NARENDRA MALHOTRA M.D., F.I.C.O.G., F.I.C.M.C.H• Prof Intermedical International University,Croatia• President FOGSI (2008)• Dean of I.C.M.U. (2008)• Director Ian Donald School of Ultrasound• National Tech. Advisor for FOGSI-G.O.I.—Mc Arthur Foundation EOC Course• Hon Prof Ob Gyn at DMIMS,Sawangi,Advisor ART unit at MAMC & SMS Jaipur• Practicing Obstetrician Gynecologist at Agra. Special Interest in High Risk Obs., Ultrasound, Laparoscopy and Infertility, ART & Genetics• Member and Fellow of many Indian and international organisations• FOGSI Imaging Science Chairman (1996-2000)• Awarded best paper and best poster at FOGSI : 5 times, Ethicon fellowship, AOFOG young gyn. award, Corion award, Man of the year award, Best Citizens of India award• Over 30 published and 100 presented papers• Over 50 guest lectures given in India & Abroad.Presented 15 orations.• Organised many workshops, training programmes, travel seminars and conferences• Editor 8 books, many chapters, on editorial board of many journals• Editor of series of STEP by STEP books• Revising editor for Jeatcoate’s Textbook of Gynaecology (2007)• Very active Sports man, Rotarian and Social worker MALHOTRA HOSPITALS 84, M.G. Road, Agra-282 010 Phone : (O) 0562-2260275/2260276/2260277, (R) 0562-2260279, (M) 98370-33335; Fax : 0562-2265194 E-mail : firstname.lastname@example.org / email@example.com Website : www.malhotrahospitals.com Rainbow Hospitals, Agra Consultant for IVF at jalandhar,ludhiana,ambala,bhiwani,gwalior,allahabad,gorakhpur,bariely,jaipur,delhi,sirsa,varanasi Neapal & Bangladesh NOW AT KANPUR AMBA HOSPITAL
MANAGEMENT OF PCOS IN VARIOUS AGE GROUPS :ADOLESCENT TO PERIMENOPAUSE narendra malhotra jaideep malhotra neharika malhotrawww.malhotrahospitals.comwww.rainbowhospitals.org
Polycystic Ovarian Syndrome (PCOS)• PCOS is a complex endocrine disorder affecting women of childbearing age characterized by increased androgen production and ovulatory dysfunction• PCOS is the leading cause of anovulatory infertility and hirsutism• Women with PCOS have an increased risk of miscarriage, insulin resistance, hyperlipidemia, type 2 diabetes, cardiovascular disease, and endometrial cancer Bauer J, et al. Epilepsy Res. 2000;41:163-167. Dunaif A, et al. Annu Rev Med. 2001;52:401-419. Franks S. N Engl J Med. 1995;333:853-861.
EPIDEMOLOGY• 20-33% of all reproductive age group have PCO• 5-10% of all reproductive age group have PCOS• 87% of women with oligomennorhea• 26% of women with ammenorhoea• 50% of them presenting with infertility• 50% women with recurrent miscarriages
DIAGNOSTIC CRITERIAASRM/EHSRE( Rotterdam consensus 2003) defined PCOS as the presence of 2 out of the following 3 criteria: – Oligo and/or Anovulation, USG Clinical appearance features – Hyperandrogenism – Polycystic ovaries on USG Biochemical (with the exclusion of other etiologies of parameters hyperandrogenism)
CLINICAL MANIFESTATIONSSYMPTOMS ASSOCIATED POSSIBLE LATE ENDOCRINE SEQUALE MANIFETATIONS Obesity(38%) Androgens(29%) Diabetes mellitus(29%)Menstrual disturbance(66%) LH(40%) Cardiovascular diseaseHyperandrogenism(48%) LH:FSH ratio HyperinsulinemiaInfertility (73% of Free estradiol Low LDLanovulatory infertility)Asymptomatic(20%) Fasting insulin Endometrial carcinoma Prolactin(27%) hypertension Sex hormone binding globulin
PCOS-A DISEASE WITH A SPECTRUM OF CLINICAL PRESENTATIONS MENSTRUAL IRREGULARITY. PCO INFERTILITY,OBESITY OVULATORY HIRSUTISM NO HIRSUTISM ACNE,NO DERMATOLOGICAL INSULIN RESISTANCE ATHEROSCLEROSIS GENETICS BMI LIFESTYLE
Genetic basis• No clear cut mode of inheritance• Initial studies suggest x-linked dominant transmission but recent says autosomal dominant inheritance• Risk of developing PCOS is 40% if sister is affected 10%if mother is affected
