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PCOS Update: The Insulin Connection - Theresa Hickey I have been a research scientist for Prof. Robert Norman, head of the Reproductive Medicine Unit, Adelaide University, for the past 6 years. PCOS is his special interest and all of my research has focused on this topic. Two years ago I enrolled to do a PhD in medical science with Prof. Norman and am working on a project that investigates androgen activity at the genetic level in the human ovary. Prior to my work with Prof. Norman, I worked on research projects that investigated hormone activity in cervical and prostate cancer. For the past 12 years I have also taught human anatomy and physiology to students studying to be massage therapists. I am 41 years old and the mother of 3 children.

PCOS is a disorder of the endocrine system, a network of glands throughout the body that produce potent chemical messengers called hormones. These hormones control many aspects of normal body functioning and imbalances in their activity can result in mild to severe health consequences. In PCOS, the hormone imbalances primarily affect female reproductive function and represent the major cause of female-related infertility. This is quite a common problem, affecting 5-10% of women regardless of ethnic origin. In the past, treatment of PCOS was mainly confined to women that sought assistance in becoming pregnant or to those that wanted relief from cosmetic conditions (excess hair and acne) that often accompany the disorder. However, research over the past decade has revealed that there are other consequences of PCOS that impose a major health concern. These include significantly higher risks of obesity, diabetes, heart disease, and certain cancers. For this reason, PCOS is receiving more attention as the medical community is being called upon to become more aware of the disorder. Many of the conditions associated with PCOS can be improved by early intervention, which include lifestyle changes and/or medication. So whether infertility is a problem or not, women with PCOS are encouraged to seek medical advice.

Ultrasound image of a polycystic ovary, demonstrating the "string of pearls" effect. The large dark circles around the periphery of the ovary are developmentally arrested follicles ("cysts"). A normal ovary usually only has one or two of these whereas a polycystic ovary usually has 8 or more.

Reproduction and Energy Supply:

The process of reproduction for any living organism is an energy-consuming process, just ask a pregnant woman! Not many would find this statement surprising or hard to understand, but less known is the fact that the ability to reproduce is also governed by the body's system for regulating energy supplies. The condition of anorexia is a dramatic example of this, where shutdown of the female reproductive system is one of the first effects of severe food deprivation. The body knows it does not have the energy to support the growth needs of new life and will not allow itself to become pregnant. In PCOS the situation seems to be reversed, where being overweight impairs or completely shuts down the reproductive process. Why, when the body obviously has plenty of fuel? And why, many infertile women with PCOS ask, do their overweight friends without PCOS not have a problem with fertility? Research indicates that many women with PCOS have a problem with the hormone insulin, which regulates the body's fuel supplies. In effect, the body has plenty of available fuel, but is unable to use it properly. This causes the body to "think" it is starving and it responds as if it were true. This response includes the dampening of reproductive potential.

Insulin: How does it work?

Insulin is a hormone secreted into the bloodstream by the pancreas in response to food entering the digestive system. Carbohydrates (sugars and starches) in the diet are digested into a simple sugar molecule called glucose, which gets absorbed into the bloodstream. The body "burns" glucose to produce the energy required for the "work" of living. This process occurs in all of the trillions of microscopic cells that make up the body. Insulin controls the level of glucose in the bloodstream and it also influences how much glucose enters a cell. This control is very important, as too much blood glucose is as damaging to health as too little blood glucose, and a cell's ability to work is dependent on the amount of energy it can produce. In the condition known as diabetes, the body cannot control its blood sugar levels due to a problem with the production or activity of insulin. People with diabetes generally need to rigorously control their dietary intake of carbohydrate and take insulin injections to control their blood glucose levels. The high incidence of a particular variation of diabetes in women with PCOS and their families alerted medical scientists to the involvement of insulin dysfunction in this disorder.

Non-insulin dependent diabetes mellitus (NIDDM):

Based on studies in North America and Europe, it is estimated that approximately 40% of women with PCOS will develop type II diabetes by the age of 40. Type II diabetes is called non-insulin dependent diabetes mellitus (NIDDM) because the problem does not arise from the inability to produce insulin. In fact, people at risk for NIDDM make too much insulin, a condition called hyperinsulinaemia. This can occur because of another condition called insulin resistance, which is a lack of sensitivity to insulin in particular parts of the body, especially the liver and skeletal muscle. Since the liver stores glucose, and skeletal muscle not only stores but is one of the most voracious consumers of glucose in the body, resistance to glucose uptake by these organs results in high levels of glucose in the blood. The body responds to this by producing more and more insulin, trying to break through the resistance and sop up the glucose. These high levels of insulin can have widespread effect on the body, including the ovary.

PCOS and insulin dysfunction:

Hyperinsulinaemia, insulin resistance and impaired glucose tolerance are very common in women with PCOS, particularly in those with a body mass index (BMI = weight in kg/height in m2) greater than 30. Insulin stimulates androgen production by the ovary, which worsens most symptoms of PCOS. Suppression of androgen production does not improve insulin resistance, leading to the belief that it may be a primary cause of PCOS, at least for some women. Many propose that insulin resistant women with PCOS should be considered a distinct sub-group within the large scope of this highly variable disorder, which may have many distinct causes. Fertility seems to be particularly affected in this sub-group, most of whom will have irregular menstrual cycles and be anovulatory.

