Why Is PCOS Still So Hard for Doctors to Understand?

When Emily S., 28, was a teenager, more than one doctor told her that irregular periods were normal for her age. Dermatologists said the cystic acne along Emily’s jawline was a natural result of being 15. These explanations never convinced Emily, but the birth control pills she was prescribed did help tame her symptoms. Then when she was 22 she stopped taking them.

Three months after stopping hormonal birth control, Emily’s breakouts returned with a vengeance. Hair started to sprout just below her belly button. Her irregular periods came back; she’d go three, four months without bleeding. She was no longer a teenager. So what was the excuse now?

A Google search led Emily to information about polycystic ovary syndrome (PCOS). Even though she couldn’t check off every symptom she read about, PCOS seemed to explain a lot. She brought up her suspicions to a new doctor and received a PCOS diagnosis after a transvaginal ultrasound confirmed her ovaries had the excess follicles (sacs that hold eggs) associated with this disease.

Now, Emily wonders whether she’ll have trouble getting pregnant, as many people with PCOS do. She wonders whether there’s a link between PCOS and other health problems she experiences, like her blood sugar issues.

“That’s the thing about PCOS,” she tells SELF. “I’m like, What the hell is actually going on?”

Doctors would like to know too.

Searching for answers to questions surrounding PCOS—like what it really is, why it happens, how to diagnose it, and how to treat it—often only leads to more questions. That’s true even for PCOS experts, many of whom consider this condition to be something of a medical mystery.

Based on what we do know, PCOS is a hormonal and metabolic disorder. Its diagnostic criteria can vary, which is a complicated issue we’ll explore in a bit. In general, though, getting a PCOS diagnosis involves some combination of irregular or absent ovulation, ovaries with excess follicles (not cysts—that’s a bit of a misnomer), and high levels of androgens, or hormones that have historically been viewed as “male,” like testosterone. These issues can present as symptoms like irregular periodsacne, excess face and body hair, scalp hair loss, and weight gain, according to the Centers for Disease Control and Prevention (CDC). Per the CDC, the disorder affects an estimated 6 to 12 percent of women of reproductive age, which translates to about 5 million people dealing with this confusing condition.

The good news is that experts aren’t giving up on figuring out PCOS. Here, SELF explores the current state of PCOS knowledge and where experts believe research on the condition is headed.

What causes PCOS?

There isn’t one definitive cause of PCOS, but researchers know of several suspected factors that might play off each other. It’s possible that PCOS is always caused by some combination of these factors, but pinpointing the exact triggers in one person is a little ambitious, even for experts, Richard Legro, M.D., chair of the Department of Obstetrics and Gynecology at Penn State, tells SELF.

Excess insulin brought on by insulin resistance is thought to be a significant factor. This gets pretty complicated, but bear with us. Your cells need the hormone insulin to absorb glucose (sugar from food) for energy, according to the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK). But if you have insulin resistance, your cells don’t absorb glucose like they should. This can confuse your body into thinking you just need more insulin to compensate and be able to absorb glucose normally, so your pancreas might churn out higher levels of this hormone. Long story short, doctors believe this excess insulin due to insulin resistance might make your ovaries produce extra androgens, like testosterone. (Insulin resistance can also lead to pre-diabetes and type 2 diabetes over time.)

Some of the most familiar markers of PCOS (think acne, excess face and body hair, scalp hair loss, and irregular or absent ovulation) can happen as the result of extra androgens, though it’s not clear if the excess androgens are an actual cause of PCOS or just a symptom of another potential cause (like excess insulin from insulin resistance). It’s probably pretty easy for you to see how extra testosterone could translate into something like more face and body hair, but you might find it harder to pin down how this would relate to irregular ovulation. Well, you’re in great company, because doctors aren’t too sure either.

One possible explanation for how androgens mess with ovulation is that these hormones build up inside ovarian follicles, keeping the follicles from maturing and releasing eggs, which can lead to the excess follicles seen on an ultrasound like Emily’s.

