new guidelines for polycystic ovary syndrome · international ebm guideline for assessment and...

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NEW GUIDELINES FOR POLYCYSTIC OVARY SYNDROME NEW GUIDELINES FOR POLYCYSTIC OVARY SYNDROME NEW GUIDELINES FOR POLYCYSTIC OVARY SYNDROME NEW GUIDELINES FOR POLYCYSTIC OVARY SYNDROME (PCOS)(PCOS)(PCOS)(PCOS)

Jon Havelock, MD, FRCSC, FACOG

Co-Director, Pacific Centre for Reproductive Medicine

DisclosuresDisclosuresDisclosuresDisclosures

Have received speaking fees from the following over the past 2 years:

Ferring Pharmaceuticals

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ObjectivesObjectivesObjectivesObjectives

Screening, Diagnostic Assessment, Risk Assessment

Lifestyle Interventions

Assessment and Treatment of Infertility

Pharmacologic Treatment for Non-Fertility Indications

Guideline published July 2018

Open access ESHRE website

Developed by Australian NHMRC

Funded and endorsed by ASRM and ESHRE

166 Recommendations and Practice Points

31 of these are Evidence Based Recommendations

PCOS PCOS PCOS PCOS –––– 2018201820182018

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PCOS PCOS PCOS PCOS –––– A Brief HistoryA Brief HistoryA Brief HistoryA Brief History

Stein-Leventhal Syndrome

First Described in 1935

Women with amenorrhea, infertility, hirsutism, and enlarged polycystic ovaries

Resumption of ovulation with ovarian biopsy

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Stein IF, et al. Am J Obstet Gynecol 1935. 29: 181-91

PCOS PCOS PCOS PCOS –––– A Brief History A Brief History A Brief History A Brief History ---- DiagnosisDiagnosisDiagnosisDiagnosis

NIH/NICHD (1990)

Must meet both criteria

ESHRE/ASRM Rotterdam Criteria (2003)

Must meet two of three criteria

Clinical and/or biochemical evidence of

hyperandrogenism

Clinical and/or biochemical evidence of

hyperandrogenism

Menstrual dysfunction Oligo- or anovulation

Polycystic ovaries

ESHRE/ASRM – European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine

NIH/NICHD – National Institutes of Health/National Institute of Child Health and Human Disease

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PCOS PCOS PCOS PCOS –––– Diagnosis 2018Diagnosis 2018Diagnosis 2018Diagnosis 2018

International EBM Guideline for Assessment and Management of PCOS

PCOS 2018 PCOS 2018 PCOS 2018 PCOS 2018 –––– What are Irregular CyclesWhat are Irregular CyclesWhat are Irregular CyclesWhat are Irregular Cycles

First year postmenarche – irregular is normal

1-3 years postmenarche - < 21 or > 45 days

> 3 years postmenarche - < 21 or > 35 days

> 1 years postmenarche - > 90 days for any one cycle

Primary amenorrhea by age 15 or > 3 years post thelarche

For adolescent with irregular cycles – PCOS assessment should be individualized

Adolescents with PCOS features – consider reassessment 8 years postmenarche

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PCOS 2018 PCOS 2018 PCOS 2018 PCOS 2018 –––– What is Clinical HyperandrogenismWhat is Clinical HyperandrogenismWhat is Clinical HyperandrogenismWhat is Clinical Hyperandrogenism

Adults – Acne, Alopecia or Hirsutism

Adolescents – Severe acne or hirsutism

Hirsutism – modified Ferriman Gallwey Score

(� 4 � 6�

Alopecia – Ludwig score

Perception more important than severity


PCOS 2018 PCOS 2018 PCOS 2018 PCOS 2018 –––– What is Biochemical What is Biochemical What is Biochemical What is Biochemical HyperandrogenismHyperandrogenismHyperandrogenismHyperandrogenism

Assessment most useful when clinical hyperandrogenism unclear

Calculated free testosterone, free androgen index, or bioavailable testosterone recommended