PCOS, obesity and insulin resistance:

Glucose can be converted to fat, and in the face of insulin resistance by the liver and skeletal muscle, the body creates fat with the excess glucose in the blood. What's worse, the high insulin levels associated with insulin resistance inhibit the breakdown of fat. In effect, women with insulin resistance gain weight easily and lose it with difficulty. Therefore, overweight women with PCOS usually have a real metabolic reason for their weight problems, and obesity is seen in 40-60% of such women. Many lean women with this disorder admit to working very hard to maintain normal weight. Both obesity and insulin resistance are thought to have a genetic basis, although the genetic effects of both can be modified by lifestyle choices (see below). Also, these conditions are not exclusive to women with PCOS, but the elevated androgens in this disorder make both conditions worse. Due to the activity of androgens, weight tends to accumulate over the abdomen rather than the hips in women with PCOS and this type of fat is highly associated with insulin resistance. It is important to note that some lean women with PCOS also demonstrate certain degrees of insulin dysfunction. Therefore women with PCOS cannot rule out insulin dysfunction if they are not obese. However, obesity in combination with insulin resistance puts one at higher risk for infertility, diabetes, and heart disease.

What tests can be done to check for insulin problems?

The simplest test that can be done in a physician's office is the measurement of glucose and insulin in a morning blood sample taken after a night with no food. Also, a glucose tolerance test can be done in which one drinks a solution of glucose and one hour later the blood is tested for glucose and insulin. Both tests are considered reasonably reliable. The more accurate tests are complicated, expensive, invasive and generally used only for research purposes.

Are there non-clinical ways of suspecting insulin problems?

Although most people experience the following symptoms at some times in their life, people with glucose intolerance or insulin resistance feel them regularly and often dramatically:
Pronounced highs and lows of energy in the course of the day
Early day irritability and late day drowsiness
Continued desire to eat (especially sweet things) despite having a filling meal
Constant cravings for carbohydrates or high fat foods
Inability to lose weight despite calorie restriction
Excessive irritability before meals or an intense need for food
Poor sleep habits
Excessive urination and unquenchable thirst (these are early warning signs of diabetes)

What can be done about insulin resistance?

The answer to this question is one that may make people groan: diet and exercise! Insulin resistance is thought to have mainly genetic causes and therefore cannot be "cured", only managed. Exercise alone can improve insulin resistance without loss of weight. This is because exercise stimulates alternative pathways for glucose to enter skeletal muscles that are independent of insulin. For women with PCOS, minimal weight loss (5-10% of total body mass)

with improved insulin resistance via exercise can restore fertility. These lifestyle changes are gaining greater emphasis in the treatment of PCOS-related infertility and are the preferred option to the use of insulin sensitizing drugs (see below). Professor Robert Norman is known for development of these ideas, which lead to a program called Fertility Fitness in which women with PCOS come together as a group to learn and implement lifestyle changes and support each other in their desire to conceive a child. A recent popular diet strategy (The Zone) encourages the consumption of greater amounts of protein in the diet to reduce insulin secretion, and this notion is now being researched in our laboratories. Preliminary data seem to indicate that the overall caloric value of the diet is more important than the relative amounts of protein and carbohydrate involved, but this must be confirmed. It is important that changes in diet and exercise routine be amenable to the person involved, as a lifetime commitment to these changes will reap the most benefit.

What drug treatments are available?

Drugs that have been developed to treat NIDDM are now being trialed for use in women with PCOS, with some very encouraging results. Metformin (Glucophage) is the predominant drug of interest and has been shown to improve insulin sensitivity, incur weight loss, and restore menstrual regularity and ovulation. However, its preliminary success sparked an Internet frenzy that heralded its marvels without sound evidence. In truth, studies to date vary considerably in the effectiveness of Metformin in women with PCOS, and its use is not yet common clinical practice. Clinical trials are ongoing to determine the optimal doses, length of treatment, and potential side effects of its long-term use. Metformin may only benefit a particular group of women with PCOS; therefore it is recommended that only a physician with expertise in this area attempt to use the drug for therapeutical purposes. As diet and exercise can bring about the same outcome as Metformin therapy, this is encouraged as the first line of treatment. A position statement on Metformin and its use in PCOS has been recently published in the Australian Medical Journal (www.mja.com.au/public/issues/174_11_040601/norman/norman.html). The "glitazones" (mainly Troglitazone) are another class of diabetes drugs that have been used in women with PCOS. They are insulin sensitizers that have a different mode of action from Metformin, and have been shown to reduce androgens and improve insulin sensitivity. While Metformin works best on obese persons, glitazones work equally well in both lean and obese people. However, due to cases of liver toxicity with glitazones their use has been somewhat curtailed, but newer less toxic forms are being developed.

Summary

PCOS is a complex endocrine disorder that may have many causes. While androgen hyperactivity is the most dominant characteristic, insulin dysfunction also plays an important role in at least a subset of women with PCOS. The combination of both androgen and insulin dysfunction increase the risk of diabetes and heart disease in women with this disorder. Drug therapy is available, but still in the early stages of determining proper use and effectiveness. Lifestyle changes in diet and exercise have proven effects in improving symptoms of PCOS, but are often difficult for women to implement without some sort of personal support from family, friends, and/or a group of women with similar difficulties. For some women with PCOS, knowing that there is a genetic basis for their problems gives some relief and added motivation to take control of the disorder and how it manifests in their lives.

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