The women possibly at higher risk for Covid-19 that no one is talking about - CNN

She is 31 years old, a pet sitter and former fitness teacher who once ran a half marathon. She was, by most measures, healthy.

When Aguilar got Covid-19 she lost her sense of taste, had mild fevers and muscle weakness. She could barely keep anything down yet gained about 30 pounds. Later, she developed pelvic pain, cystic acne, breast tenderness, headaches, brain fog and extreme fatigue.

It has been months since then, but she says the low energy, chronic pain and brain fog -- long-haul Covid-19 symptoms -- remain and she can't even go for a 15-minute walk without needing a break. She's also now dealing with insulin resistance and taking several medications to keep that and her hormone levels under some control. Her doctor told her she'll likely be dealing with this fallout of Covid-19 for the rest of her life.

More than a year into the pandemic, one study has found that some women are at higher risk for Covid-19 compared to others in their age and sex groups. These women, often young and otherwise healthy like Aguilar, have an underlying condition that isn't mentioned on any Covid-19 comorbidity list: polycystic ovary syndrome, or PCOS.

PCOS, which affect about 1 in 10 women of "childbearing age," is an imbalance of reproductive hormones that can lead to irregular menstrual cycles, high androgen levels and ovarian cysts. But it can also come with a host of other health problems, nearly all of which overlap Covid-19 comorbidities.

"PCOS is completely underestimated in its impact. It's sort of seen as some reproductive issue that is not clinically relevant. But this is completely wrong ... Patients need to be seen as a high-risk population," said Dr. Wiebke Arlt, director of the Institute of Metabolism and Systems Research at the University of Birmingham in the United Kingdom.

More than half of people with PCOS develop diabetes before their 40th birthdays, and up to 80% are overweight. They have higher risk of insulin resistance, heart disease and endometrial cancer, a cancer that begins in the uterus. Many have high blood pressure and low levels of vitamin D. These complications of PCOS have also been associated with a potentially higher risk for severe Covid-19.

Despite how common PCOS is, as well as the serious complications it can come with, health experts say the condition has long been overlooked, misunderstood and under-researched, leaving patients to advocate for themselves or even educate practitioners to get treatment. And with very little research looking at whether women with PCOS are at higher risk for more severe Covid-19 or long-term symptoms, some fear the same is happening with public health policy around the pandemic.

"My advice would be to include women with PCOS as ... potentially a high-risk group," said Dr. Katherine Sherif, chief of Women's Health at Jefferson University's Department of Medicine and a leading PCOS expert. But she warned: "We're working in a very large system that is full of silos. Nobody's going to jump up and say, 'Oh, well, don't forget about PCOS.'"

"If Anthony Fauci said, 'you need to look at the high-risk groups like PCOS,' people might pay more attention," she said.

Part of the reason PCOS flies under the radar in general and with regards to Covid-19, according to Arlt and Sherif, is because it is often dismissed as a women's health issue -- an obstacle of the ovary. Over the past year, we've learned about numerous preexisting health conditions that put a person at higher risk for severe Covid-19 illness, but PCOS isn't one of them.

For Arlt, who co-authored the first major study published in February in the European Journal of Endocrinology, the name PCOS is a misnomer. It is not a disorder of the ovary, Arlt said, but a "lifelong metabolic disease" and should be treated as such when assessing Covid-19 vulnerability.

"The higher the metabolic risk is, the higher the risk is to catch Covid-19," Arlt said. "People looked at obesity and Type 2 diabetes and hypertension and heart disease, but they have not looked at PCOS systematically before we did. Because they just don't consider this a metabolic risk factor. That's something that we would like to change."

'Something in PCOS is actually driving this'

Arlt and researchers at the University of Birmingham in the United Kingdom found that women with PCOS had a 51 percent higher chance of confirmed or suspected Covid-19 infection than women without. Using primary care records from January to June 2020, they identified more than 21,000 PCOS patients and a control group of more than 78,000 without, matched for age and location.

Researchers then "wanted to understand if the increased incidence of Covid-19 was only because of PCOS, or was it also because of the underlying risk factors that women with PCOS have?" lead author Anuradhaa Subramanian told CNN. In other words, if a woman has PCOS and Type 2 Diabetes, which one is putting her at increased risk for Covid-19?

In a fully adjusted model that took various risk factors into account, women with PCOS still had a 28% increased risk for confirmed or suspected Covid-19 infection, according to the study.

Subramanian says the results didn't surprise her. However, "it gave us more confidence... that it's not just about the risk factors associated with PCOS, but something in PCOS is actually driving this," she said.

But because the data was pulled from primary healthcare databases, researchers couldn't look at whether patients with PCOS had more severe or long-term Covid-19 symptoms. What's more, PCOS is not a one-size-fits-all disorder and Covid-19 may or may not have a different impact or risk level depending on the person. There are many questions we don't have definitive answers to yet, says Dr. Anuja Dokras, director of the Polycystic Ovary Syndrome Center at Penn Medicine.

"We need to get this information now that (Covid-19 has) lasted a full year," said Dokras. "It's affecting so many people that it would be good to look back at this literature and just sort it out because these are confounding factors."

Searching for answers

So far, whether people with PCOS have more severe complications from Covid-19 is anecdotal, leaving some women with only speculation about how Covid-19 affects PCOS.

