As explained previously, Long COVD affects twice as many women as men and has an even bigger impact on transgender individuals. Both estrogen and testosterone have significant immune-modulatory properties. Estrogen and testosterone are produced in all genders, however, at substantially different levels. Several studies have therefore analyzed reproductive events and levels of sex hormones in Long COVID patients and found that the disease can affect both reproductive health and the immune system.
Reproductive medicine specializes in fertility, and other reproductive events such as puberty, menopause, and birth control.
Long COVID and female reproductive health
Around 85% of patients with autoimmune diseases are female. At this point, it seems common knowledge that women have an elevated risk for Long COVID. We have written about this phenomenon in a previous blogpost.
Throughout a woman’s life, hormone levels change. The most impactful phases are puberty, menopause and, in some women, pregnancy and breastfeeding. Each of these phases and changes in sex hormone levels can also lead to changes in the immune system. A recent scientific review has summarized these effects.
The hormone estrogen strengthens immune responses against pathogens but also, in the case of autoimmunity, against the body itself. Estrogen levels fall drastically when a woman reaches menopause. This could be a reason why Long COVID affects women who have not yet undergone menopause (premenopausal women) the most.
Menstrual cycle
Studies indicate that premenopausal women with Long COVID often experience exacerbated premenstrual symptoms and/or worsened Long COVID symptoms correlated with menstrual cycle changes. In a cross-sectional study involving nearly 1800 participants, more than one-third of menstruating Long COVID patients reported heightened symptoms in the week before or during menstruation. In another cross-sectional study with 460 participants, 62% of Long COVID patients experienced aggravated symptoms in the days leading up to menstruation. Long COVID patients frequently note irregularities in their menstrual cycles, such as variations in cycle length, duration, and menstrual intensity.
In a retrospective cease-control study, the impact of COVID-19 (around 1000 participants) and vaccination (almost 5000 participants) on menstrual health was compared. The findings revealed that a previous COVID-19 infection, but not vaccination, was linked to heightened risks of alterations in menstrual cycle duration, intermenstrual bleeding (bleeding between periods), increased menstrual flow, and missed periods.
Fertility and ovarian health
A case report is a publication that details observations such as the symptoms, treatment, and follow-up of individual patients. It is not a detailed clinical study with control groups that provides solid scientific evidence but instead a helpful first observation that indicates where further research is needed. We explained the confidence level in different types of scientific publications in a recent blogpost.
Confidence level of different forms of publications.
Some case reports indicate a potential association between COVID-19 infection and the long-term deterioration of ovarian health, including the occurrence of premature ovarian insufficiency (POI), characterized by a decline in normal ovarian function before the age of 40, indicating early menopause.
However, due to the exclusive reliance on case reports, there are no available estimates regarding the post-COVID-19 incidence of POI or its correlation with related illnesses. Additionally, it remains unknown whether POI is more prevalent among individuals with Long COVID.
Long COVID and pregnancy
During pregnancy, levels of estrogens increase. At such high concentrations, estrogens appear to instead have immune inhibitory effects.
Limited research has delved into the intersection of Long COVID and pregnancy. In Ecuador, a cross-sectional survey involving pregnant (n = 16) and non-pregnant (n = 231) women with Long COVID revealed similar symptom experiences. Fatigue, hair loss, and difficulty concentrating were the three most commonly reported symptoms for both groups.
In a US prospective cohort study, 25% of pregnant individuals exhibited Long COVID symptoms eight or more weeks after testing positive for SARS-CoV-2. However, investigations into how Long COVID impacts pregnancy remain scarce.
A noteworthy control-matched prospective cohort study conducted in Brazil (n = 88) tracked pregnant women after testing positive for COVID-19 (n = 84), revealing that 75.9% developed Long COVID. Moreover, the study highlighted a higher risk of persistent fatigue among patients administered glucocorticoids to manage COVID-19 during pregnancy. This study demands further research in bigger populations.
Part one of this series explains what we currently know about the impact of Long COVID on female reproductive health. Part two summarizes what is known about reproductive health in ME/CFS and POTS.