Use upper limits of reference ranges

DHEAS and androstenedione have limited role

Must be off hormonal contraception for at least 3 months for valid assessment

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Normal ovary with volume ≥ 10 mL

≥ 20 follicles between 2-9 mm in ovaryEndovaginal ultrasound

8MHz or higher frequency transducer

If < 8 years since menarche, ultrasound should NOT be used to diagnose PCO

Ultrasound is not necessary if diagnosis made based on irregular cycles and hyperandrogenism

Especially if not sexually active


PCOS 2018 PCOS 2018 PCOS 2018 PCOS 2018 –––– What is a Polycystic OvaryWhat is a Polycystic OvaryWhat is a Polycystic OvaryWhat is a Polycystic Ovary

PCOS PCOS PCOS PCOS 2018 2018 2018 2018 –––– What about AntiWhat about AntiWhat about AntiWhat about Anti----Müllerian Hormone (AMH)Müllerian Hormone (AMH)Müllerian Hormone (AMH)Müllerian Hormone (AMH)

1. Dumont A et al. Reprod Biol and Endocrinol 2015;13:137-47

2. International EBM Guideline for Assessment and Management of PCOS

AMH 4.9 ng/ml – 97% specific and 92% sensitive for PCOS 1

Additional studies demonstrated lower Sensitivity and Specificity

2018 – Should not yet be used for diagnosis of PCOS 2

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PCOS PCOS PCOS PCOS –––– Diagnosis Summary Diagnosis Summary Diagnosis Summary Diagnosis Summary –––– Stepwise FashionStepwise FashionStepwise FashionStepwise Fashion

History and Physical

Irregular cycles

Hirsutism, Acne, Alopecia

Exclusion of Other Causes

TSH, FSH

Prolactin

Total Testosterone

17-hydroxyprogesterone

Biochemical Hyperandrogenism

Bioavailable Testosterone, FAI or Free testosterone above reference

Imaging

EndovaginalUltrasound

Making diagnosis helpful but not criticalDo not try to remember definitions such as irregular cycles or hirsutism

Use the duck test

More important to exclude other etiologiesThyroid dysfunction

Hyperprolactinemia

Congenital Adrenal Hyperplasia

Androgen secreting neoplasms (T usually > 2-fold upper range)

Ultrasound helpful but not criticalMust be endovaginal and sufficient frequency

Request ovarian volume and number of follicles per ovary

Duck Test

If it looks like a duck, swims like a duck, and quacks like a duck, then it probably is a duck

PCOS PCOS PCOS PCOS –––– Diagnosis Take Home PointsDiagnosis Take Home PointsDiagnosis Take Home PointsDiagnosis Take Home Points

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PCOS 2018 PCOS 2018 PCOS 2018 PCOS 2018 –––– Lifestyle InterventionsLifestyle InterventionsLifestyle InterventionsLifestyle Interventions

3/4 of patients with PCOS are obese 1

Healthy lifestyle behaviours encompassing healthy eating and regular physical activity to be recommended to all PCOS patients

5-10% weight loss in those with excess weight is considered successful weight loss within 6 months

Assess weight at every visit or at least every 6-12 monthsNeed to be respectful and considerate

Explain purpose and rationale, and implications of results

SMARTSpecific, Measurable, Achievable, Realistic and Timely

www.pacificfertility.ca15

Yildiz BO et al. J Clin Endocrinol Metab, 2008. 93:162-8

PCOS 2018 PCOS 2018 PCOS 2018 PCOS 2018 –––– Lifestyle Lifestyle Lifestyle Lifestyle InterventionsInterventionsInterventionsInterventions

No evidence for specific diet resulting in greater weight loss over another

Low carb and low fat diets appear to have similar results

500-750 kcal/day reduction (or 1200-1500 kcal/day diet) to effect weight loss

150 minutes moderate exercise/week (or 75 minutes vigorous) with 2 muscle strengthening activities on non-consecutive days to MAINTAIN weight

250 minutes moderate exercise/week (or 150 minutes vigorous) with 2 muscle strengthening activities on non-consecutive days to LOSE weight