In Aguilar's case, she was diagnosed with PCOS after she was exposed to Covid-19, despite likely having it for years but not recognizing the symptoms. "I had some of these underlying symptoms, my body was able to just manage them to a point for most of my life, and then contracting Covid really just wiped out all of my body's defenses and ability to regulate anything," she said her doctor told her.

But she still doesn't know why or whether her symptoms will ever improve.

Kris Nealon has also spent much of the past year looking for answers.

She was diagnosed with PCOS at age 12, and the disorder has left her struggling with her weight and insulin resistance. These factors, she says, made her concerned that she could have severe Covid-19 symptoms and maybe even require hospitalization. So last summer she did what most have done during the pandemic: She Googled it. She recalled searching "'should I be concerned...insulin resistance COVID?' or 'PCOS COVID?'"

Nealon didn't find answers. She got Covid-19 in October and says her symptoms were mild. But when that turned into muscle and joint pain, extreme fatigue, depression, insomnia and brain fog, she did what was recommended: Talk to her doctor.

In Nealon's case, she spoke to several. Having lived with PCOS more than half her life, she was aware of the complications and wanted to know how this could impact her long-term Covid-19 symptoms.

She says the primary doctor for her long-term symptoms said her only Covid-19 comorbidity was her weight.

"He's been nice and understanding but ... you can see him be like, 'Lady problems, don't worry about it. This is your lungs,'" she said. She told him that PCOS is linked to anxiety and depression and asked if that could be related to Covid-19 fatigue and insomnia. She also asked about her heart, explaining that PCOS and Covid-19 can cause complications.

But aside from suggesting that losing weight might help, Nealon recalled her doctor saying "it had nothing to do with PCOS. He's like, 'no, that's your ovaries and stuff.'"

After Covid-19, Nealon also noticed her PCOS symptoms "went crazy." She says she had extreme pain in her lower abdomen. An ultrasound showed her fallopian tubes "suddenly looked very concerning" and she had an ovarian cyst burst.

She went to her gynecologist, the doctor who first diagnosed her with PCOS, and asked, "Does this have anything to do with (that) I just had Covid?"

She says her doctor told her: "No, there's no literature about that."

And there wasn't. Weeks after Nealon tested positive, Allison Roach and Chitra Gotluru, two medical students at Florida International University, finished their journal article exploring the potentially higher risk women with PCOS have for Covid-19-related morbidity. No data set of patients with both diagnoses existed, they said.

Risk 'obvious but not proven'

Roach's and Gotluru's research, published in the March issue of the journal Obstetrics and Gynecology, shows the potentially higher risk for PCOS patients comes down to "comorbidities, androgens and lipotoxicity."

People with PCOS often have higher levels of and sensitivity to androgens, male sex hormones. This could "potentially directly affect the susceptibility to COVID-19," Roach and Gotluru wrote. Androgens work as a "gateway," in very simple terms, to let in Covid-19, Roach says.

What's more, it is common for people with PCOS to have chronic inflammation -- an immune system that is in a near-constant state of fighting off harm. Impaired insulin regulation and obesity can lead to a toxic buildup of fatty acid in tissue, known as lipotoxicity, potentially damaging organs.

This can also trigger the secretion of immune-signaling cells called cytokines. While cytokines are a vital part of the body's immune response, too much can cause what's known as a cytokine storm. Adding a Covid-19 infection to that can cause further cytokine secretion, potentially triggering one of these storms and causing the immune system to attack the body's cells, not just the pathogen. And there is research that suggests this can occur "whether you are overweight or not," Gotluru told CNN.

For Jefferson University's Sherif, the risk of more severe Covid-19 symptoms for PCOS patients is "obvious but not proven." Obvious because "If testosterone increases inflammation, and if ... men who are in the hospital with Covid complications and have high testosterone levels, it makes sense that it would put women with PCOS more at risk."

This is not proven, she says, because so little research exists.

Drawing from her own research about PCOS and heart disease, Sherif said, "What's important for people to understand is that this is independent of obesity."

"It's the high insulin and high testosterone that confer their risk for a greater risk for Covid compared to weight matched controls," she said. "So, you have two women who are 100 kilograms. The one with PCOS is more likely to become diabetic or have sleep apnea, or to be sick from Covid."

Without that data, some doctors and researchers say this is something patients with PCOS should be aware of, but not to panic. If you do get Covid-19, it's important to tell your doctor you have PCOS and any medications you're taking, Gotluru says.

"Let your provider know ... that there is research out there that is worrisome about PCOS and you'd like to be careful," she said.

In the meantime, women like Aguilar and Nealon are still searching for answers. Nealon says her doctors still haven't made a connection between the fallout of Covid-19 and her PCOS. She isn't surprised.

"That's what it's like, just with PCOS, let alone adding Covid in," Nealon said. "You go to a doctor with a list of symptoms, and you either get 'you're fat' or 'you're overthinking things.'"

Aguilar says that constantly having to educate people in her life has been exhausting on top of her two new diagnoses.

"A lot of people like to talk about the survival rate is so high and the death rate is so low, but what they're not taking into account is the degree that lives are changing because of illnesses that are popping up from this, or just the long-haul symptoms that are so debilitating," Aguilar said. "It's hard to overcome."

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