Female reproductive health impacts of Long COVID and associated illnesses including ME/CFS, POTS, and connective tissue disorders: a literature review

Abstract

Long COVID disproportionately affects premenopausal women, but relatively few studies have examined Long COVID's impact on female reproductive health. We conduct a review of the literature documenting the female reproductive health impacts of Long COVID which may include disruptions to the menstrual cycle, gonadal function, ovarian sufficiency, menopause, and fertility, as well as symptom exacerbation around menstruation. Given limited research, we also review the reproductive health impacts of overlapping and associated illnesses including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), postural orthostatic tachycardia syndrome (POTS), connective tissue disorders like Ehlers-Danlos syndrome (EDS), and endometriosis, as these illnesses may help to elucidate reproductive health conditions in Long COVID. These associated illnesses, whose patients are 70%–80% women, have increased rates of dysmenorrhea, amenorrhea, oligomenorrhea, dyspareunia, endometriosis, infertility, vulvodynia, intermenstrual bleeding, ovarian cysts, uterine fibroids and bleeding, pelvic congestion syndrome, gynecological surgeries, and adverse pregnancy complications such as preeclampsia, maternal mortality, and premature birth. Additionally, in Long COVID and associated illnesses, symptoms can be impacted by the menstrual cycle, pregnancy, and menopause. We propose priorities for future research and reproductive healthcare in Long COVID based on a review of the literature. These include screening Long COVID patients for comorbid and associated conditions; studying the impacts of the menstrual cycle, pregnancy, and menopause on symptoms and illness progression; uncovering the role of sex differences and sex hormones in Long COVID and associated illnesses; and addressing historical research and healthcare inequities that have contributed to detrimental knowledge gaps for this patient population.

Sex differences in symptomatology and immune profiles of Long COVID

“…It should be noted that LC symptoms have a significant overlap with those found in other PAIS conditions 5 . These findings provide support to investigate the role of sex hormones in PAIS including ME/CFS and chronic Lyme disease 11,34–37 .…”

Sex differences of post-Covid patients undergoing outpatient pulmonary rehabilitation

“…The reasons for observed sex differences are less understood in PCS compared to acute Covid-19 infections. Fatigue is a central symptom of affective disorders such as depression as well as syndromes associated with exposure to viral infections known prior to Covid-19 such as myalgic-encephalomyelitis/chronic-fatigue-syndrome (ME/CFS) [ 23 , 24 ]. A sex-gap with female overrepresentation is well-documented in both depression and ME/CFS and is putatively owed to both gender-related variables and biological factors.…”

Long read sequencing characterises a novel structural variant, revealing underactive AKR1C1 with overactive AKR1C2 as a possible cause of severe chronic fatigue

“…Gastrointestinal dysfunction and hypocortisolism are common in these conditions, as is dysregulation of the autonomic nervous system [42][43][44] which may similarly be modulated by neurosteroids [45,46]. These conditions are also more common in women [47,48], as might be expected if higher P is a factor. If there is variable expressivity then such variants could also contribute to more tissue-or organ-specific disorders where increased GABA activity or impaired progesterone clearance could play a role, such as irritable bowel syndrome or Gitelman-like renal salt wasting, or to psychiatric disorders that may be related to increased allo activity in the brain such as premenstrual dysphoric disorder [10].…”