But elevated androgen levels aren’t always a sign of PCOS. This can also happen with other health conditions like Cushing’s syndrome or congenital adrenal hyperplasia, so doctors will try to rule out other health conditions before they assume that excess androgen points to PCOS.

Another possibility is that PCOS might happen, at least in part, when the brain’s hypothalamus sends incorrect hormone signals from the pituitary gland (a pea-sized organ that produces hormones) to the ovaries, Leanne Redman, Ph.D., director of the Reproductive Endocrinology and Women’s Health Research Program at Pennington Biomedical Research Center in Baton Rouge, tells SELF. Here’s how that might work: The pituitary gland regulates levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which then prepare ovarian follicles for maturation. If these hormones are thrown off, it can prevent you from ovulating, which can lead to irregular periods—a classic sign of PCOS.

Again, this could be a cause of PCOS or it could be a symptom of another cause, since some evidence suggests that insulin resistance can influence how the pituitary gland regulates LH and FSH (though the data is too inconsistent to definitely cite it as cause and effect, according to 2012 research on insulin resistance and PCOS in Endocrine Reviews).

Genetics could also be a factor in PCOS development. PCOS tends to cluster in families, which some experts believe may point to a strong genetic link, Redman says. Whether someone develops PCOS could be the result of a genetic variation (i.e., how a DNA sequence varies in each individual’s genetic material).

Researchers have begun to unravel the genetic origins of this disorder through DNA samples. A 2019 meta-analysis of 261 people in The Journal of Clinical Endocrinology & Metabolism revealed that a gene called DENND1A could have a role in the development of PCOS in white families of European heritage.

“This may not apply to women of other races and ethnicities, but…it’s really the first gene that seems to play a major role in PCOS development and it strongly suggests—at least in the women and families that have these rare genetic variants—that altered androgen production is a key abnormality causing PCOS,” Andrea Dunaif, M.D., the chair of endocrinology at Mount Sinai School of Medicine and one of the study authors, tells SELF. Various research groups are also hoping to investigate the role of genes in PCOS in black and Chinese people to see what kind of connection may exist there, Dr. Dunaif says.

Additionally, some experts believe fetuses that are exposed to unusually high testosterone levels while in the womb (like if the pregnant person has PCOS or diabetes) may be more inclined to develop this disorder, Redman says. The excess testosterone could influence the genetic material of the fetus, including any eventual eggs and ovaries it develops. This seems to set up these individuals for developing PCOS later on, though some research suggests the deciding factor could be the environment they grow up in, Redman says. For example, not having access to nutritious foods and being inactive could mean developing insulin resistance that could further predispose someone in this situation to PCOS, she explains.

What PCOS diagnosis and treatment look like

Now that you know more about the complicated tangle of potential PCOS causes, you probably won’t be surprised to find out that diagnosis can be similarly tricky.

There are actually multiple versions of PCOS diagnostic criteria out there. Overall, doctors tend to look for at least two of these symptoms to diagnose PCOS: irregular or absent ovulation (as evidenced by irregular or absent periods), evidence or suggestion of ovaries with excess follicles (like via ultrasound), and symptoms of high levels of androgens (like excess face and body hair, weight gain, and hormonal acne).

But the specific mix of symptoms doctors are looking for depends on the exact diagnostic criteria they’re using. For instance, in 1990 the National Institutes of Health (NIH) created PCOS diagnostic criteria that required signs of hyperandrogenism and absent or irregular ovulation, but the excess ovarian follicles were optional. (Not everyone with PCOS even has these extra follicles and some people without PCOS have them, the CDC explains.) In 2003, a consensus workshop in Rotterdam, Netherlands, released their own criteria saying that any two out of those three potential signs of PCOS should be required for diagnosis. Finally, in 2009 the Androgen Excess and PCOS Society said someone would need to exhibit hyperandrogenism plus either of the other possible signs to be diagnosed with PCOS.

Confused yet? It’s no wonder why people like Emily often see multiple doctors before receiving a PCOS diagnosis.

