Mohammad A. Emam Progress In PCOS BY Prof. OB& GYN Mansoura Faculty of Medicine Mansoura integrated fertility center (MIFC) EGYPT www.ivfmifc.com

History Stein and Leventhal Polycystic Ovarian disease. Polycystic ovarian syndrome Syndrome O ( Metabolic)

Prevalence About 20% of reproductive age women demonstrate the ultrasound picture of polycystic ovaries. About 5- 10 % have clinical or biochemical signs of Anovulation and androgen excess (dunaif 1995 , Norman etal 2002)

Creation of significant Developments Rationale Knowledge base for PCOS is rapidly revived and revised Not end story Creation of significant Developments

Objective To highlight the progress in PCOS regarding : Definition. Etiology Path physiology. Diagnosis Heterogeneity of clinical presentations Management. Health risks.

Methods From recent publications in the relevant subjects of endocrinology, reproductive medicine, and gynaecology. Medline search from 1994 till 2005 for English language articles related to PCOS and "metabolic syndrome in women."

Definition of PCOS

Definition of PCOS Europe view:- Ultrasound profile. USA view (NIH ): - Endocrine Profile. Rotterdam definition PCOS (2003).

Rotterdam , May 2003 Definition PCOS could be defined when at least two of the following three features are present, after exclusion of other etiologies : (i) Oligomenorrhea and or Anovulation (ii) Hyperandrogenism and/or hyperandrogenemia. (iii) Polycystic ovaries (sonar).

What is The Difference Between Hyperandrogenism & Hyperandrogenemia? Hyperandrogenism is the clinical manifestation of hyperandrogenemia. Hyperandrogenism can exist in absence of hyperandrogenemia e.g. enhanced tissue sensitivity to androgens in many premenopausal women

Ultrasonic Criteria of PCO At least one of the following: 12 or more follicles measuring 2–9 mm in diameter, increased ovarian volume (>10 cm3). If there is a follicle >10 mm in diameter, the scan should be repeated at a time of ovarian quiescence in order to calculate volume and area. The presence of a single PCO is sufficient to provide the diagnosis. The distribution of follicles and a description of the stroma are not required for diagnosis.

What are The Pitfalls Of Ultrasonic Criteria ? Significant intra-observer and inter-observer variability .

What are Trials To Standardize Ultrasonic Criteria PCO? Ratio between ovarian stromal area and total area of ovarian section ( S/A)..with cut –off 0.34 for PCO diagnosis (Belasi etal 2004). The use of high resolution 3D.

PCO & PCOS Polycystic ovaries (PCO), observed on ultrasound are a sign of PCOS and not by themselves diagnostic of the syndrome.

PCO VS. Multicystic Ovaries Polycystic ovaries Bilateral Multiple cysts Cyst diam 2-<10 mm Stroma increased Multicystic ovaries Bilateral Multiple cysts Cyst diam > 10 mm Stroma not increased It is better to call it Polyfollicular syndrome not PCOS

Emerging & Created Phenotypes &????? Regarding Roterdam 2003 Definition

Phenotypes (Rotterdam) NB CVS risk PCO I.R Androgens Ovulation Menses +++ + ++ - Irreg Classic PCOS * -/+ Norm Anov+ PCO + N.androgen Abn Hyperandrogen+PCO + Ovul. DD - -/+ Hyperando + Anov + N.ov Not P C O S +/- N. Androgen + ovulatory +PCO

What is The significance of polycystic-appearing ovaries versus normal appearing ovaries in patients with PCOS?? The presence of polycystic-appearing ovaries usually correlates with the presence of insulin resistance (Richard J 2002).

Anovulation & Hyperandrogenism What is DD? Late onset congenital adrenal hyperplasia DHEAS > 18mmol/l 17 OH Prog > 6 mmol/l Ovarian + adrenal androgen secreting tumours V. high teslosterone > 6mmol/l Cushings Syndrome - Dexamethsone suppression test - 24 hours urinary cortisol - DHEAS > 13 mmol/l

Anovulation & Hyperandrogenism What is DD? Iatrogenic and illegal androgen ingestion Hypothyroidisms Hyperprolactinemia.

Is Fertility Normal in patients With Ovulatory PCOS? These patients should be regarded as fertile but many studies have shown that women with ovulatory PCOS have luteal phase defect (Joseph H etal 2002).

Asymptomatic PCO (Ovulatory + Normoandrogenic ) There is significantly lower levels of progesterone in the early Luteal phase. This may contribute to the delay in conception in these patients. May be the starting cascade of Pcos!!!!!!!!!

Pitfalls Rotterdam Definition doubts still exist regarding borderline groups of patients ,such as hirsute ovulatory Normoandrogenic women with PCO???. Neglect role of IR

Etiology Speculation: Complex interaction of genetic ,epigenetic and environmental factors. Recently ,PCOS is mediated by ghrelin ( gastric peptide which is orexigenic and adipogenic)

Pathogenesis Three major hypothesis (culprits ) may all interact: Insulin resistance ( central player). Hyperandrogenism & (altered Gonadotropins) Recently (target genes) : Genes encoding Inflammatory cytokines. INSR genes.

IR ( Metabolic or Syndrome x) What is? Insulin acts like a key which can open a door on the cell's surface. cells do not have enough insulin receptor sites and cannot effectively burn glucose . this excess glucose is then sent to the liver where it is converted to fat.

PCOS, starts in adolescence PCOS, starts in adolescence. But Unfortunately, not always diagnosed at that age.

The Central Player ( Insulin Resistance ) Pregnancy Aging Drugs Lifestyle Insulin Resistance Genetics Upper abdominal obesity Increased lipid storage PCOS Hyperinsulinemia Altered lipoprotein & cholesterol metabolism Altered steroid hormone metabolism

IR : The central paradox The high ovarian response to insulin. Opposed by the whole body resistance.

