Diagnosis and Treatment of PCOS Nick Macklon University Medical Centre Utrecht The Netherlands
PCOS - diagnostic dilemma’s - Endocrine features high androgens high LH insulin resistance Clinical features hirsutism obesity anovulation Polycystic ovaries increased follicle # increased stroma increased ovarian volume
PCOS diagnosis - 1990 NIH criteria - Hyperandrogenemia PCOS Chronic anovulation
Epidemiology of PCOS Population/ethnicity sample size PCOS reference Greek Island, Lesbos 192 NIH Diamanti, JCEM 99 17-45 yrs 6.8% Caucasian, reproductive age 154 NIH Asuncion, JCEM 00 Blood donors, Spain 6.5% Preemployment physical, US 400 NIH Azziz, JCEM 04 18-45 yrs (223 black, 166 white) 6.6% Knochenhauer, JCEM 98
Why Revisit the NIH Criteria? First step to standardizing diagnosis Based on Questionnaire PCOS -broader spectrum of ovarian dysfunction -regular cycles and hyperandrogenism and/or PCO -PCO without hyperandrogenism May not be suitable for trials of clinical outcomes
ESHRE / ASRM endorsed PCOS Consensus Meeting Rotterdam, The Netherlands Azziz Laven Bouchard Dewailly Legro Nestler Diamanti Pasquali Ibanez Balen Dahlgren Homburg Wild Norman Franks Wild Tan Dunaif Devoto Strauss Taylor Pugeat Filicori Magoffin Fauser Tarlatzis Rotterdam, May 2003
Revised Diagnostic Criteria for PCOS 1999 NIH Criteria (both 1 and 2) 1. Chronic anovulation 2. Clinical and/or biochemical signs of hyperandrogenism Exclusion of other aetiologies Revised 2003 Rotterdam Criteria (2 and of 3) 1. Oligo- and/or anovulation 2. Clinical and/or biochemical signs of hyperandrogenism 3. Polycystic ovaries Exclusion of other aetiologies
PCOS diagnostic criteria Exclusion of other causes of androgen excess Cushing, 21 hydroxylase deficiency androgen producing tumours Exclusion of other causes of anovulation Hypogonadotropic hypogonadism Premature ovarian failure Hyperprolactinaemia Often obesity (but not required) Often elevated LH (but not required) Often hyperinsulinemia (but not required)
PCOS - hyperandrogenemia - Clinical: Acne Hirsutism Biochemical: Testosterone total or free (unbound) Free androgen index (T x 100 / SHBG) Androstenedione? DHEAS? combination Normative data lacking Subjective May be less prevalent in East Asian Women Variable laboratory methods Wide variability in normal population Normative ranges not well established in well characterized control populations
PCOS - polycystic ovaries - Presence of 12 or more follicles (2-9mm) per ovary. Location not important. Ovarian volume >10mls 0.5 x length x width x thickness Ovarian stroma objective? One ovary sufficient for diagnosis Scan early follicular phase Balen, HRU 2003
1 PCOS Hyperandrogenemia Oligo/anovulation (WHO 2 type) PCO
PCOS phenotypes Oligo/anovulation + + + Hyperandrogenemia + + + NIH Rotterdam additions Oligo/anovulation + + + Hyperandrogenemia + + + PCO + + +
TREATMENT OF PCOS
Ovulation Induction Type of ovarian stimulation aimed at restoring normal fertility by inducing single dominant follicle selection, ovulation and hence normo-ovulatory cycles.
Ovulatory infertility and Obesity Mulders et al. Hum Reprod Update 2003
Impact of obesity of clinical, hormonal and metabolic features of PCOS Hoeger K, Clin Obstet Gynecol, 2007
Ovulation Induction Step 1: Lose weight (Guzick et al., Fertil Steril, 1994) Treatment Controls Total T SHBG SHBG - T Insuline Glucose 90 .9 16 90 120 80 .8 14 80 110 70 .7 12 70 100 60 .6 10 60 90 50 .5 8 50 40 .4 6 40 Pre Post Pre Post Pre Post Pre Post Pre Post
Ovulation Induction Non-steroidal estrogen antagonist Step 2: Clomiphene Citrate Non-steroidal estrogen antagonist Blocks negative feedback of E2 at pituitary 50-150mg from day 2-5 of cycle FSH 50-60% 70-80% ovulate 22% conception rate per cycle Cheap & effective
Ovulation Induction Step 3: Metformin? Step 3: Aromatase inhibitors? Step 3: Electrocautery of ovaries? Step 3: Gonadotropins?
Ovulation Induction 626 women with PCOS Step 3: Add Metformin? Combination of metformin and CC 50-150mg CC plus placebo from cycle day 3-7 500 mg-2000 mg Metformin plus placebo Up to 6 months treatment Obesity not an exclusion Legro et al, NEJM
Ovulation Induction Step 3: Add Metformin? Legro et al, NEJM 2007
Ovulation Induction Step 3: Add Metformin? Tarlatzis etal, Hum Rep 2007
Aromatase Inhibitors E2 E2 FSH FSH AI Day 5 Day 10 ER ER ER ER ER Halflife: 45-48 hours
Aromatase Inhibitors Few RCTS: Badawy et al; No advantage over CC Outstanding questions Impact of low intrafollicular estradiol levels? Impact of intrafollicular androgen accumulation? : positive (via increase in FSH receptors) : negative: androgen excess Impact on oocyte quality? Few RCTS: Badawy et al; No advantage over CC Teratogenicity issues?
Gonadotropin regimens hCG FSH levels FSH dose STEP-UP Protocol window 10mm FSH levels FSHdose hCG STEP-DOWN Protocol menses
Cumulative pregnancy rates after ovulation induction 1 0.8 0.6 Ongoing Singleton Pregnancy Rate Resulting in Live Birth 0.4 0.2 3 6 9 12 15 18 21 24 Follow-up (months) Eikemans et al, Hum Reprod 2003
Electrocautery of ovaries
Ovulation Induction Step 3: Electrocautery of ovaries
Step 4: IVF
IVF in PCOS: Ovarian Stimulation The ‘classical’ long protocol hCG FSH / HMG Luteal support OC GnRH agonist The ‘antagonist’ protocol hCG/GnRHa FSH / HMG GnRH antag Luteal support Cycle day 1
IVF outcomes in women with PCOS (458) vs Controls (694) A meta-analysis. Heijnen et al, Hum Reprod Update, 2006 WMD for number oocytes per ovum pick up WMD for number of oocytes fertilised OR for chance of cancellation OR for chance of live birth per started cycle OR for chance of miscarriage per started cycle
Pregnancy outcomes in PCOS Meta-analysis: 720 women with PCOS vs 4505 controls OR 95% CI Gestational Diabetes: 2.94 1.70-5.08 Pregnancy induced hypertension: 3.67 1.98-6.81 Pre-eclampsia 3.47 1.95-6.17 Pre-term birth 1.75 1.16-2.62 Peri-natal mortality 3.07 1.03-9.21
Conclusions Need for uniform definition Lifestyle as therapy Clomiphene still first line? Gonadotropins versus Laparoscopic electrocautery? Ovulation Induction works! IVF effective- and with appropriate care: safe Role of in-vitro oocyte maturation?