ENDO 2022 was once again a hotbed of new research as people convened in person and online from around the world. Here, we look at two international researchers who shared their COVID-19 studies in poster presentations that looked at the pandemic’s impact on thyroid function, thyroid dysfunction, and the impact on women’s ovulatory cycles.
ENDO 2022 took place June 11-14 in Atlanta, Ga., and was the first ENDO meeting to happen in person since 2019.
The live nature of this event meant that poster presentations could once again be shared in a more immediate way with audiences. Why is visual presentation important in research? First and foremost, it engages the audience more fully and allows them to connect with both the presenter and the science. It’s also a way to represent complex phenomena that might not otherwise be observable. And, as with any study presented at Endocrine Society meetings, sharing research with the larger scientific and medical communities increases collective understanding, which in turn ultimately translates to improved patient care.
Two researchers presented three studies relating to COVID-19: two on the safety of COVID-19 vaccination in relation to the thyroid and one on how the COVID-19 pandemic impacted ovulation.
Thyroid Function and COVID-19 Vaccination
On Saturday, June 11, David T. W. Lui, MBBS, MRCP, FHKCP, FHKAM (Medicine), clinical assistant professor in the Division of Endocrinology and Metabolism, Department of Medicine, of The University of Hong Kong, in Hong Kong SAR, China, presented highlights from “Safety of Inactivated and mRNA COVID-19 Vaccination among Patients Treated for Hypothyroidism: A Population-Based Cohort Study,” published in May in Thyroid as well as key points from the late-breaking “Effect of COVID-19 Vaccines on Thyroid Function and Autoimmunity and Effect of Thyroid Autoimmunity on Antibody Response,” that came out online in The Journal of Clinical Endocrinology & Metabolism (JCEM) just two days before the presentation.
“COVID-19 is associated with manifestations outside the respiratory system, including the thyroid gland,” Lui says. “Angiotensin-converting enzyme 2 (ACE2), the entry receptor for SARS-CoV-2, is expressed in thyroid cells, providing a mechanistic link between COVID-19 and the thyroid.” These facts coupled with case reports of Graves disease and Hashimoto thyroiditis occurring after infection with COVID-19 raised concerns among endocrinologists regarding COVID-19’s potential to cause thyroid dysfunction and trigger thyroid autoimmunity, he explains. This in turn begs the question, can vaccination against COVID-19 also induce thyroid dysfunction?
Subacute thyroiditis and Graves disease after COVID-19 vaccination have been extensively reported in patients with and without known thyroid disorders. Lui and team also recently published their findings about a 40-year-old woman who developed Graves disease five weeks after the second dose of mRNA COVID-19 vaccination (BNT162b2), on a background of longstanding hypothyroidism treated with a stable dose of levothyroxine. “Two mechanisms have been postulated to explain their associations. One is ‘autoimmune/inflammatory syndrome induced by adjuvants’ (ASIA). For example, aluminum hydroxide as the adjuvant of CoronaVac may be the culprit of inducing subacute thyroiditis in post-vaccination ASIA. Molecular mimicry is another: SARS-CoV-2 spike protein, nucleoprotein, and membrane protein all cross-reacted with thyroid peroxidase (TPO), suggesting that anti-SARS-CoV-2 antibodies may promote autoimmune thyroiditis,” Lui says.
“I was very excited to learn that ENDO 2022 had established a virtual platform allowing virtual presentations. It facilitates exchange of innovative research ideas and dissemination of important results through electronic poster presentations, and in turn, fosters collaborations among clinicians and scientists from around the world who share similar research interests. This is especially valuable since ENDO is a leading endocrine conference. Indeed, such a hybrid meeting format may be the way to go as the COVID-19 pandemic remains volatile.”David T. W. Lui, MBBS, MRCP, FHKCP, FHKAM (Medicine), clinical assistant professor, Division of Endocrinology and Metabolism, Department of Medicine, University of Hong Kong, Hong Kong SAR, China
So, to address the question of whether COVID-19 vaccination can cause thyroid dysfunction, Lui and team conducted two studies: one to systematically evaluate whether COVID-19 vaccines are associated with unstable thyroid function in patients treated for hypothyroidism and a second evaluating a prospective cohort of COVID-19 vaccine recipients without known thyroid disorders for the development of thyroid dysfunction and autoimmunity after COVID-19 vaccination.
