THE POLYCSTIC OVARY SYNDROME AND THE METABOLIC CARDIOVASCULAR SYNDROME

The polycystic ovary syndrome is the most common metabolic abnormality in young women today occurring in up to10% of female patients of reproductive age. The polycystic ovary syndrome is the most common metabolic abnormality in young women today occurring in up to10% of female patients of reproductive age.

These women were merely regarded as either having a cosmetic problem like hirsuitism and acne, trying to cope with irregular menses, or having problems with fertility. Till very recently most of the therapies were mainly directed at these complaints.

The syndrome was and is still greatly under estimated as it is a water-shed area between Endocrinologist, Dermatologist and Gynaecologist with each trying to off load often difficult to manage cases from one subspecialty to another.

We now know that this syndrome constitute the largest group of women at risk for the development of cardiovascular diseases and diabetes. Early case finding and pro-active preventive medicine should lead to reduction of serious associated medical consequences.

The 2003 Rotterdam consensus workshop (ESHRE/ASRM) concluded that PCOS is a syndrome of ovarian dysfunction along with the cardinal features of hyperandrogenism and polycystic ovary morphology.

The definition of PCOS changed from the first NIH-sponsored conference in 1990 to encompass the increasing awareness of the clinical expression of PCOS.

1999 Criteria (Both 1 and 2) 1) Chronic anovulation 2) Clinical and/or biochemical signs of hyperandrogenism with exclusion of other etiologies

Revised 2003 Criteria (2 out of 3) 1) Oligo– and/or anovlation 2) Clinical and/or biochemical signs of hyperandrogenism 3) Polycystic ovaries with exclusion of other etiologies

A rigid definition based on present or past proposed diagnostic criteria may hamper our understanding of this heterogenous disorder. P PP PCOS remains a syndrome.

Pathogenesis of PCOS: Genetic studies support the increased frequency of PCOS in first degree relatives of affected women. Most likely several genes are involved in the development of this heterogenous syndrome.

A large number of genomic variants has been associated with PCOS and many of these associations have not been replicated in different populations.

It is believed that the picture is of a multigenic etiology in which non- genetic factors such as diet and exercise have strong influence on the development of the disorder

Different Hypothesis: 1) Hypothalamic – pituitary abnormalities that result in gonadotropin – releasing hormone and leutinizing hormone dysfunction. 2) A primary enzymatic defect in ovarian or combined ovarian and adrenal steroidogenesis

3) A metabolic disorder characterized by resistance in conjunction with compensatory hyperinsulinaemia that exert adverse effects on the hypothalamus, pituitary, ovaries, and possibly the adrenal glands.

Most Reports Indicate That At Least 75% Of Women with PCOS Fulfill the Criteria for Insulin Resistance Syndrome

1)Reduction of serum HDL cholesterol to <50 mg/dL 2)Increased serum triglycerde >150 mg/dL 3)Blood pressure ≥ 130/85 mmHg 4)Insulin resistance and increased tendency to have T2 DM 5)Fasting glucose level of mg/dL 6)Glucose level of mg/dL after 75 gm glucose challenge ACE 2003 Position Statement on IRS

Each component of that list is a risk factor for CVD (cardiovasccular diseases) with greater risk for T2 DM or CVD (or both) occurring in the presence of more Abnormalities

ATP III Definition (NCEP THIRD REPORT 20001) Any three or more of the following criteria 1)Waist circumference >102 cm. in men and >88 cm. in women 2)Serum triglycerides ≥ 1.7 mmoL/L 3)Blood pressure ≥130/85 mmhg 4)HDL cholesterol <1.0 mmoL/L in men and <1.3 mmoL/L in women 5)Serum glucose ≥ 6.1 mmoL/L (5.6 mmoL may be applicable)

Metabolic Syndrome WHO Definition 1999 DM, IFG, IGT or Insulin Resistance (assessed by clamp studies) and at least two of the following : 1.WHR >0.90 in men or.85 in women 2. Serum trigylcerides ≥1.7 mmoL/L or HDL cholesterol <0.9 mmoL in men and <1.0 mmoL/L in women 3.Blood pressure ≥ 140/90 4.Urinary albumin excretion rate > 20 Mg/min or albumin to creatinine ration ≥30 mg/g

Insulin resistance is not a disease but a description of a physiologic state that greatly increases the chances of an individual developing several closely related abnormalities and associated clinical syndromes e.g. DM, CVD, HTN, PCOS, NFL, certain forms of cancer and sleep apnea.

It has much broader implication than the metabolic syndrome which focuses on one of The clinical syndromes associated with insulin resistance insulin resistance

Women with chronic anovulation and hyperandrogenism and/or PCOS appear to be at substantially greater risk for insulin resistance than those with hyperandrogenism and regular cycles.

Insulin resistance may be difficult to assess clinically short of using the hyperinsulinaemic–englycemic clamp method. Methods that measure only fasting glucose and insulin levels may be inaccurate in assessing sensitivity in these women particularly in the setting of normal or high- normal insulin levels and in the non-obese subgroup of women with PCOS. Methods that measure only fasting glucose and insulin levels may be inaccurate in assessing sensitivity in these women particularly in the setting of normal or high- normal insulin levels and in the non-obese subgroup of women with PCOS.

Therefore, underestimating the frequency of insulin resistance in patients with PCOS is common particularly in those with mild insulin resistance and borderline normal fasting glucose and/or insulin levels.

