There cannot be another disorder that can nag a woman and ruin her routine and even travel plans, like the polycystic ovarian syndrome (PCOS). Google the dreaded abbreviation, and there is an information overload—how to prevent it, how to manage it, and how anything from apple cider vinegar to soaked fenugreek is supposed to help. But, look around for the actual causes, it is absolute chaos.
Talk to experts and they would say both genetic and environmental factors can lead to PCOS—there again, the word is lead and not cause. “It is a complex hormonal disorder. In view of the high prevalence of affected individuals within families, a genetic basis has been suggested,” said Dr Nivedita D. Moulick who previously headed endocrine services at Sion hospital in Mumbai.
Not just Moulick, but many physicians and researchers are coming to the conclusion that PCOS is a disorder in a number of genes. In a review published in Nature/Endocrinology in March 2018, Hector F. Escobar-Morreale from the department of endocrinology and nutrition, Hospital Universitario in Madrid wrote, “Mounting evidence suggests that PCOS might be a complex multigenic disorder, with strong epigenetic and environmental influences, including diet and lifestyle factors.”
Research through the years has shown that most often these genes are not modified per se; the DNA remains the same, but the proteins produced from them are affected either in quantity or quality, causing severe disorders. The modification in expressions of genes is often caused by strong environmental factors, often diet and lifestyle. This also means that the disorder can be corrected with diet and lifestyle changes. In fact, there are many doctors who feel that it can even be corrected to a certain extent by just brisk-walking an hour.
What bother women the most are growth of hair on the face and the absence or loss of hair from areas where it should naturally be growing. This apart, weight gain, irregular periods and heavy bleeding also interfere with the day-to-day life of young women. In women in their twenties and thirties, it could manifest as infertility issues. Dr Muralidhar V. Pai, professor of obstetrics and gynaecology at KMC, Manipal, said the cause of infertility in PCOS is anovulation and that increased luteinizing hormone (hormone produced by pituitary gland, an acute rise of which will trigger ovulation) may also lead to untimely maturation of eggs. “Insulin resistance is another related issue. Some women may develop Type 2 diabetes and cardiac problems later in life,” he added.
While PCOS is a common endocrine, reproductive and metabolic disorder, frequently associated with a number of symptoms, the treatment is often symptom-oriented. The cause remains obscure with concrete proof yet to come in. “Unmarried women may not be worried about infertility whereas that is the main concern in married women. Irregular periods may bother some while obesity and hirsutism does it for others,” said Pai.
What goes absolutely haywire in a patient’s body are the hormones. Surprisingly, insulin is the hormone that has been found to have a major role in the mayhem, meddling in not just glucose metabolism, but also the level of the sex hormones, especially the androgens (male hormones). The increased level of androgens can wreak havoc in a woman’s body, causing abnormal hair growth on the face, loss of hair where it should naturally be growing, excessive abdominal fat, weight gain and ovarian dysfunction.
Insulin and its resistance
It is a fact that insulin’s most important role is in the regulation of sugar. The meticulous human body releases just the precise amount of insulin, enough to drive the glucose from the food to the correct cells where it is meant to go. Insulin acts like a password, by which glucose is allowed into the cells. Once it gets inside, the cells perform duties assigned to them with the fuel that glucose provides.
But at times, the cells fail to recognise the password and do not let the glucose in, leading to a higher level of glucose in the blood. The pancreas—that makes the insulin—is fooled into believing the rise in blood sugar is because of a lack of insulin, and therefore produces more. So your body ends up with both high levels of glucose as well as insulin. And, the pancreatic cells get tired and worn out. When that happens, you know that diabetes is peeping in from the corner.
“When insulin is not able to lower blood glucose levels, the body produces more insulin—a condition called hyperinsulinemia,” said Dr A.G. Unnikrishnan, CEO of Chellaram Diabetes Institute in Pune. “Hyperinsulinemia affects tissues like the ovary and this results in irregular periods, excess male hormone production and infertility.”
