Are We Finally Close To Solving The Mystery Of Pcos?

In our dominantly female-populated world, it would be expected that highly common gynaecological diseases would be well-defined. However, it may come as a surprise Polycystic Ovarian Syndrome (PCOS), a disorder which affects 1 in 10 women worldwide, largely remains a mystery. Prominent in women of reproductive age and a major cause of infertility, it also largely increases the risk of type 2 diabetes as well as endometrial cancer (EC). So why is it such a hard puzzle to solve? Is it because the scientific research community are being biased towards men and under-funding gynaecological research, or is the disease simply too complex? Let s find out!

Stein and Leventhal s discovery

PCOS, also known as Stein-Leventhal syndrome was first defined by clinical researchers Irving Freiler Stein and Michael Leventhal in 1935. Instead of modern experiments, they used clinical examinations and case reports to conduct their research. In 1930, Dr Stein began examining women presenting with abnormal menstruation habits, who had trouble conceiving and excess hair growth (hirsutism). After extensive observations, he discovered many of his patients had enlarged ovaries with cyst-like structures on them. Prompting further investigation, he controversially performed an ovarian wedge resection (surgical removal of a section of the ovary).

Stein claimed he was exceptionally careful, and it was for therapeutic purposes, not only a diagnostic measure. Nevertheless, after gathering evidence, the two presented their research at the Central Association of Obstetricians conference. Shortly after, they produced a study report titled amenorrhea associated with polycystic ovaries in which they described their 7 patient cases all showing polycystic ovaries with menstrual disturbances. It was published on the front cover of a scientific journal and till date, remains influential in the medical world.

PCOS- doesn t sound too bad?

Building on their work, researchers have tried to establish a global diagnostic criterion for PCOS. However, due to differences in presentation among sufferers, this has been difficult. As it were, many signs and symptoms have been identified: absent, irregular or heavy periods, 12 or more cysts seen on ovaries, high androgen (male hormone) levels, hirsutism, acne, scalp hair loss and even mood disorders. Finally, it was agreed, a PCOS diagnosis can be made if a woman presents with any two from the first three signs. It is a complicated condition to diagnose as some patients have all the symptoms while others have none. Also, the word polycystic implies many cysts on the ovaries but the truth is, not all PCOS patients have several cysts and not all women who do, have PCOS.

What goes wrong?

Figure 2: A comparative view of a normal versus a polycystic ovary.

Despite research focussing on deciphering the pathogenesis of this condition, the exact cause remains unknown. Essentially, in PCOS, the ovaries get overexcited and produce high levels of androgens, namely testosterone. Testosterone, also a precursor for estrogen, is a predominantly male hormone, explaining why hirsutism and alopecia are common symptoms of PCOS. Estrogen is vital in maintaining the female reproductive system, but too much causes problems.

The menstrual cycle is intricately regulated by hormones to allow regular follicle to oocyte maturation and subsequent ovulation. High estrogen levels disrupt this balance which means maturation doesn t occur properly, arresting the regular release of an egg every month. Instead, several half-mature cyst-like follicles are lined up at the starting line as Dr Legro says, hence the title polycystic .

What s to blame?Now comes the mysterious part -what causes all of this? Again, the exact causes are unestablished however, risk factors include obesity, high insulin, inflammation and high estrogen levels, all of which contribute to imbalanced hormone levels. It is difficult to determine which of these plays the biggest role because simply put, the female reproductive system is itself a labyrinth if you may, and when you add the endocrine aspect to it, it becomes a double whammy! However, research indicates insulin resistance may be a major player, which means cells cannot easily uptake sugar from the blood. To compensate, the body makes more insulin to help cells to absorb glucose.

The excess insulin that`s being produced stimulates the ovary to make testosterone, which can interfere with ovulation, rendering many women infertile, commented John Nestler, the head of internal medicine at Virginia Commonwealth University. Coincidingly, studies have found 95% of overweight women with PCOS also had insulin resistance. This indicates obesity may play a profound role in the development of the condition. Indeed, Angela Grassi, a reputable dietitian says overweight women are more at risk of becoming insulin resistant because the more weight you gain, the more corresponding insulin your body produces, and the more you continue to gain weight and so it becomes a vicious cycle. However, the exact underlying molecular mechanisms are obscure.

Can Metformin be a saviour?With no established treatment for PCOS, a healthy lifestyle is the primary recommendation for symptom management. Many doctors also prescribe Metformin, a traditional diabetes treatment which works to regulate blood glucose levels by increasing sensitivity to glucose. Shown to improve weight loss and regulate periods, it is significant because infrequent menstruation can lead to endometrial cancer, which is why women with PCOS have a 33% higher chance of suffering from endometrial cancer. When menstruation doesn t occur and estrogen levels are high, the uterine lining (endometrium) begins to grow too much and if left untreated, can quickly progress to become cancerous. Therefore, research is now looking into Metformin as a possible therapy for endometrial cancer itself.

Additionally, contrary to popular belief, taking oral contraceptives (OCs) has also been found to decrease the risk of endometrial cancer. A study showed that the use of progestin-only OCs had the best protective effect.

Many PCOS patients are prescribed OCs such as Provera, to regulate their menstrual cycle and decrease their risk of cancer. It can be said OCs and metformin may be a small light in the middle of a long tunnel for PCOS patients.

So, is it in fact gender inequality?According to PCOS Challenge, Inc., a non-profit support organisation, PCOS awareness and support establishments in America receive a small 0.1% of the governments funding, compared to other health conditions and a similar situation is hypothesised in the UK too.

Nestler says only a handful of researchers are funded to study PCOS and most is focussed on the infertility aspect. He believes it would be more advantageous if research into the underlying metabolic disturbances of PCOS was funded instead. So, perhaps the still heavily male-dominated research community possibly giving less attention to female anatomy and care is the reason the cause of this common gynaecological disease has not yet been established.