Probably other hormonal and genetic factors may influence the degree of insulin resistance and contribute to the conflicting reports of the incidence of insulin resistance in PCOS.

Therefore, it is prudent to regard all obese PCOS women as likely to have insulin resistance and at risk of IRS and to assume that most non-obese with PCOS have the IRS as well.

The incidence of IGT and T2 DM are significantly increased in women with PCOS. In one study, IGT and/or T2 DM were found in 30-40% of patients with the PCOS. A higher prevalance occurs in obese women particularly those with a family history of DM. Diabetes Mellitus

Oligomenorrhea is a surrogate marker for probable PCOS and may predict fold increase in the risk of T2DM particularly in the presence of family history of DM.

Because approximately 80% of women with irregular cycles have PCOS, it serves as a strong risk factor for DM independent of but exacerbated by obesity.

Women with PCOS, IRS and DM are not only an extremely high risk group for CAD but also the microvascular complications of uncontrolled DM. The AACE and ACE have already included PCOS as an important risk factor for diabetes and have recommended screening for DM by age 30 in all patients with PCOS.

Women with PCOS are frequently found to have atherogenic lipids abnormalities that may reflect insulin resistance as well as effect of genetics, ethnicity, obesity and lifestyle factors. DYSLIPIDAEMIA DYSLIPIDAEMIA:

Low HDL and high triglyceride levels are found in both obese and non-obese PCOS patients with hyperinsulinaemia. Also atherogenic modifications of LDL cholesterol toward smaller more dense particles were demonstrated in PCOS women. A high LDL level was found in both obese and non-obese PCOS women in one study.

Hypertension and Endothelial Dysfunction PCOS patients have higher systolic blood pressure even after adjusting for BMI, insulin sensitivity, and body fat distribution in comparison to matched control.

Women with PCOS have impaired endothelial nitric oxide synthesis which leads to impaired nitric-oxide synthesis dependant vasodilatation. This abnormally reduced vascular compliance and reduced vasodilatation correlates with long term Cardio -Vascular pro-inflammatory and atherogenic markers.

Patients with PCOS have decreased fibrinolytic activity, higher level of plasminogen activator-1 and increased CRP, all of which are markers for inflammation and correlate well with increased risk of Cardio Vascular Diseases in epidemiological studies. Elevated CRP was found in both obese and non- obese PCOS patients.

Data Suggesting Subclinical CVD Risk A Mayo clinic study showed that PCOS patients who are not diabetic had a mean of three fold higher level of coronary artery calcification(EBT) than control. In comparison with obese control they had two fold increase in coronary artery calcification. Cardio Vascular Diseases (CVD) and PCOS

A correlation was found between coronary calcifications (EBT), BMI, visceral obesity and high TG in PCOS. In another study, PCOS patients had higher prevalance of both coronary artery calcification and aortic calcification and had increased risk for metabolic cardiovascular syndrome.

The carotid-intima media thickness (USS) showed no difference between control and PCOS in those younger than 44 years but in women more than 45 years, there was a significant difference. The explanation put forward was that the metabolic alternations that occur at a younger age group translate into measurable result by middle age.

1. A 7 fold increased prevalance of T2 DM 2. A 3 fold increase in treated hypertension 3. A significantly higher WHR 4. A significant increase in plasma insulin and decrease in SHBG. Actual Cardio-Vascular event studies A risk factor model analysis calculated that patients with PCOS have 4-7 fold higher risk of MI in comparison with age-matched control. They also have:

In one study, clinical androgen excess (Hirsuitism, acne and increased WHR) was associated more with severe CVD. Oligomenorrhea is a good surrogate marker for the potential development of CVD.

In the prospective Nurses Healh Study (>101,000 women), a history of menstrual irregularity was linked to fold increase in DM and increased risk of mortality due to total CAD.

A surveillance of a subgroup (82, 439 women) over 14 years showed that a history of amenorrhea (at ages 20-35) was associated with 100% increase incidence of fatal and 50% increased incidence of non-fatal CAD after adjustment for age, BMI and cigarette smoking.

Other Abnormalities: Decreased cardiac systolic flow velocity Diastolic Dysfunction Increased LVM (left ventricular mass)

There are no large prospective studies that have documented increased cardiovascular events in women with PCOS Preliminary studies suggest an increase in CVD events in PCOS and there may be are increased risk of event in women with menstrual irregularities.

SUMMARY ↑ Prevalence of Cardio Vascular Diseases ↑ Prevalence of anatomic and functional abnormalities of underlying cardiovascular disease. ↑ Cardiovascular risk factors ( Dyslipidaemia, HTN,Obesity,etc) ↑ T2DM ↑ Prevalence IGT

Lifestyle modification - weight loss - exercise - avoidance of tobacco - correction of lipids abnormalities Insulin sensitizers - metformin - Thiazolidinediones : TREATMENT:

They reduce hyper-insulinaemia and Improve steroidegenic dysfunction. They help regulate the menstrual cycles, improve ovulation and achieve better fertility.

Early recognition of the syndrome Lifestyle modifications Measurement of glucose (and probably insulin). An oral OGTT in obese and those with family history should be considered. Detection and treatment of hyperlipidaemia RECOMMENDATIONS:

Assessing BP and treating hypertension Measurement of atherogenic markers (CRP ’ fibrinogen, and probably homocystine) Consideration of metformin as an initial preventive therapy particularly in overweight and obese PCOS patients. Thiazolidinediones improve hyperandrogenism and ovulation but they are still investigational tools.