High estradiol and low testosterone levels are associated with critical illness in male but not in female COVID-19 patients: a retrospective cohort study

Figures & data

Table 1. Baseline demographic and clinical characteristics, admission diagnosis and treatment-related variables in critically ill patients with COVID-19 and without COVID-19 (NON-COVID-19).

	COVID-19 n = 50		Non-COVID-19 n = 42		p^a
	Male n = 39 (78)	Female n = 11 (22)	Male n = 27 (64.3)	Female n = 15 (35.7)	.168
Demographics
Age	63 (58–73)	67 (59–71)	67 (58–75)	71 (69–82)	.015
Body mass index	27.4 (24.8–31.9)	25 (22.8–30.7)	25.2 (23–26.8)	23.5 (18.5–27.4)	.003
Comorbid conditions on admission
Obesity (BMI>30 kg/m^2)	11 (28.2)	3 (27.3)	3 (11.1)	2 (13.3)	.321
Arterial hypertension	20 (51.3)	5 (45.5)	19 (70.4)	9 (60)	.371
Bronchial Asthma	1 (2.6)	0	3 (11.1)	0	.350
COPD	0	1 (9.1)	3 (11.1)	1 (6.7)	.093
Coronary heart disease	8 (20.5)	1 (9.1)	6 (22.2)	4 (26.7)	.752
Diabetes mellitus	13 (33.3)	3 (27.3)	5 (18.5)	4 (26.7)	.645
HbA1C V%	6.4 (5.9–7.1)n = 30	6.2 (6–7)n = 9	6.8n = 1	6.5n = 1
ICU stay
ARDS
None	9 (23.1)	2 (18.2)	16 (59.3)	14 (93.3)
Mild	4 (10.3)	1 (9.1)	4 (14.8)	1 (6.7)
Moderate	16 (41)	3 (27.3)	7 (25.9)	0
Severe	10 (25.6)	5 (45.5)	0	0
Respiratory support
Mechanical ventilation	27 (69.2)	9 (81.8)	14 (51.6)	8 (53.3)	.856
Non-invasive ventilation	0	0	6 (22.2)	2 (13.3)
High flow oxygen therapy	9 (23.1)	1 (9.1)	4 (14.8)	0	.189
ECMO	5 (12.8)	2 (18.2)	1 (3.7)	0	.217
COVID-19 Treatment
Lopinavir/Ritonavir	6 (15.4)	2 (18.2)
Hydrochloroquin	0	1 (9.1)
Adrecizumab	6 (15.4)	0
Cytosorb Filtration	3 (7.7)	0
Suspected bacterial infection on admission			9 (33.3)	5 (33.7)
Scores
APACHE II	27 (24–30)	29 (25–32)	23 (17-25)	24 (21-31)	<.001
SAPS II	40 (32–47)	42 (36–56)	36 (30.5-48)n=21	39 (34–58)n=11	.505
SOFA	7 (4–9)	7 (5–10)	4 (3–7)	5 (3–7)	.001
Laboratory parameters on admission
White blood cell count (10^9/L)	9.2 (4.8–12.2)	6.5 (0.4–12.9)	11.7 (7.9–15.9)	11.5 (8.5–15.2)	.009
Thrombocytes (10^9/L)	204 (70–293)	143 (49–222)	199 (144–239)	258 (154–301)	.237
Procalcitonin (μg/L)	0.4 (0.2–2.3)	0.5 (0.1–1.6)	0.2 (0.1–0.4)n = 8	0.7 (0.1–1.6)n = 3	.119
C-reactive protein (mg/dl)	200 (105–278)	174 (60–293)	47 (13–106)	26 (18–82)	<.001
Lactate (mmol/L)	1.1 (0.8–1.6)	0.7 (0.6–1)	1 (0.8–1.5)	1.4 (0.7–1.9)	.36
Outcome
Recovered	27 (69.2)	8 (72.7)	24 (88.9)	13 (86.7)
Deceased	12 (30.8)	3 (27.3)	3 (11.1)	2 (13.3)

Note: Continuous variables are given as median (1st to 3rd quartile), categorical variables are given as n (%).