LAB EVALUATION• SR.TESTOSTERONE/17-OHP/DHEAS• LH/FSH• PROLACTIN No Biochemical test is required for diagnosis• 24HR FREE CORTISOL• SHBG• TESTS FOR INSULIN RESISTANCE
We have to be more careful…• South Asians• Insulin• BMI > 25• More vulnerable
SPECTRUM OF CLINICAL CONDITIONS ASSOCIATED WITH PCOS PCOS ENDOMETRIAL AN CA OVULATIONHYPERTENSION DIABETES INSULIN HIRTUTISM HIRSUTISM RESISTANCE ATHEROSCLEROSIS
MANAGING PCOS: Goals• Identify patients with risks for or with diagnosis of PCOS• Assess patients appropriately for PCOS and associated disease states• Prescribe therapy to treat complaints and prevent sequelae
COUNSELING OF A PCOS PATIENTEndocrine problemsMetabolic problemsInfertilityRisk of OHSS and multiple pregnancyPregnancy complicationsLong term sequelMOST IMP- Importance of life style modification
Any treatment for PCOS should optimally address not only the ovulatory dysfunction and hyperandrogenism, but also the dysmetabolic features such as hyperinsulinemic insulin resistance, obesity, dyslipidemia and abnormal clotting mechanism.Hence the treatment should be for all age groups .
Management• Adolescents• Newly married conception not intended• Married wanting conception• Married has one child wanting spacing• Secondary infertility• Mature woman with completed family• Perimenopausal• Menopausal
HERE IS MISS POLY PCOS CONCERNS are:• Menstrual irregularities• Obesity• Hirsutism• Acne
PROTOCOLS OF MANAGEMENT IN ADOLESCENTS• Counselling for weight reduction and life style modification.• Carbohydrate and fat restricted diet.• Diet restriction and exercise is the sheet anchor of treatment for overweight.• Low glycemic index diet upto 85% will improve menstrual cycle regularity and ovulation in about six months.
• Even 7% weight reduction may lead to spontaneous resumption of menses.• Moderate physical activity, 30-60 minutes per day should be goal of all patient with adolescent PCOS.M.O.A:-• lowers circulating free androgen and insulin levels.• Increases SHBG, thereby decreases level of free testosterone.
MENSTRUAL IRREGULARITIES• Mostly managed by OCP• MPA 10 mg/day or micronized progesterone 300 mg at bedtime for 10 - 14 days effective in Rx of abnormal bleeding.• If oligomenorrhoea and amenorrhoea does not respond to oral contraceptives and antiandrogen combinations, insulin sensitizing agents have to be added.• A lean PCOS may also have insulin resistance and therefore if they do not respond to oral contraceptive dose, insulin sensitizing drug has to be added.
WHY ORAL CONTRACEPTIVE PILLS ? Estrogenic component of the oral contraceptive suppresses luteinising hormone and thus reduces ovarian androgen production. Estrogen also enhances hepatic production of SHBG ,thereby the level of free testosterone declines. Cyproterone acetate, Drospirenone and desogestrel can be used in combination with ethinyl estradiol.
Cyproterone acetate Competitively inhibits the binding of testosterone and also 5α-dihydrotestosterone to the androgen receptor.• Ideal for Hirsut Combination of ethinyl estradiol (0.35 µg) and cyproterone acetate (2mg) PCOS. scientific in is most treating hyperandrogenicity as well as maintaining the menstrual cyclicity.Dose 1 tab. daily from D1 to D21 which has to be repeated cyclically for a period of six months.
DROSPIRENONE• Combination of ethinyl estradiol (30 µg) with Drospirenone (3mg), an analogue of spironolactone with unique antimineralocorticoid and antiandrogenic action has also been used. Ideal for Obese PCOS• Combination of ethinyl estradiol (30 µg) with Desogestrel (20 µg) can also be used.