Johnston BC et al. JAMA, 2014. 312: 923-33


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PCOS PCOS PCOS PCOS –––– Preconception Preconception Preconception Preconception Interventions Interventions Interventions Interventions –––– EvidenceEvidenceEvidenceEvidence

Obese (BMI > 29) age 18-39 infertile women

RCT to lifestyle intervention for 6 months before treatment vs immediate fertility treatment

Primary outcome

Vaginal birth of healthy singleton at term within 24 months of randomization

Mutsaerts MAQ et al. N Engl J Med 2016;374:1942-1953

PCOS PCOS PCOS PCOS –––– Preconception InterventionsPreconception InterventionsPreconception InterventionsPreconception Interventions

Intervention Group

N = 289

Control Group

N = 285RATE RATIO

Anovulation 128 (44.3%) 141 (49.5%)

Vaginal Birth Healthy Live

Singleton76 (27.1%) 100 (35.2%) 0.77 (0.60-0.99)

Live Birth 123 (43.9%) 153 (53.9%) 0.82 (0.69-0.97)

Natural Conception 73 (26.1%) 46 (16.2%) 1.61 (1.16-2.24)

Ovulation Induction 34 (12.1%) 64 (22.5%) 0.54 (0.37-0.79)

Mutsaerts MAQ et al. N Engl J Med 2016;374:1942-1953

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PCOS PCOS PCOS PCOS 2018 2018 2018 2018 ---- InfertilityInfertilityInfertilityInfertility

How to best diagnose and treat the infertile PCOS

patient

PCOS PCOS PCOS PCOS 2018 2018 2018 2018 –––– Assessment and Treatment of InfertilityAssessment and Treatment of InfertilityAssessment and Treatment of InfertilityAssessment and Treatment of Infertility

Confirm Oligo-or anovulationMenstrual cycle intervals < 21 or > 35 days

Midluteal progesterone < 10 nM

Semen testing recommendedRepeat if abnormal

Refer if total motile count (TMC) persistently < 10 million

TMC = (Volume (mL) X Motility (%) X Conc (106/mL)/100

Tubal patency testing optional - based on risk factorsPrior abdominal or pelvic sepsis

Prior abdominal or pelvic surgery

Recurrent acute pelvic pain

History of STI or PID

Endometriosis


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PCOS 2018 PCOS 2018 PCOS 2018 PCOS 2018 –––– Treatment of InfertilityTreatment of InfertilityTreatment of InfertilityTreatment of Infertility

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PCOSPCOSPCOSPCOS----Ovulation InductionOvulation InductionOvulation InductionOvulation Induction

Clomiphene Citrate

Selective Estrogen Receptive Modulator (SERM)

Shown to induce ovulation in 1961

Ovulation rates of 70-80%

Pregnancy rates of 30-40%

Twin pregnancy rates 5-7%

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Letrozole

Aromatase inhibitor

Adjuvant treatment estrogen receptor positive breast cancer

First described in 2000 for ovulation induction

Number of small studies showing similar success to clomiphene

Mitwally MF et al. Reprod Technol 2000. 10:244-47


Metformin

Oral biguanide/insulin sensitizer

Has been used alone, or in conjunction with clomiphene

Initial studies

Ovulation rates 90% with metformin and clomiphene

Ovulation up to 75% with metformin and clomiphene in clomiphene resistant patients

Nestler JE et al, 1998. N Engl J Med; 336: 1876-1880

Vandermolen DT et al, 2001. Fertil Steril; 75: 310-315

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PCOS PCOS PCOS PCOS –––– Ovulation InductionOvulation InductionOvulation InductionOvulation Induction

Practical questions

What drug is best

How do I use the drugs

How do I monitor for effectiveness

How should I counsel my patients

PPCOS I PPCOS I PPCOS I PPCOS I ----Ovulation InductionOvulation InductionOvulation InductionOvulation Induction

