Igno Siebert University of S bosch Aevitas clinic at Vincent Pallotti

Igno Siebert University of S bosch Aevitas clinic at Vincent Pallotti

Definitions Emphasis on Lifestyle/weight loss Current of evidence of each modality Suggested algorithm/current opinion

Rotterdam statement 2003 - oligo-anovulation - PCO - Hyperandrogenism with the exclusion of CAH, Cushing s, adrenal, Thyroid and Prolactin abnormalities.

NIH 90 (oligo-anovulation/high androgens) 06 AES ( NOT PCO + oligo-anovulation)

1 st Lifestyle

5-10% Weight loss = 80% OVULATION Weight loss pre pregnancy: - decrease GDM - decrease pregnancy complications - miscarriage

0.00 1.00 ovulbin Means 2.00 2.50 3.00 3.50 sqrtfstg 20.00 30.00 40.00 bmi

Hurdles: Drop out: Moran 09 = 30-35% Annchen Weideman TBH = 50-60% Diet : - Calorie restriction - GI vs GL - Trans fatty intake

Support - spouse - follow up Lifestyle

Limit liquid fructose to 20gr/day 3 fruits/day ( 25gr/day) ++ water High quality proteien with meals Exercise Only successful after the 3 rd visit 60% dropout Dietician

Bariatric surgery :if all else fail BMI > 40 BMI > 35 with a co morbidity Time to pregnancy! Lifestyle!

It is a recommendation of the Rotterdam ESHRE/ASRM consensus meeting that women with PCOS and a BMI in excess of 27 kg/m 2, should undergo a glucose tolerance test and a metabolic screen.

Risk factor Cut off 1. Abdominal obesity (waist circumference) >88cm 2. Triglycerides 150mg/dL /1.8mmol/L 3. HDL cholesterol <50mg/dL /<1.3mmol/L 4. Blood pressure 130/85mmHg 5. Fasting and 2-h glucose from oral GTT Fasting glucose 110-126mg/dL or 6-7mmol/L, 2-h glucose 140-199mg/dL or 7.8-11.1mmol/L

1 st drug of choice? Role of metformin? Role of ovarian drilling? Role of gonadotrophins?

Most common drug/1 st line Anti oestrogen/oestrogen receptor Start with the lowest dose: OHSS 25mg 150mg max 80% ovulation rate

Monitor EL/ Cx mucous quality Follicle development, day 21 Monitor ovulation with LH levels

Aromatase inhibitor Androgens to oestrone/e2 Increases gonadotrophin production NO effect on oestrogen receptors Mono follicle development

Biljan 05 (150pt s)?? Cong cardiac/bone abn 05 Novartis: NOT for OI Off-label indication for OI Tulandi and Casper 06 No increase risk 911 babies

26 RCT s Not better than ovarian drilling? Improved preg rates vs CC Not good data

Inform pt off-label indication/international As effective as CC 2,5mg=7,5mg for mono OI?Use when CC and metformin not successful?use if thin EL and poor mucous on CC

1 st drug of choice? Role of metformin? Role of ovarian drilling? Role of gonadotrophins?

Insulin sensitizer Biguanide (2 nd generation) Extensively studied 95 Side effects - GIT effects( Fleming 30% stopped Rx)

IS METFORMIN INDICATED AS PRIMARY OVULATION INDUCTION AGENT IN WOMEN WITH PCOS? A SYSTEMATIC REVIEW AND META-ANALYSIS 12

Statistically significant difference between the 2 groups, in favour of the combination

Significant increase in pregnancy rate in the group of patients treated with the combination (CC+M)

No Non-significant difference when the combination was compared to Clomid alone

THE EFFICACY OF METFORMIN FOR OVUALTION INDUCTION IN CLOMIPHENE-RESISTANT PCOS WOMEN: A SYSTEMATIC REVIEW 06

Not a 1 st line Definitely indicated in CC-resistance Addition to lifestyle to loose weight? With IVF/ICSI: lower OHSS/improve preg rates Current data: stop when pregnant

1 st drug of choice? Role of metformin? Role of ovarian drilling? Role of gonadotrophins?

