Put simply, PCOS is a metabolic syndrome that manifests in women of childbearing age (between 15-30 years). Its external symptoms include irregular or no period for months, growth of excess facial and body hair, mild to severe acne, and weight gain. Internally, it’s characterised by increased levels of androgens (male hormones) in the body, resistance to insulin and/or multiple cysts (follicles containing immature eggs) on one or both ovaries.
Swati’s blood work bore this out. It confirmed high levels of androgens, leading to hirsutism (excess growth of hair on the female body), and above normal (>100mg/dL) fasting sugar levels, indicating insulin resistance. And Swati is far from alone. It is estimated that PCOS affects 1 in 5 women in India, compared with a global prevalence of 1 in 10.
Women with PCOS are at risk of developing type 2 diabetes, obesity, cardiovascular disorders (CVD) and infertility. And while research is yet to prove exactly why women develop this condition, lifestyle and genetics are considered to be major factors.
But here’s the thing—we don’t know what comes first.
Does weight gain, due to an unhealthy lifestyle, cause insulin resistance that, in turn, leads to the production of excess androgens and irregular menstrual cycles? Or does genetic predisposition to developing insulin resistance lead to a hormonal imbalance that causes women to miss their period and consequently put on weight?
Opinion is divided.
Dr Padmaja Pepalla, for example, believes it is heavily lifestyle related. Poor eating, sleeping and exercise habits, she says, lead to weight gain. Dr Pepalla is a gynaecologist at Padma Hospital in Vadodara.
Dr Maya Hazra agrees that lifestyle plays a major role in the development of PCOS. However, she leans towards genetic predisposition as the primary cause. “There is a definite correlation with diabetes. I have seen women who have a family history (especially mother or maternal aunt) are extremely prone to developing insulin resistance themselves and consequently PCOS,” she says. Dr Hazra has been a practicing obstetrician and gynaecologist (OB/GYN) in Vadodara for the past forty-five years. She has seen PCOS grow its claws over time, with her experiences leading her to believe it is a condition born of diabetes.
Both Pepalla and Hazra, however, are only making educated guesses. The reason could be both or neither, as research doesn’t clearly spell out the cause. This lack of clarity has led to contrasting opinions in the medical fraternity on how to treat a large population which is at risk of developing diabetes, obesity, and infertility.
But despite the uncertainty surrounding PCOS, there has been a diagnosis and prescription overdrive. Indeed, in 2016, the global PCOS market was valued at $3.3 billion, according to US-based Grand View Research. By 2024, it is estimated to reach $5 billion—growing at a compound annual growth rate of 5%.
With the prevalence of PCOS in India higher than the global average, India’s own PCOS market is bound to be a significant contributor. One Mumbai-based pharma consultant The Ken spoke with conservatively pegged the healthcare and pharmaceuticals market for PCOS at $0.9 billion. The pharmaceuticals market, he opined, made up about a third of this.
On its own, this shouldn’t raise red flags. But there’s a problem—PCOS management is currently the Wild West. This inconsistency is fuelling the off-label use of many drugs available in the market. Off-label refers to the use of a drug for purposes other than what it was officially approved for. This poses its own concerns and challenges, and the trend shows no signs of slowing.
Trick or treat?
When it comes to treating PCOS, Dr Pepalla is sceptical about pharmaceutical intervention. “I find long-term dependency and effectiveness of these medicines to be dubious,” says Dr Pepalla. “I would rather her not take any medicine; exercise and eat healthy.”
And she definitely has a point. According to several international guidelines as well as the national guidelines by the Ministry of Health and Family Welfare, the first-line of treatment is weight management through proper diet and exercise. However, most doctors prescribe medication. This buys patients time by regulating their cycles and pacifying them through the principles of placebo.
On the treatment front, oral contraceptive pills, or OCPs, are commonly prescribed as hormone therapy to induce and regulate the menstrual cycle. Metformin, an insulin sensitiser, is also used to induce the menstrual cycle and manage insulin resistance. Depending on the reports, doctors can prescribe either or both.
“There is a plethora of medicines in the market. Medical representatives line up to show the ‘true’ (read: off-label) benefits of these medicines to treat PCOS. They are meaningless,” says Dr Hazra. She does, though, feel that metformin is worth consideration.
Indeed, metformin is one of the most anecdotally effective medicines when it comes to PCOS. It also helps with weight loss and acne, making it more popular among patients. However, only a limited number of clinical trials have proven its long-term efficacy.
Metformin isn’t necessarily a lifelong treatment. “Women’s bodies often correct themselves at a hormonal level and the associated PCOS problems vanish when they get pregnant. But until then, metformin and monitoring at regular intervals is the only way out,” says Dr Hazra.