Clomiphene

N = 209

Metformin

N = 208

Combination therapy

N = 209

Ovulation 49.0% 29.0% 60.4%

Conception 29.7% 12.0% 38.3%

Pregnancy 23.9% 8.7% 31.1%

Twins 4.0% 0% 3.1%

Live Birth 22.5% 7.2% 26.8%

Legro R et al., N Eng J Med; Feb 8, 2007

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PPCOS 2 PPCOS 2 PPCOS 2 PPCOS 2 ----Ovulation InductionOvulation InductionOvulation InductionOvulation Induction

Clomiphene

N = 376

Letrozole

N = 374P value

Ovulation 48.3% 61.7% <0.001

Conception 35.8% 46.5% <0.007

Twin birth 6.9% 3.9% 0.49

Live Birth 19.1% 27.5% 0.007

Legro R et al., N Eng J Med; July 10, 2014

PCOS PCOS PCOS PCOS –––– Ovulation inductionOvulation inductionOvulation inductionOvulation induction

How to Use the Ovulation Induction Medications

Drug Letrozole Clomiphene

Initial dose 2.5 mg daily 50 mg daily

Dosing regimen Cycle day 3-7 (5 days)

Recommended maximum cycles 6 ovulatory cycles

Confirmation of ovulation Cycle day 21-23 progesterone > 10 nM

Indication for dosage increase Absence of ovulation

Dosage increase 2.5 mg daily increment 50 mg daily increment

Maximal daily dose 7.5 mg daily 150 mg daily

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PCOS PCOS PCOS PCOS –––– Ovulation InductionOvulation InductionOvulation InductionOvulation Induction

Practical Points

Remind intercourse timing – one of:

Ovulation predictor kits

Day before and day of ovulation best chance of conception

Kits typically positive 1-2 days before ovulation

7% false positive rate

Intercourse every other day from cycle day 10-20

Greater frequency neither helpful or harmful

Multiple pregnancy rate

4-7% twins

Higher order multiples <1%

PCOS and Infertility PCOS and Infertility PCOS and Infertility PCOS and Infertility –––– When When When When to to to to ReferReferReferRefer

Male factor – TMC < 10 million/ml

Refer to urology

Failure to conceive after 6 ovulatory cycles

Refer to Fertility Specialist

Fallopian Tube disease/obstruction

Refer to Fertility Specialist or OBGYN

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PCOS PCOS PCOS PCOS –––– Persistent AnovulationPersistent AnovulationPersistent AnovulationPersistent Anovulation

Refer to Fertility Specialist

Management Options

Addition of Metformin to oral ovulation induction agents

Laparoscopic ovarian drilling

Gonadotropins

IVF

Reserved for resistance to ovulation induction with oral agents

4-8 cautery holes per ovary at 40 W

Similar live birth rate to gonadotropins

Lower multiple pregnancy rates

OR 0.13

C Farquhar et al. Cochrane Database Syst Rev. 2012 Jun 13;(6):CD001122

PCOS PCOS PCOS PCOS –––– Laparoscopic Ovarian DrillingLaparoscopic Ovarian DrillingLaparoscopic Ovarian DrillingLaparoscopic Ovarian Drilling

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PCOS PCOS PCOS PCOS –––– Pharmacotherapy for NonPharmacotherapy for NonPharmacotherapy for NonPharmacotherapy for Non----Fertility IndicationsFertility IndicationsFertility IndicationsFertility Indications

Symptomatology Management

Irregular menstrual cycles

Hyperandrogenic symptoms

Medications Commonly Used

Combined Oral Contraceptive Pill (COCP)

Metformin

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COCP

Management of irregular cycles

Risk reduction for endometrial cancer

Management of hyperandrogenic symptoms

Requires at least 6 months

May consider addition of antiandrogens if not effective after > 6 months of therapy

Requires continuation of COCP to prevent unwanted conception

May be used for adolescents as well as adults for symptom control



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Metformin (in addition to lifestyle)

Reduction in weight and BMI with those with starting BMI > 25 kg/m2

Off-label usage

Need to review incidence of GI side effects and possibility of low B12 levels with long-term use



PCOS PCOS PCOS PCOS –––– LongLongLongLong----Term Risk AssessmentTerm Risk AssessmentTerm Risk AssessmentTerm Risk Assessment