Because the consensus among experts is that PCOS has no cure, researchers focus on treatment. If your doctor thinks you have PCOS, they may recommend hormonal birth control to regulate your hormone levels and menstrual cycle, according to the Mayo Clinic. They may also prescribe drugs like metformin to help your body become more sensitive to insulin, spironolactone for skin issues like acne brought on by androgen excess, or medications to stimulate ovulation if you’re having trouble getting pregnant.

While the FDA has approved medications to treat the symptoms of PCOS, it has yet to approve a drug specifically for the disorder. Many people with PCOS have to mix and match drugs to find relief. Emily, for example, decided to go back on hormonal birth control and added spironolactone to help with her symptoms.

Redman believes more and more research will focus on prevention in at-risk girls, like those who are insulin-resistant or whose mothers or sisters have PCOS. Doctors could, for example, test babies for any potential PCOS-related genes, then test whether certain diets prevent children with those genes from developing issues like insulin resistance that can lead to excess insulin production, Redman says. (Diet has been shown to help reduce PCOS symptoms in some people. You can read all about that here.)

“The future needs to be on prevention,” Redman says. “I think with more prevention in younger girls we can also improve the dialogue and the conversation about symptoms so that we can tackle them earlier.”

The challenges of researching PCOS

So why don’t we know enough about this disorder? Recruiting participants and keeping them enrolled is one major challenge in investigating PCOS, Redman says. Researchers typically want to recruit more patients than necessary since some people drop out of studies, she says, and this can be tough to do.

For patients with PCOS, the major benefits of participating in research could include free testing, evaluations, and recommendations that would otherwise cost them. It’s not just about the personal payoff, though. “My experience over more than 30 years has been that women with PCOS are very interested in helping us better understand their problem,” Dr. Dunaif says. “They’ve been so frustrated with their own cases that they want to help out.”

But participating in PCOS studies often requires that patients stop other medications, including hormonal birth control and insulin-sensitizing drugs, Redman says. She speculates that people do not want to give up medications that manage their symptoms for an unknown result, which can lead to less than ideal sign-up numbers.

Then there’s the process of actually participating in the studies. In general, the more prolonged studies are, the higher the dropout rates are, Dr. Dunaif adds.

“The highest dropout rates in these studies are usually in your control group, your normal subjects. They really have no incentive other than getting compensated for time and effort, and we don’t compensate them enough just on that basis,” Dr. Dunaif says. Controls can generally earn between $5 to $25 for one blood sample to hundreds of dollars for studies that last eight hours or so and require intravenous procedures, she tells SELF.

Dr. Dunaif has found that getting participants on board with gene-sequencing research has been easier because it usually involves getting their blood drawn once without the need for follow-up visits. “We really have to be very pragmatic when designing studies with human participants to not make it a burden,” she says.

A lack of financial backing is another huge barrier in PCOS research. The NIH is the largest public supporter of biomedical research in the world, according to the World Health Organization (WHO). Looking at how much of that funding goes to PCOS paints a pretty telling picture.

A 2017 study in The Journal of Clinical Endocrinology & Metabolism used the NIH Research Portfolio Online Reporting tool to look at how many grants the organization awarded to PCOS, rheumatoid arthritis, lupus, and tuberculosis between 2006 and 2015. Those last three illnesses affect about as many people in the U.S. as PCOS (or fewer) and appear to have a similarly negative impact on quality of life, according to past research. The study found that the NIH awarded less funding to PCOS ($215.12 million) than to these other conditions ($454.39 million for rheumatoid arthritis, $773.77 million for tuberculosis, and $609.52 million for lupus). The study authors concluded that “PCOS research may be underfunded considering its prevalence, economic burden, metabolic morbidity, and negative impact on quality of life.”

There are a few reasons why this may be the case.

“Most of the studies, most of the researchers, and most of the administrators tend to be [men] who are not necessarily interested in women’s health,” Ricardo Azziz, M.D., M.P.H., M.B.A., chief officer of academic health and hospital affairs at the State University of New York and lead study author of the NIH grant report, tells SELF. “The reality is that while some disorders of women have received a lot of attention, like breast cancer, others have not.”