For the first study that took place in late 2021, Lui collaborated with members of the Department of Pharmacology and Pharmacy from the University of Hong Kong, as part of the COVID-19 Vaccines Adverse Events Response and Evaluation (CARE) Programme, which was funded by a Research Grant from the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region. The team analyzed population-based electronic medical records, linked to population-based COVID-19 vaccination records, in 47,086 adults taking levothyroxine identified between February and September 2021. Vaccinated participants received either the BNT162b2 Pfizer-BioNTech mRNA vaccine (12,310) or the CoronaVac inactivated vaccine (11,353), and 23,423 participants were unvaccinated.
“This vaccine safety data linkage has been used to conduct population-based pharmacovigilance studies of COVID-19 vaccines on Bell palsy, arthritis flare-up, and myo-/pericarditis as well as whether patients with various diseases are at a higher risk of experiencing adverse events,” Lui says. The team compared the rates of changes in the dose of levothyroxine during follow-up between the vaccinated and unvaccinated groups in addition to emergency department visits, unscheduled hospitalization, adverse events of special interest according to the World Health Organization’s Global Advisory Committee on Vaccine Safety, and all-cause mortality.
Neither vaccine was associated with dose reduction or escalation of levothyroxine nor increased incidence of any of the secondary outcomes.
But the team didn’t stop there. “While a population-based database can elucidate whether COVID-19 vaccination is associated with significant thyroid dysfunction, a prospective cohort study is necessary to evaluate changes in thyroid autoimmunity following COVID-19 vaccination,” Lui says. Consequently, they recruited 215 adults without a history of COVID-19 or thyroid disorders who received two doses of COVID-19 vaccine between June and August 2021 to measure thyroid function and antithyroid antibody titers at baseline and again at 8 weeks. Neutralizing antibody titers against SARS-CoV-2 were also measured. Following vaccination, only a modest increase in antithyroid antibody titers was seen, without significant changes in antithyroid antibody positivity. Only three participants showed non-clinically overt abnormal thyroid function post-vaccination. Changes in thyroid function and antithyroid antibodies were consistent between mRNA and inactivated vaccine recipients, except for a greater antithyroid peroxidase increase with the mRNA vaccine. Importantly, neutralizing antibody responses were not influenced by the presence of preexisting thyroid autoimmunity.
“Believe women when they say that they got an early period after the COVID-19 vaccination — and if they report that, suspect that they are not ovulating normally, which explains why it happens. Ensure that your premenopausal women patients, especially if they had more cramps, or early post-vaccination bleeding during the pandemic, have recovered to normally ovulatory cycles.”Jerilynn C. Prior, BA, MD, FRCPC, professor of endocrinology and metabolism, University of British Columbia, Vancouver, Canada
These findings from both studies should reassure both clinicians and patients that there are no major changes in thyroid function after COVID-19 vaccination. In addition, the ability to disseminate this good (and potentially life-saving) news so quickly and directly is also important. “COVID-19 has just appeared for the past two and a half years. Researchers from around the world have put in immense efforts to elucidate the various aspects, including the endocrine aspect, of COVID-19 to advance our understanding of the disease and combat this global pandemic,” Lui explains. “I was very excited to learn that ENDO 2022 had established a virtual platform allowing virtual presentations. It facilitates exchange of innovative research ideas and dissemination of important results through electronic poster presentations, and in turn, fosters collaborations among clinicians and scientists from around the world who share similar research interests. This is especially valuable since ENDO is a leading endocrine conference. Indeed, such a hybrid meeting format may be the way to go as the COVID-19 pandemic remains volatile.”
Jerilynn C. Prior, BA, MD, FRCPC, professor of endocrinology and metabolism at the University of British Columbia in Vancouver, Canada, has long been studying women’s reproductive health, in particular the importance of maintaining the balance of estrogen and progesterone. In “Epidemic of Subclinical of Ovulatory Disturbances during SARS-COV2 Pandemic—an Experiment of Nature,” Prior presented an analysis of two independent studies undertaken 13 years apart. The Menstruation Ovulation Study (MOS) conducted from 2006 to 2008 with 301 reproductive-age women (ages 19-35 years) acted as a control for the similarly designed MOS2 that studied 112 women during the COVID-19 pandemic 2020-2021.