OCPs, on the other hand, are generally more frowned upon. All six doctors The Ken spoke to for this story unanimously agreed that, culturally, Indian women rarely use OCPs for their primary purpose—contraception. However, when packaged as hormone therapy for PCOS management and facial hair reduction, consumers are more open to it. Doctors, though, have their reservations. Dr Hazra, for instance, doesn’t recommend hormonal therapy such as OCPs to induce or regulate menses. “The side-effect on the uterus is not worth it,” she says.
It is important to note that both metformin and OCPs have not been approved by the regulatory authorities of most countries, including India, for the treatment of PCOS. However, they have been recommended by widely published papers put out by national and international endocrine and fertility societies. These though, are just the tip of the off-label PCOS drug iceberg.
Letrozole is another such drug. It has had a more chequered history with PCOS than either metformin or OCPs. Originally used in the treatment of breast cancer in postmenopausal women, it was banned by the Indian government in 2011 due to its misuse by doctors to induce ovulation in young women with fertility problems.
Novartis—which originally manufactured letrozole, and sold it under the brand name Femara—had warned that this usage came with serious health risks. However, Novartis’ warning fell on deaf ears, and the drug was subsequently banned thanks to its rampant prescription for women with ovulation issues, including PCOS.
At the time of the ban, Dr Chandra Mohan Gulhati, editor of the Monthly Index of Medical Specialties, a journal on drugs, spoke of letrozole’s popularity in an interview with the Times of India. “It is no longer the first drug of choice for breast cancer now that new ones are available. But it still has a big market. This clearly shows how letrozole’s use for inducing ovulation is still rampant in India,” said Gulhati. Before its ban, letrozole was experiencing high double-digit growth.
However, just five years later, the ban was walked back. First, a local manufacturer fought the ban, even forming an expert committee comprised of scientists from the Indian Council of Medical Research (ICMR) to study letrozole. Finally, the Drug Technical Advisory Board (DTAB)—the nation’s top drug advisory body—cleared the path for letrozole’s reintroduction on the back of a research report submitted by ICMR. By 2017, letrozole was back in pharmacies. This time, however, it had ICMR’s approval for use in ovulation treatment, something ICMR had originally opposed.
Dr Sonia Malik, an OB/GYN, infertility specialist, and former president of the Indian Fertility Society, is also the principal author of a set of India-specific PCOS guidelines. Malik believes that the guidelines should be updated to include letrozole as a treatment for infertility in PCOS. But letrozole has the medical fraternity divided. Many doctors do not agree with the ICMR report on using it for ovulation treatment—especially for PCOS.
No Country for Young Women
Though Dr Malik’s PCOS guidelines are an important step towards consistency in PCOS treatment across India, it is barely enough. For one, it is built using several international guidelines (predominantly Caucasian-based) as reference points. As such, the recommendations have epidemiological gaps to address since ethnic/racial variations can shape how PCOS presents. Malik agrees that the currently available data to support robust guidelines is limited. This is why they had to put together a multi-disciplinary panel and simply agree on diagnostic and intervention parameters.
“A Caucasian woman has her menopause five years after an Indian woman does. Asian and Indian girls hit puberty earlier. That means the spectrum of dealing with PCOS is different from what the international guidelines recommend,” Malik explains. Similarly, decisions to prescribe medicines based on clinical trials carried out in other geographies would be similarly unhelpful.
“One of the most important opportunities is preventative management of PCOS in adolescent Indian girls,” concludes Malik. But more India-specific research is needed for this. The starting point? Determining prevalence. Today, we don’t know exactly how many women in India have PCOS, nor do we know and about its relationship with its implicative comorbidities—i.e, conditions like diabetes and obesity that occur alongside PCOS, the primary condition. Unfortunately, government-funded research on young adolescent women is next to nil, according to Dr Malik.
In 2016, ICMR had proposed a five-year task force study to understand prevalence in 11 sites—both urban and rural. As of 2018, however, it had yet to action this. At present, convenience community studies point to a prevalence range between 10% and 36%. This indicates that roughly 1 in 5 women of reproductive age has PCOS. Observational reports from general physicians, gynaecologists, endocrinologists and dermatologists all validate this due to the rising number of cases year on year.
Of widening definitions and over-prescription
This prevalence was not the case a few decades back. “In 2019, everyone knows someone who is dealing with PCOS-related symptoms” Dr Pepalla says. “Ten years back, I used to get a maximum of one or two cases every month. Now, we see five to ten cases every two days.” This works out to hundreds of cases a month at a single clinic.