RCOG Grade A Guidelines : Women with PCOS who have not responded to clomifene citrate should be offered laparoscopic ovarian drilling because it is as effective as gonadotrophin treatment.

No significant differences: laparoscopic ovarian drilling after 6-12m follow-up vs 3-6 cycles of ovulation induction with gonadotrophins in: cumulative pregnancy (OR 1.42; 95% CI 0.84 to 2.42 miscarriage rate (OR 0.61; 95% CI 0.17 to 2.16) Farquhar C, Vandekerckhove P, Lilford R. Laparoscopic "drilling" by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome (Cochrane Review). In: The Cochrane Library, Issue 3, 2004

A retrospective study showed that three punctures per ovary appeared to be the plateau dose for laparoscopic ovarian diathermy 3-5 punctures/30watts/5seconds/anti mesenteric side/fine needle Amer SAK, Li TC, Cooke ID. Laparoscopic ovarian diathermy in women with polycystic ovarian syndrome: a retrospective study on the influence of the amount of energy used on the outcome. Hum Reprod 2002;17:1046 51.

200 patients BMI>35 Serum Testosterone >4,5nmol/l Free androgen index >15 Duration of infertility > 3 years Amer SAK, Li TC, Ledger WL. Ovulation induction using laparoscopic ovarian drilling in women with polycystic ovarian syndrome: predictors of success. Hum Reprod 2004;19(8):1719-1724.

Cumulative preg rate 86% vs 81% Cumulative rate for 2 nd child 61% vs 46% Twins 5% vs 8% None in the menopause Ectopics 5/175 vs 3/159

C/C resistant Drilling as effective as gonadotrophins - ovulation - live birth rates BUT: adhesions/use fine needle/?long term effect/invasive procedure/predictors of success Human Reproduction: 2011

1 st drug of choice? Role of metformin? Role of ovarian drilling? Role of gonadotrophins?

As effective as drilling NB OHSS/GnRH analogue trigger Low dosage step up protocol Fertility specialist? IVF/ICSI

Controversy persists in the diagnosis of PCOS AMH emerges as a marker of the severity of symptoms

FERTILITY IN PCOS: OVULATION INDUCTION Lifestyle modification before ovulation induction in obese PCOS cases Clomiphene citrate is still the medical treatment of first choice Aromatase inhibitors are as effective, but more safety data are needed Metformin alone is less effective than clomiphene for inducing ovulation The addition of metformin to clomiphene may be indicated in C/C resistance

Gonadotrophins in low-dose protocols aiming for monofollicular development represent an effective treatment option Laparoscopic ovarian drilling is as effective as gonadotrophins for ovulation induction and pregnancy, with lower risk of multiples IVF is a reasonable option,

1 st Weight loss Role of metformin 2 nd Clomid/? Femara 3 rd Drilling vs gonadotrophins 4 th IVF/ICSI

Myo-inositol is isoform of inositol Role in glucose metabolism Lowering insulin levels Intra cellular activity- better quality oocytes Pre treat: 4gr myo inositol + folic acid (30 days) Future : PRCT metformin vs inofolic

Metformin: RJ Norman;Human Reproduction 2009 14 trials, metformin vs placebo Favours metformin 1,5gr for longer than 8weeks Additional 2,9% weight loss, BMI > 35 Orlistat: Padwal 2003 Prevent uptake of lipids in diet: Taken for 1 year 2,9% additional weight loss

Sibutramine: Padwal and Makumbar2007 Oral anorexiant; Taken for 1 year 4,6% additional weight loss Taken off most markets- strokes

OVULATION INDUCTION IN PCOS: PROSPECTIVE RANDOMIZE CONTROL TRIAL 09

Bayar 06 (Femara vs C/C) No difference EL No difference in ovulation/preg Badawy 07 Ideal dose: no difference for mono OI

From the scatterplot one can see that all women with BMI <=27 ovulated. Except for two women all women with fasting glucose <(2.2)*(2.2)=4.84 units ovulated. This gives a sensitivity for this simple cutpoints are 66% for ovulation and a specificity of 88% for non-ovulation. Drawing non-linear boundry around the nonovulation group sensitivity can be 78% and specificity 82% which is reasonable for practical use. The number of non-ovulation women is actually so small that the estimates linked (specificity) to this group is not reliable they have to be at least 50 women with unsuccessful ovulation.