This sort of insulin resistance does not end its story there. Insulin tinkers around with the functioning of the ovary and the liver. It causes the shooting up of androgen production in the ovaries, and brings down the level of sex-hormone-binding globulin (SHBG) that the liver produces. The SHBG generally keeps the testosterone chained and in control. When there is no SHBG to control, there are a whole lot of free testosterone molecules roaming around like charged elephants in a sugarcane plantation. The wayward hormones cause a whole lot of disturbances—the reproductive system goes awry, not to mention weight gain and irregularities in hair growth.
Insulin resistance is now said to be at the root of several serious problems, including dementia, some cancers, stroke and even accelerated ageing. Also, it can lead to GDM (gestational diabetes/diabetes diagnosed during pregnancy) and type 2 diabetes in PCOS patients.
Chicken or the egg
A sudden shift to sedentary life, obesity and family history are definite risk factors that are believed to bring on the disorder. Many doctors say it is the weight gain that causes an increase in the level of androgens and other typical symptoms of PCOS. Patients swear that they started gaining weight only after other symptoms like acne and irregular periods showed up. An overlap is evident. The puzzle as to what comes first—obesity or PCOS—is further complicated by the presence of PCOS in women who are lean. That question is as puzzling as the million-dollar one on the chicken and the egg. “However, in our experience, weight reduction by means of diet and exercise significantly brings down the PCOS symptoms,” said Dr Parasu Gopinath, infertility consultant and medical director at Centre for Infertility Management and Assisted Reproduction (CIMAR) in Kochi.
The diagnosis requires judicious application of a few clear and simple principles based on clinical guidelines for proper diagnosis. Most appropriate diagnostic criteria for the diagnosis is the Rotterdam criteria. The gynaecologists say that the disorder can be diagnosed if two to three characters are present—clinical and/or biochemical hyperandrogenism, ovulatory dysfunction and polycystic ovary. “However, we have come across a number of patients, who, with just a couple of symptoms like acne and delayed periods for example, decide for themselves they have the disorder,” said Dr Gopinath.
Role of androgens
Some women who exhibit extreme obesity and insulin resistance do not develop PCOS. Therefore, many researchers conclude that the most crucial factor for the development of the disease is not just weight gain, but excessive androgen secretion.
Mounting evidence suggests that it causes not only polycystic condition of the ovary, but also favours weight gain in the abdominal area, wrote Hector F Escobar Morreale in the review paper in Nature/ Endocrinology. “My colleagues and I have hypothesised that PCOS results from a vicious circle of androgen excess favouring abdominal adipose tissue disposition and visceral adiposity by inducing insulin resistance and hyperinsulinism, which further facilitates androgen secretion by the ovaries and adrenal gland in women with PCOS,” he said.
The visceral adipose tissue from women with PCOS are quite different from those of healthy women, and resemble those of men, indicating that androgen excess contributes to their adipose tissue dysfunction. However, biochemically, the level of androgen is difficult to measure as the available methods lack the sensitivity and specificity needed to accurately measure the very low androgen concentrations in women.
Cysts that are not cysts
The question whether excess androgen production comes first or insulin resistance comes first is also widely debated in the medical circles. The excess androgen interferes with ovulation and causes infertility and, under ultrasound scan, ovaries show the presence of cyst-like structures in the outer margins. “There are many misconceptions about PCOS, especially regarding the cysts,” said Dr Divya Jose, consultant gynaecologist at MOM, Premium Women’s Hospital, an initiative of CIMAR in Kochi. “The cysts are nothing but follicles sticking together. In a PCOS patient, the maturation of eggs gets affected and often take up the appearance of cysts. The name unnecessarily raises concerns about potential for malignancy.”
