Hormonal stratification of COVID-19 risk categories
Women exhibit highly dynamic oestrogen trajectories across their lifespan, from the initial pre-pubertal surge, to the regular cyclical fluctuations with menstruation, the substantive increases with pregnancy followed by post-partum resolution, and then the dramatic declines observed with the onset of menopause or in the pathogenic state of premature ovarian insufficiency. The scale of these changes is immense, with pregnancy oestradiol levels frequently exceeding 1,000pg/ml as compared to 30 to 400pg/ml for ovulating premenopausal women, and almost undetectable levels in post-menopausal women. Progesterone levels exhibit a 10-fold increase in across the menstrual cycle with formation of the corpus luteum, with a further 10-fold increase during pregnancy, before becoming negligible in the menopause. Female androgen concentrations decline with age, to levels that approximate 50% of peak values, however, even when testosterone is pathologically raised in polycystic ovarian syndrome the values are still a fraction (~1/20th) of that observed in males. Notably these hormonal fluctuations underpin stratification of risk for a range of diseases including hormonally sensitive cancers, cardiovascular disease and thromboembolic disease.
Whether these marked changes in sex steroids underlie some of the differences observed for disease progression for different female populations is an area for further study6. The relative low impact of SARS-Cov-2 on pregnant women may reflect their relative shielding, or the pregnancy specific sex-steroid mediated differential immune response. The increased incidence of complications post-partum period may reflect resolution of physiological adaption to pregnancy or hormonal changes but recording gestational age or time from delivery is a prerequisite to understand disease course. For the non-pregnant population epidemiological studies should record the contraceptive methods being used and menstrual cycle characteristics, as oestrogen containing oral contraceptive pills, progesterone only pills and implants all frequently stabilise oestrogen levels removing ovulatory fluctuations and early follicular troughs but with differing efficacy. For older women where disease severity is increased, clarification of the independent effect of the menopausal transition on disease progression would be useful as age and reproductive stage may be independent variables in determining disease severity7. Whether exogenous hormone replacement therapy is being taken, and if single or combined preparations and dose may be central to help clarify if oestrogen supplementation mitigates risk. Selective oestrogen receptor modulators like tamoxifen, which may increase circulating oestradiol levels with prolonged use, also need to be recorded.