Author:  Patricia Nicholson

Polycystic ovary syndrome (PCOS) is often thought of as a condition that primarily affects the reproductive system. However, research has linked PCOS to increased risks for metabolic conditions such as obesity and Type 2 diabetes. PCOS appears to affect – and may be affected by – both reproductive function and metabolism.

That connection was the subject of the 2010 F.M. Hill Lecture at Women’s College Hospital – an annual event honouring Dr. F. Marguerite Hill, former physician-in-chief at Women’s College Hospital – on Dec. 8. This year’s lecture, entitled Reproduction and Metabolism: Ancient Traits with Modern Implications, was given by Dr. Andrea Dunaif, chief of endocrinology, metabolism and molecular medicine at Feinberg School of Medicine at Northwestern University in Chicago. Dr. Dunaif is also Charles F. Kettering professor of medicine at Northwestern, and director of the Center for Clinical Research at Northwestern University Clinical and Translational Sciences Institute.

It does make sense that there should be a connection between reproductive function and metabolism (the system of chemical processes that the body uses to turn food into energy).

‘If your environment is not replete with nutrients, the last thing you want to be doing is reproducing. You want to be surviving,’ Dr. Dunaif said. Although the ancient links between these traits have been conserved throughout evolution, we now live very differently than our ancestors did thousands or hundreds of years ago – or even decades ago.

‘We’ve gone from not having enough food to having far too much food. So what we see now are not the consequences of undernutrition, but the consequences of overnutrition,’ Dr. Dunaif said. ‘In fact WHO announced several years ago that obesity has become a worldwide epidemic that is more serious than undernutrition.’

Because body fat distribution is associated with hormone levels, men and women tend to gain weight differently. Women tend to carry weight in the lower body. These fat cells that congregate below the waist function differently than the fat cells associated with the typical male pattern of apple-shaped obesity, in which fat accumulates in the abdomen.

‘So women tend to be pear-shaped,’ Dr. Dunaif said. ‘But there is a subset of women who have this male-pattern obesity, and they have higher male hormone levels than women who have the typical pear-shaped pattern of obesity.’

PCOS

The classic definition of polycystic ovary syndrome is chronic anovulation (lack of ovulation) and high levels of male hormones (androgens), Dr. Dunaif said.

‘It’s the most common endocrine disorder in women of reproductive age, with the classic syndrome affecting about seven per cent of premenopausal women. Eighty per cent of women – at least in the United States – who have irregular periods turn out on further evaluation to have PCOS,’ she said. ‘It’s the leading cause of hormonally related infertility, it’s a major risk factor for Type 2 diabetes and metabolic syndrome, and we still don’t know what causes it.’

The diagnostic criteria for PCOS have changed a bit in the past 20 years. Expert opinion in 1990 defined the classic two symptoms. Later, a third symptom – enlarged ovaries with multiple cysts – was added, and a diagnosis of PCOS could be made with any two of the three symptoms. However, Dr. Dunaif noted that it is becoming increasingly clear that only women who fulfill the ‘classic’ definition of high androgens and anovulation have the metabolic risks associated with PCOS.

‘So there’s something about the association between ovulatory disturbances and metabolic risk,’ she said.

One of the metabolic risks of PCOS is its association with a condition that called insulin resistance. Insulin is a hormone that does many things in the body, but one of its major roles is regulating glucose. Insulin helps cells in the body absorb the glucose they need for energy. In insulin resistance, the cells don’t absorb enough glucose, so the pancreas must secrete more insulin to boost the process. When it becomes severe, the result is too much glucose remaining in the blood instead of being absorbed by cells. This excess glucose in the blood leads to diabetes.

Women with PCOS tend to have high levels of insulin related to insulin resistance, Dr. Dunaif said. They also tend to have an associated condition called the metabolic syndrome: the constellation of having central or ‘apple’ obesity, high blood pressure, high triglycerides (one of the fats in the blood), and low ‘good’ cholesterol.

Metabolism or Reproduction?

‘So how are these conditions related?’ Dr. Dunaif asked. ‘It comes down to which came first: the insulin resistance or the abnormal androgen levels.’

Although insulin is usually considered a metabolic hormone, it does affect the reproductive system. One of insulin’s reproductive effects is to stimulate production of the hormone androgen in both the ovary and the adrenal gland. It also increases the amount of luteinizing hormone (another reproductive hormone) released by the pituitary gland.

In women with PCOS who are not ovulating, treating their insulin resistance with medications to improve insulin sensitivity often restores ovulation, Dr. Dunaif said. And in morbidly obese women with polycystic ovary syndrome, the PCOS can be reversed with bariatric surgery, which is known to improve insulin sensitivity.

‘So insulin is really a major reproductive hormone,’ Dr. Dunaif said. ‘So what about the metabolic actions of reproductive hormones?’

Androgen appears to contribute to ‘apple-pattern’ obesity. In a study of women with PCOS who were losing weight, those who were taking androgen-blocking drugs lost more belly fat, and also had greater improvements in insulin sensitivity.

There is also evidence that exposure to androgens during certain stages of prenatal development may have permanent effects. In animal studies, when pregnant animals were exposed to androgens, the offspring developed features of PCOS or metabolic syndrome as adults.

A Lifelong Condition

Its links to reproductive and metabolic function suggest that PCOS may have long-term health consequences, but little is known about its effects on the post-menopausal women.

‘This has been very difficult to study because this has just been considered a reproductive disorder and there are no long-term prospective trials to see what happens to these women after their reproductive years,’ Dr. Dunaif said.

Because there are no studies specifically tracking PCOS, Dr. Dunaif looked at women in large studies who had very irregular periods – a good indicator of PCOS (among women who have six or fewer periods per year, about 80 per cent turn out to have PCOS).

Data from the Nurses’ Health Study – a large prospective study launched in the 1970s – on menstrual cycle length between the ages of 18 and 22 showed that women whose cycles were longer than 40 days had approximately twice the risk of developing Type 2 diabetes as women with cycles between 21 and 35 days.

‘What we would suggest is it’s because the irregular menstrual cycles are a proxy for polycystic ovary syndrome,’ Dr. Dunaif said.

More data from the Nurses Health Study suggests a link between PCOS and cardiovascular events (such as heart attack and stroke). Women who described their menstrual cycles at ages 18-22 as either usually irregular or highly irregular had a 50 per cent higher risk of cardiovascular events later in life, compared to women with regular cycles.

‘Which is certainly a concern: that an independent increased risk is conferred just by having irregular menses – probably a surrogate for PCOS,’ Dr. Dunaif said.

In the Women’s Ischemia Syndrome Evaluation (WISE) study, which looked at survival rates following cardiovascular events, women who had high levels of testosterone (an androgen) and a history of irregular periods were significantly less likely to survive than women who did not have these features.

‘I think in the absence of the gold-standard prospective longitudinal trial, we have pretty suggestive evidence that these women with polycystic ovary syndrome are at increased risk of cardiovascular disease, as we predict from all the metabolic abnormalities earlier in life as well as an increased risk of Type 2 diabetes,’ Dr. Dunaif said.

The take-home message from Dr. Dunaif’s talk is that the menstrual cycle should be considered a vital sign, and may predict risk of diabetes and cardiovascular disease.

‘I think we need to start thinking about polycystic ovary syndrome as a condition that goes across a woman’s lifespan,’ she said. ‘But we also have to remember that it’s a major metabolic disorder.’