When Jennifer Ching first developed symptoms of COVID-19 in early March, little did she know she would become one of many “long-haulers” — patients who had lingering symptoms weeks after their initial infection.
For Ching, the long-haul was a constant low-grade fever that ebbed and flowed, coupled with headaches, fatigue and exhaustion. Her symptoms persisted for months, subsiding and resurfacing from March all the way to June.
As she tracked the cycle of her symptoms, Ching found one consistency. Every time her symptoms of COVID-19 infection diminished, there was one constant: she was menstruating.
“There was something weirdly cyclical for me,” Ching told MedPage Today. “I kept not having the fever when I had my period.”
Ching, a Brooklyn resident in her mid-forties, said that each time her infection improved, it coincided with menstruation. Yet when the bleeding stopped, her symptoms re-emerged.
Ching also noticed abnormalities within her menstrual cycle itself. At one point while she was sick, her periods were only 17 days apart, and she said the duration was shorter than normal.
“One of the reasons why I’m feeling confident that I am better now is because I just experienced my first, regular cycle,” Ching said. “Going back to early March, it’s just been kind of wacky.”
Ching is one of several patients who spoke with MedPage Today about changes in their menstrual cycles since the onset of COVID-19. Jaime Horowitz, a 25-year old from New Jersey, said that her period was the most painful it had ever been when she first got infected, then disappeared entirely for three months. Anna Lefer Kuhn, 45, of Washington, D.C., maintains that the virus brought her period to a halt. Keely Enright, 55, a Charleston resident who receives hormonal therapy, said that her period came back when she caught the virus — two years after she went through menopause.
Is there some relationship between coronavirus and menstruation? Ob/gyns are hesitant to speculate, as there’s plenty of room for correlation over causation.
However, evidence that women with COVID-19 fare better than men has raised questions about the biological factors that may account for sex differences, and scientists are looking into whether female sex hormones and menstrual status are protective.
In April, a study of 5,700 COVID-19 patients at Northwell Health in New York revealed that males made up a majority of those with severe illness — 60% of all who were hospitalized — and had higher rates of mortality than age-matched females.
“It appears that gender was a factor, as far as the severity of the illness,” Michael Nimaroff, MD, director of obstetrics and gynecology at Northwell Health, told MedPage Today. “There clearly is something going on that protects women.”
Doctors in the ob/gyn department at Northwell Health also noticed that pregnant patients did not experience an increased risk of severe outcomes, as observed with previous viral infections. While they did see a number of pregnant patients who were severely affected and in the ICU, the numbers were no greater than age-matched individuals who were not pregnant, Nimaroff said.
Last week, however, the CDC reported a higher risk of mechanical ventilation and ICU admission among pregnant women with COVID-19 — one of the largest datasets suggesting increased illness severity among this population.
It’s still possible that pregnant women, who have higher levels of estrogen and progesterone, could be protected from serious outcomes, but Nimaroff said there’s not yet enough evidence to support this.
Regarding the sex differences in COVID-19 severity, Nimaroff said that it is likely that comorbidities like heart disease, higher rates of smoking, or higher levels of androgens might explain worse outcomes among men. But theories that female sex hormones may be protective are still possible, as estrogen improves the immune response to infection.
Estrogen — specifically estradiol, or E2 — stimulates the humoral response to viral infection, activating higher levels of antibody production, researchers said. Immune cells have estrogen receptors and can respond to estrogen stimulation, which may improve immune response.
“Estrogen is a hormone that has multiple effects on the body,” said Alison Stopeck, MD, co-investigator of a clinical trial that is treating COVID-19 patients with estrogen at Stony Brook University in New York. Not only does the hormone activate antibody production, she said, but it also prevents the hyper-cytokine release that causes an excessive inflammatory response.
“It has a lot of immune effects, and it can actually work in a way that would improve the body’s response to a viral infection such as the novel coronavirus,” Stopeck told MedPage Today.
Research published by a group in Italy hypothesized that estrogen — including E2 and synthetics such as ethinylestradiol — may prevent women from experiencing severe COVID-19 outcomes, or that combined hormonal contraceptive use (which contain both estrogen and progesterone) may be protective. Oscillation of estrogen levels during the menstrual cycle might impact immune system response.
“The fluctuation of E2 levels during the menstrual cycle can make women differently immune-reactive before ovulation in the advanced proliferative phase when E2 levels are highest,” the researchers wrote.
Others have concluded that menstrual status may be associated with COVID-19 outcomes. In a preprint analysis of more than 400 female COVID-19 patients published in March, researchers in China found that “menstruation showed a definite protective effect” after controlling for multiple confounders, including age.
Non-menopausal patients experienced shorter hospitalization times, earlier discharge, and lower disease severity than those who had already gone through menopause. The group also found that levels of E2 and antimüllerian hormone (AMH) were negatively correlated with disease severity, “probably due to their regulation of cytokines related to immunity and inflammation.”
The anti-inflammatory properties of female sex hormones have driven scientists to investigate how estrogen and progesterone may improve the immune response in men and postmenopausal women. Clinical trials have emerged in New York and California to evaluate how increased hormone levels may impact populations other than non-menopausal women.
Stopeck’s group is conducting an estrogen patch trial in adult men with moderate COVID-19 illness, as well as women over age 55. Participants apply a 100-mg estradiol patch directly to the skin for 7 days.
“We definitely think that it will work in earlier patients,” Stopeck said, which is why the trial was designed for patients who have not been intubated. Researchers are expecting that patients with less severe disease will be the best responders to estrogen.
“We would hope to see that the patients who are treated with estrogen have a lower incidence of being intubated or severe respiratory illness and recover rapidly,” Stopeck said. She added that the group ideally hopes to analyze antibody titers, as well, to see if estradiol affects longitudinal antibody expression.
Participants that have a history of thromboembolic events, such as deep vein thrombosis or pulmonary emboli, are excluded from the trial as estrogen may increase risk of clotting.
Researchers from Cedars-Sinai in Los Angeles are exploring another route: injecting male patients with progesterone. Sara Ghandehari, MD, the principal investigator of the California-based trial, said that the use of progesterone targets various immune cells to “dampen this inflammatory cascade.”
Ghandehari’s group will conduct a single-center trial of 40 male patients hospitalized with COVID-19. Participants are randomized to progesterone injections along with standard of care, or conventional treatment alone. Patients in the intervention group receive subcutaneous progesterone injections (100 mg) twice a day for 5 days, and are followed up for approximately two weeks.
Both clinical trials started in April, and are still recruiting participants.
While preliminary evidence shows that female sex hormones may provide some protection against the inflammatory effects of COVID-19, Nimaroff emphasized that multiple factors are at play.
“There’s so many pieces to this, and it takes a lot of patients for us to really see a benefit or not,” Nimaroff said. “The science shows that there’s some benefit to estrogen, so it’s certainly reasonable to go down that path.