Consistently Observed Phenomena Reflect Reality
…and the reality is that men with COVID19 are more likely to become severely ill, require intensive care, and die than COVID19+ women (Chakravarty et al., 2020; Conti et al., 2020; Di Stadio et al., 2020; Jin et al., 2020; Nascimento et al., 2020; Richardson et al., 2020; Wang et al., 2020; Wenham et al., 2020; Zhao et al., 2020; Zijian et al., 2020).
In this review, we summarize and discuss 19 reasons for the widely documented sex difference in COVID mortality rates. A portion of the explanations focus on evolutionary differences (e.g., XX advantage over XY; estrogen), a portion of the explanations focus on gender socialization & role differences (e.g., men only seeking care when it gets serious or interferes with work; people more likely to spare women in both real life & videogames; men avoiding preventive care if care hours conflict with work hours due to desire to earn income to support family; mancave issues), & a few look at nature-nurture interactions.
Costeira et al., 2020: Women between 18–45 taking oral contraception had a lower rate of predicted COVID-19 (based on symptomatology) & lower rates of hospitalization, & a lower frequency of symptoms. Among women between 25–30, those taking contraception were less likely to be COVID-19 positive.
To be clear, it’s entirely safe to continue using contraception — and may even be recommended given the protective, immunostimulatory influence of estrogen (Costeira et al., 2020; Fruzzetti et al., 2020).
Estrogen Patch Experiment
Drug: Estradiol patch
→ The estrogen group received estradiol (a single-use Climara 25cm2 estrogen patch) 100 micrograms/day for 7 days through a patch applied on the upper buttock.
→ The control group received standard COVID19+ care.
“As the COVID19 pandemic has spread, it has been observed that adult men of all ages and older women are at higher risk of developing serious complications from infection with the virus. …Animal and human studies support immune modulating effects of estrogen that are acute acting in viral infections and wound repair processes that may reduce the damaging effects of the virus on the lung and symptom severity.”
Hypothesis → A transdermal estrogen patch applied to the upper buttock in COVID19+ or presumptive positive patients will reduce symptom severity in adult men & older (postmenopausal) women.
Inclusion Criteria → Male ≥ 18 years of age or female ≥ 55 years of age
Official Title → Phase II Clinical Trial of Estradiol to Reduce Severity of COVID19 Infection in COVID19+ & Presumptive COVID19+ Patients
Information provided by (Responsible Party):
Sharon Nachman, Stony Brook University
(ClinicalTrials.gov Identifier: NCT04359329)
Why women ≥ 55 years of age?
Menstrual Status and Sex Hormones (Ding et al., 2020, p. 3–4):
“…obvious differences existed in nonmenopausal females and age-matched males… fewer nonmenopausal females suffered severe COVID-19 disease” & ‘they were more likely to survive.’ Moreover, nonmenopausal women “showed a definite protective effect” as they ‘were less likely to be hospitalized & they were “discharged earlier than patients in menopause.”
In short, estradiol levels greater than 70 picograms per milliliter (>70pg/mL) “showed a clear protective effect against the disease.”
Pre-menopausal women with estradiol serum levels above 70 pg/ml are less likely to have severe COVID-19, as well as those using combined oral contraceptives (Mikhail & Wali, 2020).
Finally, supplementary data provided by Ding et al. (2020) was obtained & utilized for descriptive checks/insights. Of their participants who were 50 or older, 723 were women (median age 63) & 690 were men (median age 62). Despite the higher number of women 50 & older, AND despite the fact that an equal number of men & women had a severe diagnosis (n = 523 for both), a higher absolute number of men died (45; 4.81%) than women (16; 1.65%). This is consistent with the chorus of findings around the world of an XX advantage over XY in coronavirus mortality rates.
4.81% of men died whereas only 1.65% of women died
Contraception & Vitamin D
A study of Danish women found that contraceptive use was positively associated with Vitamin-D levels (Moller et al., 2013).
Brunettes, dark haired, & darker-skinned people are ‘more likely to have a vitamin-D deficiency due to the melanin in their skin mitigating the absorption of the sunlight needed to convert Vitamin D & facilitate the maturation of immune cells’ (Evans & Lippman, 2020-UCSD Team; Zhang & Liu, 2020). The prevalence of Vitamin D deficiency is higher for Black Americans & Hispanic Americans than White Americans (Araujo et al., 2009; Jacobs et al., 2008; Yetley, 2008; Zadshir et al., 2005), higher among Asians than non-Asian Britons (Shaw & Pal, 2002), and it’s higher among Hispanic men than Hispanic women (Forrest & Stuhldreher, 2011). The finding regarding Hispanic men relative to women is unique considering that the majority of Vitamin-D deficiency studies in China, Singapore, South Korea (Nimitphong & Holick, 2013), India (estimated 90% hypovitaminotic VD; Goswami et al., 2000), around the world have generally found higher deficiencies in women (Glerup et al., 2000).
Thus, research suggesting a beneficial role of contraception in relation to Vitamin D may be particularly relevant for individuals with darker skin tones.
Here’s a D-lightful Finding =^.^=
A study of Black American women (N = 1,662) found that Vitamin D levels were 20% higher for those taking estrogen-containing contraception (Harmon et al., 2016).