For background, Prior explains the role of progesterone: “Although we tend to focus on estrogen as being ‘woman’s hormone’ (which balances with testosterone as ‘man’s hormone’), in reality, the normal menstrual cycle requires estrogen and progesterone. Like estrogen, progesterone acts everywhere in the body — and there are good reasons that estrogen and progesterone need to be balanced in their actions. The most important one is that estrogen is a powerful growth-stimulating hormone. Progesterone is needed in high amounts because it slows or stops the proliferation that estrogen causes. It also causes each cell to differentiate into its specific role.”
In both MOS and MOS2, women participated in a single-cycle study. All completed an interviewer-administered questionnaire to obtain demographics, socioeconomic status, medical history, lifestyle, and reproductive variables. In addition, body measurements were taken. The team taught participants to record their menstrual cycle and everyday experiences in the Menstrual Cycle Diary© and to take their first morning temperature (for later Quantitative Basal Temperature© analysis of ovulation characteristics). Overall, the two cohorts were very similar regarding most individual participant characteristics.
Differences emerged with subclinical ovulatory disturbances (SODs), such as short luteal phases and anovulation that occur in regular, clinically normal cycles. Although MOS and MOS2 had similar average 30-day cycles (with 10% and 9% longer cycles, respectively) plus six-day flow lengths, nearly two-thirds of MOS2 participants experienced either a luteal phase too short to allow fertilization, or no ovulation at all, compared to only 10% of women from MOS experiencing SOD. Not surprisingly, the diary data of MOS2 participants showed significantly more anxiety and depression, perceived outside stress, sleep disturbances, and headaches than those in MOS.
Importantly, MOS2 was not originally intended to reveal insights about the pandemic. “We were doing a follow-up study to collect urine for environmental contaminants. That this cycle study happened during the pandemic was just plain serendipity,” Prior says. As estrogen and progesterone counterbalance each other’s actions in every tissue, it stands to reason that SOD means insufficient progesterone with normal estrogen levels. “We knew how monumental the changes that occurred in women’s lives during the pandemic, and the worries and isolation that went with these changes. We know that these can cause SOD, but I’ve never seen that high a prevalence of anovulation in my 40 years of menstrual cycle research,” Prior says.
In addition to the obvious effect to decrease fertility, persistent SOD can lead to bone loss, early heart attacks, and breast and endometrial cancers, owing to the associated imbalance between estrogen and progesterone. The “experiment of nature” that Prior calls it, demonstrates that the COVID-19 pandemic disrupted this balance, causing SOD but not overtly impacting the menstrual cycle. This suggests an important takeaway for clinicians treating infertility: “When you know a woman is under stress (can be emotional, social, economic, nutritional, illness etc.),” Prior says, “don’t assume all is well if she reports a regular menstrual cycle; check to see if she is normally ovulating. I believe that women reporting infertility need to have their ovulation checked (at least with a timed serum progesterone level) on several cycles before they start in vitro fertilization therapy. If they have ovulatory disturbances, it is common that working with them to understand and decrease the stressors, and/or cyclic progesterone therapy (started after the luteinizing hormone peak) will resolve the infertility issue.”
For all clinicians, Prior advises, “Believe women when they say that they got an early period after the COVID-19 vaccination — and if they report that, suspect that they are not ovulating normally, which explains why it happens. Ensure that your premenopausal women patients, especially if they had more cramps, or early post-vaccination bleeding during the pandemic, have recovered to normally ovulatory cycles.”
“COVID-19 has just appeared for the past two and a half years. Researchers from around the world have put in immense efforts to elucidate the various aspects, including the endocrine aspect, of COVID-19 to advance our understanding of the disease and combat this global pandemic.”David T. W. Lui, MBBS, MRCP, FHKCP, FHKAM (Medicine), clinical assistant professor, Division of Endocrinology and Metabolism, Department of Medicine, University of Hong Kong, Hong Kong SAR, China
About the ENDO 2022 meeting itself, she describes it as “a chance to identify who is doing the interesting work and to potentially talk in person with them.” Again, this kind of direct, immediate collaboration is what will ultimately move the needle in understanding the hormonal changes in women’s reproduction as well as other endocrine conditions.
Horvath is a freelance writer based in Baltimore, Md. In the July issue, she wrote about the GRADE methodology being used to create the Endocrine Society’s Clinical Practice Guidelines.