Cardiovascular Disease

Diabetes Mellitus 2 and Impaired Glucose Tolerance

Endometrial Hyperplasia and Endometrial Cancer


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PCOS PCOS PCOS PCOS –––– Risk Assessment Risk Assessment Risk Assessment Risk Assessment –––– Cardiovascular DiseaseCardiovascular DiseaseCardiovascular DiseaseCardiovascular Disease

Well-defined longitudinal cohorts with and without PCOS lacking

Focus on CVD risk factors rather than clinical events

Systematic review of 6 retrospective and 1 prospective study

No differences in

Myocardial infarction

Stoke

Coronary artery disease

Consensus Recommendations

Annual BMI and BP assessments

Assessment for cardiovascular risk factors and global CVD risk

Overweight and Obese PCOS to have fasting lipid profile



PCOS 2018 PCOS 2018 PCOS 2018 PCOS 2018 –––– Risk Assessment Risk Assessment Risk Assessment Risk Assessment –––– DM2, DM2, DM2, DM2, IGTIGTIGTIGT

DM2 and IGT increase in PCOS, independent of obesity

2.5-fold for IGT

4-fold for DM2

Baseline screening for all PCOS patients

Fasting glucose or HgA1C

Every 1-3 years after, based on risk factors

BMI > 25

BMI > 23 for Asian population

Acanthosis nigricans

Family History

Consider 75g-OGTT for high risk


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PCOS 2018 PCOS 2018 PCOS 2018 PCOS 2018 –––– Risk Assessment Risk Assessment Risk Assessment Risk Assessment ---- Endometrial Endometrial Endometrial Endometrial CancerCancerCancerCancer

PCOS 2018 PCOS 2018 PCOS 2018 PCOS 2018 –––– Risk Assessment Risk Assessment Risk Assessment Risk Assessment ---- Endometrial CancerEndometrial CancerEndometrial CancerEndometrial Cancer

Risk Factors for Endometrial Cancer (EC)

Obesity

Unopposed Estrogen

Infertility

Hypertension

Type 2 Diabetes

2.9- fold greater risk of EC with PCOS

9% Absolute Lifetime Risk

Barry JA et al. Hum Reprod Update. 2014; 20:748-58.

Haoula Z etal. Hum Reprod 2012; 27:1327-31

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PCOS 2018 PCOS 2018 PCOS 2018 PCOS 2018 –––– Risk Assessment Risk Assessment Risk Assessment Risk Assessment –––– Endometrial CancerEndometrial CancerEndometrial CancerEndometrial Cancer

Routine Screening for Endometrial Cancer not warranted

Should have a low threshold for investigation of endometrial cancer in PCOS

Recommend endometrial biopsy when:

Persistent thickened endometrium

Prolonged amenorrhea

Abnormal vaginal bleeding

Increased BMI increases risk

Optimal prevention for endometrial Cancer and hyperplasia not known

OCP or progestin therapy when cycles longer than 90 days



PCOS 2018 PCOS 2018 PCOS 2018 PCOS 2018 –––– Endometrial Hyperplasia Endometrial Hyperplasia Endometrial Hyperplasia Endometrial Hyperplasia ---- TreatmentTreatmentTreatmentTreatment


Chandra V et al. Gynecol Oncol. 2016 Jan; 27(1): e8

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PCOS PCOS PCOS PCOS –––– Final ThoughtsFinal ThoughtsFinal ThoughtsFinal Thoughts

Much remains to be understood about the genetics and phenotypic heterogeneity of PCOS

PCOS is a diagnosis based on consensus

“New scientific ideas never spring from a communal body, however organized, but rather from the head of an individually inspired researcher who struggles with his problems in lonely thought and unites all his thought on one single point which is his whole world for the moment”

Max Planck, Nobel Prize, Physics

There is no such thing as consensus science. If it's consensus, it isn't science. If it's science, it isn't consensus. Period.”

Michael Crichton, MD

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new guidelines for polycystic ovary syndrome · international ebm guideline for assessment and...

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