IGT/T2D should be done by OGTT (level B) • Measuring insulin is meaningless (level C) • Screening important in : hyperandrogenaemia and anovulation, acanthosis nigricans, high BMI, family history T2D (level C) • Metformin may be used for IGT/T2D (GPP)Human Reproduction 27:14-24 (2012)
    21. 21. Clinical questions relating to lifestyle management of PCOS Dietary • Effectiveness of lifestyle interventionsintervention • Comparative effectiveness of individual lifestyle intervention components • How best to deliver lifestyle interventions Exercise • Amount of weight loss required forintervention improvements • Specific strategies for prevention of weight gain or weight maintenanceBehavioural • Lifestyle intervention compared tointervention pharmacological or surgical interventions
    22. 22. Are lifestyle interventions effective?• Evidence-based recommendation • Lifestyle management (single or combined approaches of diet, exercise and/or behavioural interventions) for weight loss, prevention of weight gain, or for general health benefits should be recommended in women with PCOS
    23. 23. Effectiveness of diet versus exercise• Evidence-based recommendation • Lifestyle management targeting weight loss (BMI ≥ 25 kg/m2 (overweight)) and prevention of weight gain (BMI < 25 kg/m2 (lean)) should include both reduced dietary energy (caloric) intake and exercise and should be first line therapy for all women with PCOS
    24. 24. Type of dietary interventions• Evidence-based recommendation • Weight loss should be targeted in all women with PCOS and BMI ≥ 25 kg/m2 (overweight) through reducing dietary energy (caloric) intake in the setting of healthy food choices, irrespective of diet composition • Prevention of weight gain should be targeted in all women with PCOS through monitored caloric intake, in the setting of healthy food choices, irrespective of diet composition
    25. 25. Delivery of diet information• Evidence-based recommendation • Face to face, tailored dietary advice, including education, behavioural change techniques and ongoing support should be provided to women with PCOS and BMI ≥ 25 kg/m2 (overweight). – Dietary modification is the joint responsibility of all health professionals, partnering with women with PCOS • Behaviour change techniques should target prevention of weight gain in all women with PCOS including those with BMI < 25 kg/m2 (lean)
    26. 26. Clomiphene Citrate
    27. 27. Clomiphene Citrate (CC) Comparison Clomiphene citrate vs Placebo in PCOS Results Increased ovulation per woman(OR = 7.5; 3 RCTs) Increased pregnancy rate per woman (OR = 5.5; 3 RCTs) Recommendation CC should be first line pharmacological therapy (Grade A) to improve fertility outcomes in women with PCOS and anovulatory infertilityCC resistance = CCRCC failure = CCF
    28. 28. Metformin (Met)
    29. 29. MetforminComparison Metformin vs Placebo/no Treatment in PCOS♀Results Increased ovulation rate per woman(OR=2.12; 13 RCTs; 875♀) Increased pregnancy rate per woman(OR=3.86; 6 RCTs; 479♀) Equivalent live birth rate per woman(OR=1.0; 95%CI 0.16-6.39; 2 RCTs; 50♀)Recommendation See later (interpret with other evidence)(Grade)
    30. 30. Metformin versus CC
    31. 31. Metformin versus CCComparison Metformin vs clomiphene citrate in PCOS♀Results Overall ♀ (3RCTs): Decreased ovulation rate + decreased pregnancy rate and equivalent live birth rate with metformin BMI > 30 ♀ (2RCTs): Decreased ovulation rate + decreased pregnancy rate and decreased live birth rate with metformin BMI < 30 ♀ (1RCT): Equivalent ovulation rate + decreased pregnancy rate and equivalent live birth rate with metformin Overall lower BMI better response to metforminRecommendation See later (interpret with other evidence)(Grade)
    32. 32. Met versus CC: BMI < 30-32: Meta-analysis (4RCTs, 465♀)
    33. 33. Metformin +clomiphene citrate (CC) versus CCComparison Metformin + clomiphene citrate vs clomiphene citrate in PCOS♀ (all[overall], CCR or not, BMI < or > 30)Results Increased ovulation rate + increased pregnancy rate and increased live birth rate with Metformin +CC seen only in “CCR PCOS ♀”Recommendation See later (interpret with other evidence)(Grade)