IMPROVEMENT OF HYPERINSULINEMIA BY INSULIN SENSITIZERS Directly sensitizing insulin receptors. Preventing neoglucogenesis. Reducing absorption of glucose from intestine. Increasing hepatic synthesis of SHBG level thereby reducing the level of bioactive free testosterone.
Metformin Decreases basal hepatic glucose output in patients and lowers fasting plasma glucose concentration. It increases the uptake and oxidation of glucose by adipose tissue as well as lipogenesis. S/E- diarrhoea, nausea, vomiting ,specially initially. To avoid them metformin should be taken with meals and the dose increased gradually. Or SR release formulations are used once a day 1000 mg SR or 500mg SR twice a day
OTHER DRUGS WHICH CAN BE USED• Rosiglitazone ,• Pioglitazone,• D chiro inositol,• Myoinositol• N acetyl cysteine.• Micronutrients
OTHER DRUGS WHICH CAN BE USED IN ADDITION TO O.C.P.• In cases of failure or where there is clinical or biochemical evidence of gross hyperandrogenicity or hyperinsulinemia, addition of metformin is recommended.• Spironolactone- it has antiandrogenic effects in doses 100-200 mg daily.• Finasteride - a competitive inhibitor of Type-2 5a reductase to treat hirsutism. Dose 1-5 mg/day.
COSMETIC TREATMENT• Antiandrogens used in PCOS will prevent further hair growth but the hair which have already grown have to be treated by epilation, waxing, by electrolysis or laser treatments.• Acne may require oral antibiotics like erythromycin and isotretinoin ointment.• Acne also gets cleared in 6-9 months by use of oral contraceptive pills containing cyproterone acetate.
RESPONSE TO TREATMENT IS ASSESSED BY• Resumption of menstrual cyclicity.• Reduction in features of hyperandrogenicity.• Improvement of biochemical parameters like reduction of free serum testosterone and normalization of fasting glucose insulin ratio.
MISS POLY PCOS IS NOW MRS POLY PCOS SHE IS 24 YRS OLD• Newly married not wanting conception• Married wanting conception• Married has one child wants spacing• Secondary infertilityNewer concepts in medical management
HER CONCERNS:•High BMI•Hirsutism•Oligo/amenorrhoeaMOST IMPORTANT : DOESN’T WANT APREGNANCY NOW
Best treatment option- After lifestyle modification ORAL CONTRACEPTIVE PILLS Prefer third generation pills like •Drosperinone containing pills •Cyproterone acetate containing pills •Low dose estrogen newer progesterone pills Advantages: •Cycle regularisation •Effective contraception •No weight gain •Control androgenic symptoms
PCOS – Treatment Algorithm ESHRE/ASRM consensus workshop Preconception counseling*on life style modification 1st line Clomiphene Citrate(CC) Ovulation Ovulation 2nd line Gonadotropin or LOS Ovulation 3rd line IVFSuccess rates: •Metformin- only in cases withLOS alone effective in <50% cases glucose intoleranceCC-Gonadotropin paradigm – 70% •Aromatase inhibitors- insufficient evidence to be recommended *(wt reduction and exercise) Fertil Steril 2008;89:505-22
1 CC binds to ER and depletes receptor concentrations Depletion of ER in pituitary Hypothalamus and hypothalamus due to Pituitary3 prolonged stimulation FSH stimulation continues 2 estrogen –ve feedback Estrogen feedback loop gets interrupted interrupted FSH secretion increased leading to multiple follicle growth 4 More smaller follicles are rescued Peripheral anti estrogenic effect 5 Multiple follicles develop Longer half life
3 Releases off -ve feedback Inhibits aromatase in ovaries and stimulation peripheral tissues reducing estrogen 4 GnRH released Hypothalamus levels Pituitary Negative feed back being active released, stimulates hypothalamus- FSH stimulation pituitary axis 5 GnRH release produces FSH Falling FSH estrogen –ve feedback FSH-mediated stimulation of follicle 2 Rising estrogen level from follicle suppresses FSH leaving a single dominant-follicle Smaller follicles undergo atresia 16 Single follicle develop androstenedione estrogen aromatase inhibition
PCOS• Stimulation in PCOs is a problem• Response is not predictable• Dose is not predictable• Number of days of stimulation is not predictable.• Control over the cycle is difficult.• OHSS is a real problem.