Lesbians & Bisexual women have higher rates of teen pregnancy than straight women
Given the potentially protective effects of contraception, health providers should strive to redress ongoing inequities in gay and bisexual women’s access to & delivery of reproductive health services.
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Cautionary Note on Contraception for Women at Risk of Venous Thromboembolism (VTE)
(Paraphrasing & quoting several articles; see references below)
→ ‘Coagulation hyperactivation in symptomatic COVID-19 severe patients may have an increased risk of VTE when in use of estrogens (Pires et al., 2020).
→ Thus, it may be good to replace combined hormonal contraceptives (CHC) with contraception containing progestogen alone for women with severe COVID, as the use of contraceptive methods that contain only progestogens is not associated with an increased risk of VTE (e.g., oral, IUD, & implants; Mantha et al., 2012). Compared to the transdermal route of estrogen administration, the oral route is associated with increased VTE risk (Marianne Canonico et al., 2007).
→ Women with mild COVID-19 symptoms (e.g., fever, cough) may keep using CHC (Fruzzetti et al., 2020).
→ Mantha et al., 2012 (p. 4): “Our analysis also suggests that the relative safety of progestin-only agents may be limited to oral and intrauterine formulations, whereas the thrombotic risk associated with injectable progestin seems to be of similar magnitude to oral contraceptives containing oestrogen.”
Injectable progestins are associated with a “twofold increase in thrombotic risk” (Mantha et al., p. 4).
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Costeira, R., Lee, K. A., Murray, B., Christiansen, C., Castillo-Fernandez, J., Lochlainn, M. N., … & Ourselin, S. (2020). Estrogen and COVID-19 symptoms: associations in women from the COVID Symptom Study. medRxiv.
Ding, T., Zhang, J., Wang, T., Cui, P., Chen, Z., Jiang, J., … & Ma, W. (2020). Potential influence of menstrual status and sex hormones on female SARS-CoV-2 infection: a cross-sectional study from multicentre in Wuhan, China. Clinical Infectious Diseases.
Fruzzetti, F., Cagnacci, A., Primiero, F., De Leo, V., Bastianelli, C., Bruni, V., … & Grasso, A. (2020). Contraception during Coronavirus-Covid 19 pandemia. Recommendations of the Board of the Italian Society of Contraception. The European Journal of Contraception & Reproductive Health Care, 1–2.
Harmon, Q. E., Umbach, D. M., & Baird, D. D. (2016). Use of estrogen-containing contraception is associated with increased concentrations of 25-hydroxy vitamin D. The Journal of Clinical Endocrinology & Metabolism, 101(9), 3370–3377.
Mantha, S., Karp, R., Raghavan, V., Terrin, N., Bauer, K. A., & Zwicker, J. I. (2012). Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis. Bmj, 345, e4944.
Pires, A. L. R., Batista, J. G., Aldrighi, J. M., Massaia, I. F. D. S., Delgado, D. M., Ferreira-Filho, E. S., & Soares-Junior, J. M. (2020). Risk of venous thromboembolism in users of contraception and menopausal hormone therapy during the COVID-19 pandemic. Revista da Associação Médica Brasileira, 66, 22–26.
General Estradiol (E2) Levels for
- Premenopausal women = 30 to 400 pg/mL
- postmenopausal women = 0 to 30 pg/mL for postmenopausal women
- men =10 to 50 pg/mL for men
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“Female patients are able to achieve viral clearance significantly earlier than males” (White & Kirby, 2020).
Males are generally more susceptible to infections than females (Jaillon et al., 2019), and COVID19-positive males are more likely to shed than females (Mizumoto et al., 2020), and males shed (M = 18 days) for a longer duration of time than females (M = 15.2) (Xu et al., 2020).
Nelson et al., 2020: “Even when female testosterone is pathologically raised in polycystic ovarian syndrome the values are still a fraction (˜1/20th) of that observed in males.”
Cell-mediated immunity following vaccination is higher in women (Umlauf et al 2012), as the protective antibody response is twice as high in women (Klein et al., 2010).
Hormonal contraceptive users also had higher daily intake of Vitamin C (Moller et al., 2013).
How much will gaining an hour of sleep due to Daylight Endings Time worsen men’s COVID19 clinical outcomes in November? For instance, Zhang et al. (2020) found that the extra hour in Autumn was associated with a 12% increase in psychoactive substance use… in males.
How can we invest in lesbian bars (reportedly only 16 left in the United States) while maintaining social distancing?
Gender Socialization & Women’s Vitamin D Deficiency
- Asia: Male Gaze → women’s desire to have whiter skin → avoid sunlight → women more likely to buy parasols → parasols & umbrellas depicted as a woman’s accessory for centuries (Sangster, 1855) → 1623 painting by Sir Anthony van Dyck of Marchesa Grimaldi with her parasol.
- India (Sonam Joshi & Aashmita Nayar, 2016): daughters receive less nutrition than sons → desire to have whiter skin complexion → avoid sunlight
- Islamic women wearing veil → less exposure to sunlight. Also, would Islamic women’s infection rate have been lower than men’s in pre-mask March/April due to wearing burka/niqab/chador?
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Note: This is a standalone companion piece of the larger 19 Reasons Why series.