Fructose contents Sucrose (50 %) HFCS (55 90 %) Fruit juice (75 %) 16 20 g /day stimulates glucokinase OGTT + 7.5 g fructose = improved glycaemic response in type 2 diabetes Westernization of diets?? fructose intake to 85 100 g / day

Post-prandial rise TG within 24 hrs short-term studies Earliest metabolic perturbation Evidence that post-p rise TG may specifically promote lipid deposition in visceral fat ApoB degradation drop when hepatic lipid content rise [ApoB] rise by 25 % in subjects consuming high fructose Stanhope & Havel, 2008

1 st - Weight loss 2 nd - Clomid Role of metformin 3 rd - Laparoscopic ovarian drilling vs Gonadotrophins 4 th - IVF/ICSI

General advice Lifestyle advice C/C 50-150mg Ovulation resistant ADD Metformin If pregnant, -Stop metformin?, not sufficient data Screen for gestational diabetes later in pregnancy Not effective after 6 months Letrozole or earlier Consider ovarian drilling Consider assisted conception New, immature aspiration

53 % Reduction in Ovulation when Metformin was used compared to Clomid alone

53 % Reduction in LBR in the group treated only with Metformin

PCOS most common endocrinopathy 5-10% of reproductive age Etiology remains unclear/ INSULIN Definitions

This leaves one with the question of how much weight loss should be aimed for. Hollmann et al. as well as Clark and co-workers, proved that only a small amount of weight loss is needed for resumption of ovulatory function. 2 5 % reduction of body weight was associated with restoration of ovarian function, an 11 % reduction of abdominal fat, a 4 cm waist circumference reduction and the added benefit of a 71% increase in insulin sensitivity. Diabetic prevention trial: metformin vs lifestyle

Herriot et al. (2008) Subjective, debilitating symptoms Understanding symptom profile : CHO cravings (sugar & starch) Similar incidence in all PCOS Central weight gain Hypoglycaemia More frequent in lean General lethargy/chronic fatigue 82 % of all PCOS Urgent sense of hunger IBS/food intolerance 68 % all PCO Symptoms improved with lowered glycaemic load

betref is daar ook n persepsie dat one size fits all wat versterk is deur die media wat so baie crap oor dieët en gewigsverlies sensasionaliseer. 3. Oorgewig PCOS pasiënte toon duidelike versteurings in honger en versadigings-cues (mooi beskryf in die literatuur), sodat kalorie-beperking vir hulle eintlik pynlik is om te verdra, en hulle is bang daarvoor. a. Derhalwe my spesifieke riglyne van proteïen-insluiting ens. b. GI is nog nooit gewys om enige utility in PCOS te hê nie, alhoewel daar n wydverspreide geloof bestaan dat PCOS lyers dadelik op n lae GI dieët moet gaan. Dit lei tot verhoogde koolhidraat-inname met swak prognose vir verbetering van insulienweerstandigheid. GL (glycaemic load) is waarskynlik die belangrikste aspek om aan te spreek, op n individuele basis. 4. Die pasiënte wat die beste doen is die wat onbevooroordeeld is, en die ondersteuning van hulle spouses het

Human Reproduction 2011/vol26 Long term effects 8-12 year follow up Drilling vs gonadotrophins Pregnancy /menopause

Cumulative preg rate 86% vs 81% Cumulative rate for 2 nd child 61% vs 46% Twins 5% vs 8% None in the menopause Ectopics 5/175 vs 3/159

Human Reproduction 2011/vol26 Long term effects 8-12 year follow up Drilling vs gonadotrophins Pregnancy /menopause