Laparoscopic Ovarian Drilling WHO BENEFITS FROMMechanism LEOS • ?Removalresistant, CC androgen-producing tissueProblems Slim, Anovulatory , • Hazards of laparoscopic surgery & GA (although rare) raised S.LH • TemporaryEfficacy • <50% clomiphene-resistant women conceive (ovulation rate 80%+) • Hormone profile returns to normal • ?Fewer miscarriages compared to gonadotrophin injection treatment
OVULATION INDUCTION REGIME IN PCOS• OC Pill pretreatment (1-2 cycle)• Long protocol• Antagonist protocol• Lower than usual starting dose• FSH preferable to hMG• Close follicular monitoring• Serum estradiol whenever required• Close vigilance for OHSS
RESPONSE OF PCOS TO STIMULATION• Poor responders/ hyper-responders• Decreased fertilization rate• Cleavage rate same• Pregnancy rate same• Live birth rate same• OHSS risk increased• High order multiple increased
GnRH Agonist with low dosegonadotropin in• High serum LH•Repeated prematureleutinisation•Do not conceive withgonadotropin alone•Early miscarriage on morethan one occasion
The ideal Indian protocol 5000 hCG 0.25 mg antagonist/day 75 / 150 IU rec FSH 100 mg CC / day Letrozole 5mg 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Should we continue Metformin?• In women with PCOS, continuous use of metformin during pregnancy significantly reduced the rate of miscarriage, gestational diabetes requiring insulin treatment and fetal growth restriction. No congenital anomaly, intrauterine death or stillbirth was reported in this study. Aga Khan Publication 2010There is a statistically significant reduction in the incidence of GDM infavor of metformin group (OR: 0.17, 95% CI: 0.07-0.37). There is astatistically significant reduction in the incidence of pre-eclampsia infavor of metformin group (OR: 0.35, 95% CI: 0.13-0.94).Conclusion. Metformin is a promising medication for the preventionor reduction of the incidence of GDM and pre-eclampsia in PCOS Khattab etal Gynec endoocrinol 2011
Screening for gestational diabetes when?At first prenatal visit, women at high risk of GDM (severe obesity,personal history of GDM or previous delivery of large-for-gestationalage infant, glycosuria, PCOS or a strong family history of diabetes)should undergo standard diagnostic testing for diabetes. If abnormal,consider these individuals to have "overt" (not gestational) diabetes. Ifnormal, retest between 24 - 28 weeks (ADA Standards of Medical Care2010). 75 gms OGCT as per latest DIPSI/IDA guidelines in everytrimester• Women seeking ART and being treated with metformin still show a very high rate of GD or IGT after achieving pregnancy by ART. Therefore in women undergoing ART screening for GD should be performed as soon as pregnancy is confirmed to avoid miscarriages due to overlooked uncontrolled glucose metabolism Bals-Pratsch M, Großer B Clinical endocrinol 2011
Monitoring of pregnancies as any other high risk pregnancyAntenatal checksRBT and GDM screening first visit,if negative,repeat at 24 wks 75gOGTTEarly USG scan11-14 wks scanUterine artery notchTwo weekly checks after 24wksColor Doppler if IUGR
Oral contraceptive pills are thebest option for them but if wishto use other contraceptive thenensure 2 monthly withdrawal toavoid the long termcomplications of unopposedestrogen action on theendometrium
MRS POLY PCOSHAS ABORTIONS/CHILDAND NOW WANT ANOTHER ONEAND IS NOT CONCIEVING Secondary infertility
Diet / exercise/ weight reductionIf ovulating search for other causes-tubal or uterinefactor,male factor,If anovulatory– ovulation inductionIf recurrent pregnancy loss with no other causes- suppressLH-DEW/ insulin sensitizers/GNRH agonist
MRS POLY PCOS HAS COMPLETED FAMILY• IRREGULAR PERIODS• PERIODS OF AMEN OF 2-6 MONTHS• OBESITY• LETHARGY• ACNE AGAIN• SLIGHT EXCESS BODY HAIR
Importance of Diagnosis - Mature PCOs.• A firm & convincing diagnosis will allow us to offer strong base for counselling about prognosis & definitive line of treatment to prevent dangerous sequele. Diagnostic Criteria are same as suggested by ESHRE/ ASRM.