    34. 34. Metformin: Recommendations Evidence-based recommendations • 7.2a Metformin should be combined with clomiphene citrate to improve fertility A outcomes rather than persisting with further treatment with clomiphene citrate alone in women with PCOS who are clomiphene citrate resistant, anovulatory and infertile with no other infertility factors. 7.2b Metformin could be used alone to improve ovulation rate and pregnancy B rates in women with PCOS who are anovulatory, have a BMI ≤30kg/m2 and are infertile with no other infertility factors. Research recommendationWhether there is a difference in effectiveness between clomiphene citrate and metforminin women with PCOS who are anovulatory, infertile and have BMI ≤30kg/m2 to improvefertility outcomes
    35. 35. Gonadotrophins
    36. 36. GonadotrophinsComparison Gonadotrophin ovulation induction versus placebo/no Rx in PCOS♀Evidence No randomised trials Large body of observational evidence supporting gonadotrophin ovulation induction in CCR/CCF PCOSRecommendation Gonadotrophins should be 2nd line pharmacological therapy in(Grade B) women with PCOS who have clomiphene citrate resistance and/or failure, are anovulatory and infertile, with no other infertility factors
    37. 37. Gonadotrophins (Gn)Comparison rFSH ovulation induction vs clomiphene citrate ovulation induction in therapy naïve PCOS ♀Results cumulative PR per ♀ (42% v 24%; p=0.09; RR=1.78; 95%CI 0.92-3.54) cumulative LBR per ♀ (29% v 16%; p=0.17; RR=1.83; 95% CI 0.79-4.0) Homburg RCT 2009: cumulative PR per ♀ (56% v 41%; p=0.03)Recommendation Gonadotrophins could be considered as first line pharmacological(Grade C) therapy in women with PCOS who are therapy naive, anovulatory and infertile, with no other infertility factors.
    38. 38. Laparoscopic Ovarian Drilling (LOD)
    39. 39. Laparoscopic Ovarian DrillingComparison Laparoscopic drilling vs FSH ovulation rateResults Equivalent live birth rate, ongoing pregnancy rate, ovulation rate and miscarriage rate per woman Decreased multiple pregnancy rate per ongoing pregnancy (1% vs 17%; OR=0.13; 95%CI 0.03-0.59)Recommendation Laparoscopic Ovarian Drilling should be 2nd line therapy in women(Grade B) with PCOS who are clomiphene citrate resistant , anovulatory, and infertile, with no other infertility factors
    40. 40. Bariatric Surgery
    41. 41. Bariatric SurgeryComparison Bariatric Surgery Vs placebo/no Rx or other infertility treatments in PCOS♀Results NilClinical Bariatric surgery could be considered 2nd line therapy toConsensus improve fertility outcomes in adult women with PCOS whoRecommendation are anovulatory, have a BMI ≥35kg/m2, and who remain infertile despite undertaking an intensive (frequent multidisciplinary contact) structured lifestyle management programme involving reducing dietary energy (caloric) intake, exercise, behavioural and/or drug interventions for a minimum of 6 months.
    42. 42. The role of IVF• Not usually needed• If required needs skill to handle cycle• Risks of hyperstimulation• Risks of multiple pregnancy• Problems of pregnancy
    43. 43. Models of care Specialists: Allied Health: Endocrinologist Psychologist Gynaecologist Dietitian Dermatologist Exercise Physiologist Patient central to care and holds management planReputable education sources and General Practitioner: consumer support group: www.managingpcos.org.au Central to ongoing carePOSAA: www.main.posaa.asn.au and co-ordination
    44. 44. Where to get advice• Internet – Jean Hailes/FertilitySA site• Booklets – Merck Serono/PCOS Alliance• Hirsutism and metabolic – reproductive/medical endocrinologist• Ovulation induction – gynaecologist/fertility specialist ie FertilitySA• Other fertility – reproductive endocrinologist ie FertilitySA
    45. 45. Guideline“These guidelines were approved bythe Chief Executive Officer of theNational Health and MedicalResearch Council (NHMRC) underSection 14A of the National Healthand Medical Research Council Act1992. In approving these guidelinesthe NHMRC considers that they meetthe NHMRC standard for clinicalpractice guidelines.”