Mohammad A. Emam Phenotypes Of Polycystic Ovarian Syndrome BY Prof. OB& GYN Mansoura Faculty of Medicine Mansoura integrated fertility center (MIFC) EGYPT www.ivfmifc.com

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) Estimation of 'true' prevalence PCOS must be made with caution since there is no overall consensus on the diagnostic criteria that must be satisfied to make a diagnosis (Ledger and Clark 2003).

Rationale Creation of new sub phenotypes and ?????? Roterdam new definition PCOS (2003). Role of insulin resistance in pathogenesis. Heterogeneity of clinical presentations. Creation of new sub phenotypes and ??????

Objective To highlight the different phenotypes of PCOS created from : The refined Rotterdam definition of PCOS 2003. Role of IR in the pathophysiology of PCOS. Heterogeneity of clinical presentations.

Methods From recent publications in the relevant subjects of endocrinology, reproductive medicine, and gynaecology Medline search from 1994 till 2004 for English language articles related to PCOS and "metabolic syndrome in women."

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) Clinical and/or biochemical Hyperandrogenism. (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

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

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 .

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

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

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.

Anovulation + PCO + Normoandrogenemia What is The difference bet Anovulation + PCO + Normoandrogenemia What is The difference bet. Regular and irregular menst ? Patients with anovulatory PCOS and normal menses seemed to be leaner and have lower insulin and gonadotropin levels than those with irregular menses (Carmina 2000).

Anovulation & Hyperandrogenism + Normal ovaries What is workup needed? May have non classic congenital adrenal Hyperplasia:. Screening for 17 –hydroxyprogesterone durig follicular phase... If 17 OH progesterone is high ….adrenocorticotropic H stim test should be performed. Prolactin to exclude hyperprolactinaemia

PCO + Hyperandrogenism (Ovulatory ) What Is Needed? Evaluation of insulin sensitivity. Assessment of cardiovascular risk (Carmina 2000 , Katza 2000).

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 some alterations in their early luteal phase (Joseph H etal 2002).

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

Asymptomatic PCO (Ovulatory + Normoandrogenic ) No variation in cycle length between PCO (ovulat + Normoandrog) & fertile women with normal ovaries. There is significantly lower levels of progesterone in the early luteal phase. This may contribute to the delay in conception in these patients.

Pathogenesis Three major hypothesis (culprits ) may all interact: Insulin resistance ( central player). Hyperandrogenism & (altered Gonadotropin dynamic). Recently ,genes encoding Inflammatory cytokines are identified as target genes for PCOS.

Conclusions Ultrasonic diagnosis of PCO should depend on new objective parameters with minimal inter and intraobserver variability if using 2D or 3D ultrasonic.

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

The Central Player ( Insulin Resistance ) The central paradox regarding the role of insulin in PCOS: Is the high ovarian response to insulin, as opposed by the the whole body resistance.

How IR Can Be Assessed ?? OGTT ( the best ). Fasting insulin (mu/ L) to fasting glucose (mmol/L) ( Hyperinsulinemic – euglycemic). Clamp technique ( Gold standard) , too expensive time consuming

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

Phenotypes According to IR PCOS + IR ( 50-70 % ). PCOS without IR (Legro etal 2004).

1) IR Phenotype of PCOS: What are the characteristics ? Patients with IR (50 -70%) are more likely to be : Obese Acanthosis Nigerians( AN). Hirsutism. Resistance to CC, Lower LH, LH/FSH ratios.

2) PCOS Without IR: What are characteristics? Lean. Enhanced Ovarian Sensitivity to insulin.

Does Association Between Insulin Resistance and Hyperandrogenemia Necessarily Precipitate Anovulation? Hyperinsulinemia is not necessarily associated with Anovulation: Insulin resistance and Hyperinsulinemia are well-known components of obesity,( most obese women have normal ovulatory cycles and normal fertility). Insulin resistance is a common finding: In lean apparently normal women. In insulin resistance syndrome or syndrome X.

Clinical / P Of PCOS Asymptomatic. Any or all of these symptoms may be present ): Irregular menstrual cycles. Weight gain. Abnormal hair growth on the face or the body. Infertility. Asymptomatic.

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

1) Symptomatic PCOS : What is the most important parameter ? Increased BMI is associated with increased severity of the PCOS. No differences in basic , clinical and biochemical parameters between eumenorrhoic and oligomenorrhoic PCOS (Vanky etal 2004).

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

Conclusions After Roterdam consensus 2003, the diagnostic approach for PCOS should be based largely on history and physical examination, thus avoiding numerous laboratory tests that do not contribute to clinical management

Conclusions Roterdam diagnostic criteria represent important progress in diagnosis of PCOS . However doubts still exist regarding borderline groups of patients ,such as hirsute ovulatory normoandrogenic women with PCO???.

Recommendations A large multicenter study comparing anovulatory patients with normal and irregular menses is yet to be done. 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

At The End We Can Say That PCOS is A never – ended story.

Prof. Mohammad Emam Thank you OB& GYN, Mansoura Faculty of Medicine Mansoura Integrated Fertility Center (MIFC) EGYPT Telfax 0020502319922 & 0020502312299 Email. mae335@hotmail.com www.ivfmifc.com