Insulin Resistance and PCOS.

Our understanding of the metabolic factors that play a role in PCOS has advanced dramatically over the past few years. A metabolic state exists where the patient is resistant to some of the effects of insulin resulting in elevated serum insulin as the body tries to compensate, which appears to alter ovarian function. There are insulin receptors in the ovaries as well as other organs. The pattern of metabolic disturbances is very similar to “The Metabolic Syndrome X’ or ‘Syndrome X.’ Insulin resistance may be associated with abnormal lipid profiles (i.e. increased LDL-cholesterol, increased triglycerides, and decreased HDL-cholesterol) that may be associated with increase cardiovascular disease and atherosclerosis. Also, patients may have increased incidence of Non-Insulin Dependent Diabetes Mellitus (NIDDM, Type 2 DM) and hypertension which are linked to the insulin resistance. Studies show that almost ½ of obese PCOS patients have impaired glucose tolerance and about 10% have Type 2 DM. The metabolic picture is somewhat variable from patient to patient. In hirsute women that ovulate, slight increases in insulin and total and free testosterone is noted. The glucose to insulin ratio may be decreased which is consistent with a metabolic dysfunction. In non-hirsute women that ovulate but have polycystic ovaries on ultrasound slight increases in free testosterone, DHEAS and insulin are seen which is also consistent with a metabolic condition. No real long-term studies have been done on these more mild forms of PCOS at present.

It is important for patients to understand the concept of hormone resistance. With hormone resistance the body does not see the effects of the hormonal signal it sends out. Insulin is normally secreted by the pancreas into the blood stream where it travels to distant organs (i.e., liver, muscle, fat) and binds a receptor on a cell to transmit a chemical signal. It is kind of like turning on a light switch. It seems that something in the switch is not working well so that the signal is not completely turned on. Thus, the endocrine gland, in this case the pancreas, begins to over-produce the hormone in order to compensate for the perceived lack of effects. The ovaries are excessively stimulated by insulin and produce abnormal amounts of androgen and fail to ovulate normally.

The following paragraphs explain some of the reasons why we think insulin over-secretion and resistance is present in PCOS. Some women may show signs of insulin resistance by careful examination of the skin. Darkened patches around the neck and under the breasts or arms may be seen. This is called Acanthosis Nigricans. The photo below in Figure 1 shows this.

Figure 1. Acanthosis Nigricans. Note dark thickened patches.

Other women may have elevated serum insulin levels, impaired glucose tolerance or diabetes mellitus. Some investigators have measured insulin production over several hours and found that it is increased. They found high levels of c-peptide suggesting that insulin is being over produced and secreted.

Others have shown that both lean and obese patients with PCOS have an exaggerated response of serum insulin in response to a glucose challenge test, shown in the diagram below (Figure 2). In addition, the obese patients have abnormal glucose levels (i.e. diabetes). This study is very important because it shows that all patients with PCOS have insulin resistance which is unique and intrinsic to the condition and that obese patients with PCOS have a form of insulin resistance that is related to obesity which is superimposed.

Figure 2. Insulin levels in response to two-hour glucose tolerance test in obese and lean PCOS patients.

Another study examined PCOS patients that had a positive family history of Diabetes (Figure 3). It was interesting that there was an uncoupling of the insulin and glucose. This indicated that the pancreas is not working normally in the patients with PCOS and may be an early manifestation of future problems of diabetes. Normally insulin and glucose are tightly linked. When glucose levels rise after a meal, insulin secretion from the pancreas increases in like fashion. They are coupled. In PCOS patients with a family history of Diabetes but not Diabetes themselves, the glucose and insulin were not tightly linked. At times glucose would be low and insulin high and vice versa. The diagram below represents this.

Figure 3. Insulin and glucose relationships in patients with and without a family history of Diabetes.

No Family History DM

Glucose level –Red

Insulin level- Black

Time

Family History DM

Glucose level – Red

Insulin level –Black

Time

In general, obese patients have impaired glucose tolerance (31%) or diabetes (7.5%) and lean PCOS patients have impaired glucose tolerance (10 %) and diabetes (1.5%). These are significantly increased compared to the normal population.

Taken together, all of these studies point to insulin resistance as a crucial metabolic derangement in PCOS. It is reasonable to assume that a patient may progress from normal glucose tolerance (NGT) to insulin resistance (IR) to impaired glucose tolerance (IGT) and eventually Type 2 Diabetes Mellitus (T2DM). It has been estimated that 30% - 50% of obese PCOS patients may develop impaired glucose tolerance or diabetes by the age of 30. In PCOS patients the conversion of IGT to T2DM is 25 fold increased with 16% conversion per year from NGT to IGT and 2% conversion per year from IGT to T2DM. As mentioned above, about 30% of PCOS patients have the “Metabolic Syndrome.” In order to make this diagnosis, 3 of the following5 are needed; 1, waist circumference >35 in.; 2, increased triglycerides (>150 mg/dL); 3, low HDL-C (<50 mg/dL); 4, increased blood pressure >130/>80; 5, abnormal glucose tolerance test (fasting glucose 110 mg/dL to 126 mg/dL or 2 hour glucose between 140 mg/dL and 199 mg/dL).

Several tests have been used to evaluate IR in PCOS patients. The glucose to insulin ratio (G/I ratio) if less than 4.5 is a very good indicator. Pro-Insulin is increased when insulin is produced and if increased may indicate b cell (cell in pancreas that makes insulin) dysfunction. Some have seen an association of this marker with increased cardiovascular disease. Sex Hormone Binding Globulin (SHBG) is inversely related to insulin and insulin resistance. We prefer the 75 gm Glucose Tolerance Test (GTT) combined with the lipid profile in order to find diabetics and those with increase cardiovascular risk factors that we may be able to treat more quickly. Studies have shown that the risk for diabetes may be decreased with metformin (30%) and diet plus exercise (58%), which translates into a lower conversion of NGT to IGT. This has lead to treatment protocols, which will be discussed, elsewhere on our site.

Another associated problem patients must deal with us sleep apnea and other sleep disorders. This is associated with increased weight (i.e. central obesity) and increased glucose and insulin levels. As many as 50% of PCOS patients may suffer from sleep disorders and we should address this health concern. Disturbed sleep may complicate the patient’s life immensely.