This increased prevalence is attributed to increased awareness. “We are definitely seeing more cases, but that could be because of general awareness in both the doctor and patient community,” says Dr Duru Shah, president of the PCOS Society of India. “In the 1990s, if I prescribed metformin to a woman with PCOS, after learning it is a diabetes medication, they used to distrust my expertise. That has changed.”
The year 1990 was a turning point in PCOS management. A National Institutes of Health conference in the US declared irregular menstruation and hyperandrogenism (excess androgens) to be the basis of core diagnosis of PCOS. Then, in 2003, another conference in Rotterdam issued a further criterion—conducting an ultrasound for the presence of polycystic ovaries.
This broadened the population of women who meet the PCOS criteria. According to an Indian community study in Mumbai, prevalence of PCOS shot up from 10.7% to 22.5%—over 1 in 5 women—under the new criteria. The need for an ultrasound, though, still remains debatable, as polycystic ovaries are seen in women without PCOS and there is no clear line that divides normal variability from the abnormality of PCOS, especially in young women.
This is important because if the one in five number is true, back of the envelope calculations point to a whopping 12 million PCOS cases in urban India alone. And if about 70% of women with PCOS are overweight and likely be categorised as at risk of developing type 2 diabetes, it means 8 million women in India are pre-diabetic; this is a huge prescription market.
Similarly, women who exhibit mild PCOS symptoms are still labelled as “at risk” of cardiovascular disorders (CVD) or infertility and are medicated, even if they don’t need it. The psychological manifestations of labels in diagnosis are also enormous. These women may end up with anxiety, depression and body-image issues—another market.
A Mumbai-based OB/GYN and laparoscopic surgeon, speaking on condition of anonymity, said, “When it comes to PCOS, as a doctor community we are not aligned on a definitive treatment plan. Neither have we set up prospective clinical trials to see the correlation of these illnesses with PCOS, nor do we have any evidence from retrospective research that proves PCOS was responsible for causing diabetes, CVD, infertility or certain cancers.”
He believes that understanding the cause rather than mindless medicating should be the medical fraternity’s priority. Something that was a paragraph in a gynaecology textbook a decade ago is now systematically put in as a chapter, which only focuses on the treatment despite the lack of information on causality. So is PCOS pharma-driven hogwash?
“Consider this, obesity was deemed as one of the main factors [of PCOS], but now we’re learning a debatable concept called lean PCOS and are asked to prescribe another class of diabetes medication such as inositol. We are holding national conferences sponsored by the pharma companies and prescribing medicines to low-risk patients while they develop a dependency or consume daily pills at a young age, all to feed the pharma market. How is that responsible?” he concludes.
And it is not just the pharma industry that is opening its doors to a booming market.
Much ado about something
PCOS management involves various disciplines and industries. A single patient could visit a string of medical professionals, from general physicians to endocrinologists, gynaecologists, fertility specialists, sonologists, psychologists, nutritionists and dermatologists. All of this happens through various diagnostic, pharmaceutical, cosmeceutical and nutraceutical touchpoints.
Then there are alternative medicines—the likes of naturopathy, homeopathy and Ayurveda—that attract women who are wary of side-effects from conventional medications. All of this makes PCOS an extremely expensive proposition for patients, and an extremely lucrative one for any of the various PCOS treatment touchpoints.
As for it being a public health epidemic, there is much more to learn about the anticipated health burden. Sure, there are undisputed benefits of metformin and hormone therapy for women exhibiting severe symptoms. However, the inconsistency of diagnosis and a growing population of women at low risk who need not be on medication provide cause for concern.
All available protocols point toward the current scenario being more market-centric. They focus on managing symptoms instead of preventive measures such as robust research and lifestyle interventions. If India does end up following the PCOS industry patterns from western geographies, it will miss out on an opportunity to develop a refreshing, patient-centric approach. Additionally, there is a risk of not establishing indigenous research, which is vital both for understanding the cause and identifying local solutions.
Fiona Godlee, editor-in-chief at The BMJ (formerly the British Medical Journal), has on several occasions called out the flexible threshold of diabetes and rampant use of insulin in managing low-risk patients. She’s even labelled it an industry scam. “To put patients on insulin is a big push by industry and the doctors who in turn are influenced by the industry. Rather than tackling lifestyle issues, going straight to insulin is not the right option. With diabetes becoming such an epidemic in India, we need to look at the root causes and put money there rather than putting people on insulin,” she said in a 2016 interview.
That India is the diabetes capital of the world is not news, but it need not be the same for PCOS.