Funding agencies prioritize disorders that have the greatest public health impact, such as the highest death rates, Dr. Dunaif says. This helps explain why conditions like heart disease and breast cancer (which kill around 300,000 and 41,000 women each year, respectively) have so much research behind them.

The confusion about the causes of PCOS may also make it a bit easier to fall through the research cracks. Institutes within the NIH tend to consider PCOS a reproductive disorder rather than a reproductive and metabolic disorder, Dr. Azziz says. So most of the funding (about 68 percent) that goes toward PCOS research comes from the National Institute of Child Health and Human Development (NICHD), which focuses on reproductive issues. Limiting PCOS to being viewed as just a reproductive disorder means researchers who are interested in metabolic aspects of PCOS, like its link to diabetes and nutrition, can have trouble securing funding, Dr. Azziz says. That doesn’t mean this doesn’t happen, but it’s less common.

The lack of funding for PCOS research also discourages some young scientists from entering this field, Dr. Dunaif says. On top of student-loan debt hanging over new graduates’ heads, a dearth of research money can steer potential scientists away from taking a chance on grant writing, she explains.

In addition to all of that, sometimes good researchers end up leaving the field, Dr. Azziz says. His own data shows that the number of PCOS research grant applications dropped 42 percent from 2006 to 2015, much more than any of the other conditions studied. With fewer competitive researchers come fewer breakthrough studies, Dr. Azziz explains.

What really needs to happen next

We need groundbreaking research on how to better diagnose PCOS, better treat it, and better understand its causes so that experts may be able to help prevent it.

One proposed solution to expand the PCOS funding pool is a name change to be more all-encompassing. (This would also nod to the fact that not everyone with this condition has excess ovarian follicles and people with excess ovarian follicles don’t always have this condition.) Experts haven’t agreed upon a new name yet. As Dr. Azziz describes in a fascinating 2014 paper in The Journal of Clinical Endocrinology & Metabolism, potential options might include “metabolic hyperandrogenic syndrome,” “polycystic ovary-hyperandrogenic syndrome,” and “polycystic ovary-anovulatory syndrome,” which would each correspond to different mixes of symptoms this condition most commonly causes.

As Dr. Azziz notes in the paper, the final consensus from an earlier NIH meeting about PCOS said, “The right name will enhance recognition of this major public health issue for women, educational outreach, ‘branding,’ and public relations and will assist in expanding research support.” Ideally it could have a domino effect that would address many of the research-related barriers in learning more about PCOS.

On-the-ground advocates are helping to push for this much-needed research as well.

Sasha Ottey founded PCOS Challenge in 2009 with the goal of mobilizing PCOS advocates to reach out to their representatives on behalf of people with the disorder. Congressional action can lead to more awareness and research funding, Dr. Azziz says. “PCOS Challenge has been doing a tremendous amount of work trying to move awareness forward,” he adds.

Ottey and her team found that other conditions had earned spots on the calendar of National Health Observances. So, the organization decided that PCOS needed an awareness month. PCOS Challenge formed a caucus to scout out members of Congress who were willing to work with the organization as its advocates on Capitol Hill, Ottey says.

Fast forward to December 2017, and the U.S. Senate passed a resolution introduced by Senator Elizabeth Warren to acknowledge “the seriousness of” PCOS, dubbing September 2018 as the first official PCOS Awareness Month. In February 2019, the U.S. House introduced its resolution to make September 2019 the second official PCOS Awareness Month. (These resolutions are generally introduced and passed every year, even for observances that are more established, like American Heart Month in February.)

“We’re taking back control by sharing our stories,” Ottey tells SELF. “Patients with PCOS, physicians, and researchers are now feeling more empowered because there is a sort of pipeline to get to an end result: more financial resources for PCOS research, awareness campaigns, and other initiatives to educate patients and health care providers.”

That’s what so much of this quest to demystify PCOS comes down to: the need for validating, illuminating, and potentially life-changing knowledge about this disease. “When I was diagnosed, I was more relieved than anything,” Emily says. “Why would you subject yourself to being uncomfortable or in pain or internally struggling with whether or not something’s wrong with your body? I would just rather know.”.

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