How IR Can Be Assessed ?? OGTT ( the best ). Fasting insulin (mu/ L) to fasting glucose (mmol/L) ( Hyperinsulinemic – euglycemic).

Emerging & Created PHENOTYPES &????????????? Regarding Pathogenesis

Phenotypes According to IR PCOS + IR ( 50-70 % ). PCOS without IR.

1) IR Phenotype of PCOS: What are the characteristics ? Obese ( may be lean) Acanthosis Nigerians. Hirsutism. Resistance to CC,

2) PCOS Without IR: What are characteristics? Lean. Euinsulinemic/ Euglycemic Enhanced Ovarian Sensitivity to insulin (although no Hyperinsulinemia).

Diagnosis In the past (before 2003) Necessary Lab Tests or sonar Recently ( after 2003)…clinically.

What is needed after clinical diagnosis PCOS? Body weight Ideal body weight Body Mass Index (BMI) Lipid profile Fasting blood glucose Fasting insulin levels Blood pressure Medications BMI: >31 = Obesity Lipid profile: Triglycerides: <200 mg/dl LDL <100 mg/dL HDL >45 mg/dL Cholesterol <200 mg/dL 2 hour fasting blood glucose: 140-200 mg/dL = impaired glucose tolerance Fasting insulin >15 uU/ml Main reason to diagnose insulin resistance is go further on to look for type 2 diabetes Blood pressure: Normal systolic <130 mm Hg Normal diastolic <85 mm Hg Medications: Birth control methods Insulin-sensitizing agents Weight control drugs Hypertensive drugs Fertility drugs

CREATED PHENOTYPES & ????????? REGARDING CL/P

1) Symptomatic PCOS : What is the most important parameter ? Increased BMI ( severity of the PCOS). Any or all of these symptoms may be present: Irregular menstrual cycles. Weight gain. Abnormal hair growth on the face or the body. Infertility.

The less symptoms, the better response to medication and treatment. 2) Asymptomatic PCOS Very lean Athletic women May be underweight. This may mask the PCOS. The less symptoms, the better response to medication and treatment.

Controversy Epilepsy & PCOS Miscarriage & PCOS

Definite Long term risks in PCOS Type 2 diabetes Dyslipidemia (Hypercholesterolemia with diminished HDL2 and increased LDL) Endometrial cancer.

Long term risks in PCOS Possible Unlikely Hypertension Cardiovascular disease Gestational diabetes mellitus Pregnancy-induced hypertension Ovarian cancer Unlikely Breast cancer

Long Term Risks Of PCOS PCOS CVD Gout Infertility Hypertension Endometrial Cancer PCOS NIDDM Infertility Gout (deposits of sodium urate crystals in small joints and surrounding tissues) due to increased uric acid levels (associated with obesity). Gallbladder disease due to ↓ HDL & ↑ triglycerides (associated with the five “F’s”—female, fat, forty, fair, fertile). Endometrial cancer caused by proliferation of uterine cells in response to increased levels of estrogen. If this proliferation is left unopposed by progesterone, periodic loss of endometrium at menstruation is prevented and a build-up of the endometrium occurs. Fat cells have the ability to convert precursor hormones in the blood to estrogens. Obesity due to increased lipogenesis (associated with high levels of insulin). NIDDM due to glucose intolerance and hyperinsulinemia. Hypertension and CVD due to ↑ triglycerides, ↑ LDL cholesterol, and ↓ HDL cholesterol. Infertility due to anovulation or other menstrual disturbances. Obesity Gallbladder Disease

HOW????? How is PCOS treated? The target is to: Till now there is no cure for PCOS. The target is to: Try causative ttt. prevent further problems. HOW?????

Causative ttt Life- style modifications: Improve IR ( Metformin) Diet modification Weight loss Exercise Psychosocial support. Cessation smoking. Improve IR ( Metformin)

Targets for treatment PCOS

A weight loss of only 5% of total body weight is associated with: Decreased insulin levels improved menstrual function reduced hirsutism and acne lower testosterone levels.

Drug Therapy: Insulin-Sensitizing Agents (Metformin) Potential Advantages ↑ glucose tolerance ↑ insulin sensitivity ↓ blood lipid levels ↑ weight loss or stabilization Improved fat distribution ↓ blood pressure ↓ androgen levels Restoration of regular menses Postponement of diabetes Potential Disadvantages Gastrointestinal disturbance in 1/3 of patients Generalized feeling of unwell ness Decreased absorption of vitamin B-12 Lactic acid buildup

Laparascopic Treatment of Polycystic Ovaries: Is Its Place Diminishing? Laparascopic ovarian drilling and Metformin improve ovulatory dysfunction and pregnancy rate to a similar extent. The advantages of Metformin continue beyond conception: It reduces the miscarriage rate Decreases the likelihood of developing gestational diabetes.

Proposed APPROACH FOR ttt of PCOS

Conclusions Gynecologists should categorize any case of PCOS ,depending on : Rotterdam definition IR or not Asymptomatic or symptomatic

Conclusions Conclusions Treatment of PCOS should be directed towards causative rather than symptomatic especially if IR is proved as the central player !!!!

Conclusions NOW We Can Decide That Polycystic Ovary Syndrome is An Open Door for Dietetics Professionals

Recommendations The pathogenesis of altered ovarian morphology in asymptomatic PCO should be evaluated by 3D and Doppler ultrasonic in those apparently normal women where up to 20% of fertile women have PCO on ultrasound

Thank you Prof. DR. MOHAMMAD EMAM Telfax 0020502319922 & 0020502312299 Email. mae335@hotmail.com www.ivfmifc.com