Impact of gender-affirming hormone therapy on the development of COVID-19 infections and associated complications: A systematic review

Table 1 Laboratory studies

Ref.	Study type	Focus	Results
Youn et al[37]	In vitro cell line treatment	Investigated potential protective effects of estrogen on endothelial cells against oxidative stress induced by IL-6 and by SARS-COV-2 spike protein (S protein)	17B-Estradiol reversed S protein induced activation of NADPH oxidase isoform 2 (NOX2) and ACE-2 dependent ROS production, as well as ACE2 upregulation and induction of pro-inflammatory gene monocyte chemoattractant protein-1 (MCP-1) in endothelial cells, effectively attenuating endothelial dysfunction completely
			Implications: Estrogen inhibits initial viral response and attenuation of cytokine storm induced endothelial dysfunction, especially in men and post-menopausal women. Data supports hypothesis that estrogen may be used to alleviate viral infection and cytokine storm-induced endothelial dysfunction, a critical mediator of ARDS/multi-organ failure. Thus, attenuating disease progression, severity and mortality
Samuel et al[42]	In vitro stem cell lines and high throughput drug screens	Established a screening strategy to identify drugs that reduce ACE2 levels in human embryonic stem cell (hESC)-derived cardiac cells and lung organoids. Target analysis of hit compounds revealed androgen signaling as a key modulator of ACE2 levels	Inhibitors of 5-alpha reductase, which dampen androgen signaling reduced ACE2 levels in target cells; Treatment with antiandrogenic drugs reduced ACE2 expression and protected hESC-derived lung organoids against COVID-19 infection; Study also found that clinical data on COVID-19 patients with prostate cancer, which is associated with elevated androgen levels, are significant risk factors and that genetic variants that are associated with higher androgen levels are associated with higher diseases severity

Table 2 Current literature on hormone therapy and coronavirus disease-2019 clinical trials