Since the polycystic appearance of the ovaries found in PCOS patients is caused by the accumulation of ovarian follicles in different stages of maturation, the name PCOS can be confusing. Some of the other names suggested are metabolic reproductive syndrome, syndrome xx, and even prevalent cardio-metabolic ovary syndrome, which would also take the abbreviation of PCOS.
Treatment and medicines
Treatment varies from oral contraceptive pills to anti-androgens, insulin sensitisers, or aromatase inhibitors. Neither the US Food and Drug Administration (FDA) nor the European Medicines Agency has approved a drug specifically for the treatment of PCOS. The most likely explanation for the current apparent lack of interest of health authorities and the pharmaceutical industry maybe because PCOS remains one of the most poorly understood medical disorders among patients, physicians and even scientists.
One medicine commonly used by doctors to treat PCOS symptoms is metformin. Metformin makes insulin work better to lower blood glucose. Hence the body now needs to produce less insulin and this results in reduction of hyperinsulinemia. “Hyperinsulinemia also results in the non-metabolic effect of insulin—for example on the skin or the nape of the neck and flexural regions, where insulin worsens pigmentation. This happens because insulin reacts with some receptors on the skin called IGF-I receptors,” said Unnikrishnan.
Women with PCOS have an increased risk of pre-term delivery, say studies. The increased risk was confined to hyperandrogenic women with PCOS, who had a two-fold increased risk of pre-term delivery and pre-eclampsia (a pregnancy complication characterised by high blood pressure and signs of damage to another organ system). In an unpublished study at MOM, a women’s hospital in Kochi, women with PCOS showed a higher tendency for abortion in the first trimester. “The PCOS women have a higher risk for abortion and pre-term birth of the baby. They also showed a higher tendency towards developing diabetes during pregnancy, or what is called gestational diabetes,” said Jose.
Such complications have been reported by many other research teams including that of Dr K.V. Naver and team, department of obstetrics and gynaecology, Hvidovre University Hospital in Denmark. “As a consequence of anovulation, fertility treatment is often necessary to achieve a pregnancy. Recent studies indicate an increased risk of pregnancy complications such as pre-eclampsia, gestational diabetes, pre-term delivery, and hypertension in PCOS pregnancies,” they reported in the Journal of Obstretics and Gynaecology in 2014. Studies also indicate that altered metabolism in mothers creates an unfavourable environment for the foetus, increasing the likelihood of diseases in the child.
It was in 1935 that Stein and Leventhal first described the syndrome as a combination of hirsutism (abnormal hair growth on the face) and amenorrhoea (absence of menstruation). Though it affects a large majority of women, it took another 55 years for the WHO to actually include PCOS among the disorders of ovarian dysfunction in the International Classification of Diseases.
HEART OF THE MATTER
PCOS: Points to remember
By Dr I. Sathyamurthy
* PCOS is associated with obesity, mainly visceral obesity. In 30 to 70 per cent of cases, the waist-hip ratio increases.
* Obesity results in insulin resistance, so insulin levels increase in blood. This is called hyperinsulinism, which results in impaired glucose tolerance (IGT). Majority of IGT patients turn into overt diabetes mellitus patients in a shorter duration of time.
* High blood pressure is common in PCOS patients due to vascular dysfunction. Inflammatory markers in blood increase, and affect the vascular compliance.
* PCOS patients could suffer from dyslipidemia—elevation of triglycerides and reduced HDL called good cholesterol.
* The heart muscle relaxation gets disturbed, which is called diastolic dysfunction of the heart. This can result in symptoms of heart failure.
* Coronary artery disease is very common because of the above-mentioned risk factors.
* Increased androgens disturb the clotting metabolism. So, PCOS patients are prone to thrombotic occlusions.
* Most PCOS patients have sleeping disturbances because of obstructive sleep apnoea resulting in low oxygen saturations while sleeping. This can result in cardiac rhythm abnormalities.
Sathyamurthy is senior interventional cardiologist, Apollo Hospital, Chennai.