Post on 27-Sep-2020
6/24/2019
1
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
6/24/2019
2
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
6/24/2019
3
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
5
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
6/24/2019
4
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
8
International EBM Guideline for Assessment and Management of PCOS
6/24/2019
5
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
International EBM Guideline for Assessment and Management of PCOS
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
10
International EBM Guideline for Assessment and Management of PCOS
6/24/2019
6
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
International EBM Guideline for Assessment and Management of PCOS
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
6/24/2019
7
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
6/24/2019
8
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
International EBM Guideline for Assessment and Management of PCOS
6/24/2019
9
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
6/24/2019
10
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
International EBM Guideline for Assessment and Management of PCOS
6/24/2019
11
PCOS 2018 PCOS 2018 PCOS 2018 PCOS 2018 –––– Treatment of InfertilityTreatment of InfertilityTreatment of InfertilityTreatment of Infertility
21
International EBM Guideline for Assessment and Management of PCOS
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%
6/24/2019
12
PCOSPCOSPCOSPCOS----Ovulation InductionOvulation InductionOvulation InductionOvulation Induction
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
PCOSPCOSPCOSPCOS----Ovulation InductionOvulation InductionOvulation InductionOvulation Induction
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
6/24/2019
13
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
6/24/2019
14
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
6/24/2019
15
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
6/24/2019
16
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
6/24/2019
17
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
33
International EBM Guideline for Assessment and Management of PCOS
PCOS PCOS PCOS PCOS –––– Pharmacotherapy for NonPharmacotherapy for NonPharmacotherapy for NonPharmacotherapy for Non----Fertility IndicationsFertility IndicationsFertility IndicationsFertility Indications
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
www.pacificfertility.ca34
International EBM Guideline for Assessment and Management of PCOS
6/24/2019
18
PCOS PCOS PCOS PCOS –––– Pharmacotherapy for NonPharmacotherapy for NonPharmacotherapy for NonPharmacotherapy for Non----Fertility IndicationsFertility IndicationsFertility IndicationsFertility Indications
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
www.pacificfertility.ca35
International EBM Guideline for Assessment and Management of PCOS
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
www.pacificfertility.ca36
6/24/2019
19
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
www.pacificfertility.ca37
International EBM Guideline for Assessment and Management of PCOS
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
International EBM Guideline for Assessment and Management of PCOS
6/24/2019
20
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
6/24/2019
21
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
www.pacificfertility.ca41
International EBM Guideline for Assessment and Management of PCOS
PCOS 2018 PCOS 2018 PCOS 2018 PCOS 2018 –––– Endometrial Hyperplasia Endometrial Hyperplasia Endometrial Hyperplasia Endometrial Hyperplasia ---- TreatmentTreatmentTreatmentTreatment
www.pacificfertility.ca42
Chandra V et al. Gynecol Oncol. 2016 Jan; 27(1): e8
6/24/2019
22
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
43