Ref.	Focus	Predictors or conditions	Sample Population	Outcomes/Findings
Ghandehari et al[36]	Los Angeles, California; Effect of progesterone therapy in men with moderate to severe COVID-19	Randomized control trial	42 hospitalized men with confirmed moderate to severe COVID-19	There was a 1.5 point overall improvement in median clinical status score on a seven-point ordinal scale from baseline to day 7 in the progesterone group (n = 18) compared with the control group (n = 22)
			Experimental Cohort: re received 100 mg of progesterone subcutaneously twice a day for 5 d while hospitalized
				This study shows that the use of progesterone may help to lower the length of hospital stay, use of supplemental O2 and need for mechanical ventilation
			Control Cohort: Standard of care
Dhindsa et al[12]	Association of concentration of serum sex hormones with COVID-19 Severity	Prospective cohort study	152 consecutive patients (59% men and 40.8% women) presenting with COVID-19 to the hospital were recruited. Of the participants, 143 (94.1%) were hospitalized. The mean age of participants was 63 yr	Lower testosterone concentrations and increased estradiol to testosterone ratios during hospitalization are associated with disease severity, inflammation, and mortality in men with COVID-19. Men with severe COVID-19 had 65%-85% lower testosterone concentrations compared with men with milder disease course, and was independent of other known risk factors associated with COVID-19 severity
van Zeggeren et al[25]	Assess the association between androgen levels and mortality in patients with severe COVID-19	Observational Case-control study	16 postmenopausal women (age > 55), and 24 age matched men	Total and free testosterone were lower in deceased men than in survivors. Significantly lower SHBG levels were associated with in both deceased men and women compared with survivors
				Low SHBG levels were associated with mortality rate in patients with COVID-19 and low total and free testosterone levels were associated with mortality in men. However, whether these hormone levels influence the disease severity, or are a marker of disease severity needs elucidation
Seeland et al[31]	Evidence for treatment with estradiol for women with SARS-COV2 infection	Retrospective cohort study	Electronic health record for a large, 68,466 case international COVID-19 cohort	Incidence of SARS-CoV-2 infection is ≥ 15% higher in women than men, but fatality rate is higher is 50% higher in men. Age stratification showed, that while preadolescent men and women had same risk of infection and fatality rate, compared with men of the same age, premenopausal women had a higher risk of infection, but peri and post-menopausal infection rates were similar to men of the same age; -fatality risk for women > 50 yr receiving hormone therapy with estradiol was reduced by > 50% (OR 0.33, HR 0.29) compared with women not receiving HRT. For younger women, (15–49 yr of age) risk of COVID-19 fatality was the same irrespective of estradiol treatment
Infante et al[24]	Asses testosterone levels at time of admission with inflammatory state and in-hospital mortality rate	Retrospective cohort study	40 symptomatic men with confirmed COVID-19 infections admitted to hospital. Patients were divided into two groups, survivors (n = 20), and non-survivors (n = 39)	Low total testosterone levels and elevated E2/T ratios (a marker of aromatase activity) were associated with a hyperinflammatory state. Low testosterone was an independent risk factor for in-hospital mortality
Rambhatla et al[27]	Assessed the outcomes of COVID-19 infection in men on testosterone replacement therapy	Retrospective case control study	32 men diagnosed with COVID-19 on testosterone replacement therapy (TRT) were matched to 63 men with COVID-19 diagnosis but not on TRT	No statistically significant difference in outcome endpoints (hospitalization, ICU admission, ventilator utilizations, thrombotic event, death) between two groups. Results suggest that no statistically significant difference in outcomes for men treated with TRT than men not on TRT.
Salonia et al[26]	Evaluated testosterone levels in men with COVID-19 compared with healthy men	Retrospective case control study	286 symptomatic men with COVID-19 requiring hospital admission Control group: 281 healthy men	Men with COVID-19 had significantly lower serum testosterone levels than healthy men. Lower testosterone levels were independently associated with COVID-19 infection status, and lower levels of testosterone predicted more severe clinical outcomes
Ding et al[30]	Examined how menstrual status and sex hormones affect the progression and outcomes of COVID-19	Retrospective cohort study	All confirmed hospitalized COVID-19 patients from three hospitals (n = 1902). Cohort 1: Sex differences and disease severity (n = 1902); Cohort 2:Women with menstrual status (n = 509)Cohort 3:Serum hormone levels (n = 78), Cytokines levels (n = 263)	Non-menopausal (NM) women had milder severity and better outcomes compared with age match males. Menopausal(M) patients had longer hospitalization times compared with NM patients. -Anti Mullerian hormone (AMH) and estradiol (E2) negatively correlated with infection severity. Menopause is an independent risk factor for female COVID-19 patients, AMH and E2 inversely corelated with COVID-19 severity. Thought to offer protective benefits, E2 specifically through regulation of cytokines related to immune inflammatory response
Lee et al[43]	Assessed the effects of female sex hormones on clinical outcomes of COVID-19 using national claims data	Retrospective cohort study	Adult patients with COVID-19 infection (n = 5061). Subgroup analyses using aged matched case-control data	There was no significant difference in mortality rate between males and females, and HRT was not associated with improved clinical outcomes

Table 3 Transgender care and coronavirus disease 2019

Ref.	Study type	Findings
Masterson et al[38]	Prospective Case study	TW patients treated with E+P as part of feminizing GAHT showed reduced testicular ACE-2 R expression in testicular tissue. In comparison to control group (cis-gender males with no hormone therapy) and the TW cohort treated with E only, O+E cohort also had higher degree of tissue fibrosis. Significance: Support the possibility that short course of E+P or P alone could help protect men against COVID-19 infection through downregulation of ACE-2 Receptor
Durcan et al[39]	Single center, cross-sectional web-based survey	Of 238 participants (179 FTM, 59 FTM) with GD receiving hormone therapy, the risk of contracting COVID-19 was 3.46x higher in FTM receiving testosterone therapy, compared with FTM patients receiving estrogen and anti-androgen therapies. Furthermore, among the FTM cohort, longer treatment periods with testosterone was associated with increased risk of contracting COVID-19; Significance: TM receiving Testosterone as part of GAHT are at an increased risk for contracting COVID-19