Mature PCOs – Therapeutic Goals. IN WOMEN WHO HAVE COMPLETED THEIR FAMILIES NOW PCOS MANAGEMENT HAVE TO BE THOUGHT IN TERMS OF :• MENSTRUAL IRREGULARITIES• CARDIOVASCULAR DISEASES• DIABETES• MALIGNANCY• SEIZURE DISORDER
Mature PCOs Some Common Features.• This predisposes to : METABOLIC SYNDROME – Type 2 Diabetes. – Atheroscelerosis. Hyper tension. – Coronary Artery Disesase. – Severe Oligo menohrea / Amenohrea. – Increases Incidence of Endo Cancer. ( 5.3 times ↑). – No significant change in the incidence of breast cancer. – Epilepsy. – Sleep Apnea. Franklin C 2008.
PCOS MONITORING• Yearly testing• Complete history• Thorough physical exam• B P assessment• FBS &OGTT periodically• Lipid profile• Homocysteine levels• Other cardiac risk factors
MANAGEMENT• life style and excercises• diet• insulin sensitisers• ocp’s• progesterone for bleed• statins/diabetes /antihypertensives if needed• omega 3 and micronutrients(inositol or myoinositol or n-actyl cysteine or alternative medicines
MRS POLY PCOS IS PERIMENOPAUSAL 44 YRS• irregular cycles• androgen excess• diabetes x 7• hypertension x 4• lipid profile• cardivascular ds and accidents• endometrial cancer• Metabolic Syndrome
MRS POLY PCOS IS MENOPAUSALHAS DEVELOPED ALL LONG TERM COMPLICATIONS:METABOLIC SYNDROME
The Metabolic Syndrome: WHO criteria IGT/IFG or type 2 diabetesCentral Obesity Insulin resistanceBMI > 30 kg/m² (glucose uptake below lowest quartile) METABOLIC SYNDROMEMicroalbuminuria Blood pressureUAE 20 µg min 160/90 mmHg Triglycerides > 150 mg/dl & HDL-Ch < 35 mg/dl Alberti & Zimmet WHO 1998 Diabetic Medicine.
Adult Treatment Panel IIIRisk Factor Level – Waist Circumference – >40 in (m) >35 in (f) – Triglycerides – >150 mg/dl – HDL Cholesterol – <40 (m) <50 (f) – Blood Pressure – >130/85 – Fasting Blood Glucose – >110 Dysmetabolic Syndrome = 3 out of 5 ATP III, Nat. Chol. Ed. Program, NIH
Treatment of Metabolic SyndromeRisk Factor TreatmentCentral Obesity Lifestyle ModificationDyslipidemia Statins and/or FibratesHypertension (and/or ACE I or ARBsendothelial dysfunction)Prothrombotic State ASA, Quit smokingInsulin Resistance If T2DM: TZDs with orAnd Hyperglycemia without metformin
CONCLUSION• PCOS is Enigmatic,still lesser understood• Diagnosis can be tricky• Management is age and need oriented• Lifestyle modification is the crux.• Fertility can be difficult.• Prevention of longterm implications should be kept in mind(prevent MS)
Take home message• When evaluating women with PCOS, including younger adolescents, physicians should assess for the presence of components of metabolic syndrome. Therefore, clinical evaluation should include assessments of blood pressure, waist circumference and/or BMI, fasting lipid profile, and glucose tolerance by a 2-hour oral glucose tolerance test.
Take home message• Combination therapies ,most effective• Diet control and lifestyle modification only may not be adequate• Pharmacotherapy is required• Insulin sensitizers before development of overt diabetes controversial,but increasingly used.• As PCOS is the “thief of womanhood” it must be treated at all ages