^a Wilcoxon–Mann–Whitney U or student T-test was performed for continuous variables, as appropriate and Fisher’s exact or Chi-Square test for categorical variables. APACHE II: Acute Physiology and Chronic Health Score, COPD: Chronic obstructive pulmonary disease, COVID-19: Corona Virus Disease 2019, ECMO: Extracorporeal membrane oxygenation, SAPS II: Simplified Acute Physiology Score II, SOFA score: Sepsis-related organ failure assessment score

Figure 1. Sex hormone levels in COVID-19 patients, non-COVID-19 patients, patients with coronary heart diseases and healthy individuals. Estradiol (a,c) and testosterone (b,d) levels were measured in plasma obtained from critically ill COVID-19 patients (ICU_COVID-19), critically ill non-COVID-19 patients (ICU_non-COVID-19), patients with coronary heart diseases (CHD) and healthy individuals (HC). Male data sets are shown in blue color-toned columns and female data sets are shown in red color-toned columns. The laboratory assessed hormone reference ranges are indicated in grey. Percentile boxplots represent 25–75% of values, with the median value indicated by a crossline, and mean values by a plus icon. Statistical significance was assessed via one-way-ANOVA.

Table 2. Hormone levels in critically ill patients with COVID-19.

	COVID-19 n = 50
	Male n = 39 (78)	Female n = 11 (22)
Free testosterone pg/mL	2.6 (1.7–3.7)	2.3 (0.9–3.6)
Normal males	13 (33.3)
20–39 yr: 7–22.7 pg/mL
40–60 yr: 6.3–17.8 pg/mL
≥61 yr: 2.5–17.8 pg/mL
Low (all age groups, below reference)	26 (66.7)
Normal females		5 (45.5)
40–60 yr: ≤2.3 pg/mL
≥61 yr: ≤2.1 pg/mL
High (all age groups, above reference)		6 (54.5)
Sex hormone-binding globulin nMol/L	31.3 (19.2–49.9)	33.2 (22.6–58.6)
Normal males: 10–40 nMol/L	27 (69.2)
Low: <10 nMol/L	1 (2.6)
High: 41–100 nMol/L	7 (17.9)
Very High: ≥101 nMol/L	4 (10.3)
Normal females: 26–110 nMol/L		7 (63.6)
Low: <26 nMol/L		3 (27.3)
High: ≥110 nMol/L		1 (9.1)
Luteinizing hormone mIU/mL	5.5 (2.8–11.8)	6.5 (2.6–16.4)
Normal males: 0–8.6 mIU/mL	27 (69.2)
High: ≥8.7 mIU/mL	12 (30.8)
Normal females: <58.5 mIU/mL		11 (100)
Follicle-stimulating hormone	4.2 (2–9.9)	20.1 (6.5–33.7)
Normal males: 1.5–12.4 mIU/mL	32 (82.1)
Low: <1.5 mIU/mL	2 (5.1)
High: 12.5–25 mIU/ml	5 (12.8)
Normal females: 25.8–134.8 mIU/mL		6 (54.5)
Low: 10–25.7 mIU/mL		5 (45.5)
Thyroid-stimulating hormone µU/mL ^ns	0.8 (0.4–1.5)	0.45 (0.4–1.5)
Normal: 0.27–4.2 µU/mL	30 (76.9)	7 (63.6)
Low: <0.27 µU/mL	7 (18.0)	3 (27.3)
High: >4.2 µU/mL	2 (5.1)	1 (9.1)
Free T4 ^ns	13.2 (11.2–14.7)	11.1 (10.3–15.1)
Normal: 8–17 ng/dL	38 (97.4)	11 (100)
High: >17 ng/dL	1 (2.6)
Cortisol µg/dlL^ns	20.6 (14.8–26.5)	26.7 (14.8–26.5)
Normal: 2.5–19.5 µg/dL	16 (40.0)	2 (18.2)
Low: <23 µg/dL	1 (2.6)	6 (54.5)
High: 23–30 µg/dL	22 (56.4)	9 (81.8)

Note: Continuous variables are given as median (1st to 3rd quartile), categorical variables are given as n (%). ^nsWilcoxon–Mann–Whitney U-test was performed; the difference between sexes is not significant.

Figure 2. Estradiol levels in dependency of disease severity. Estradiol levels measured in plasma obtained from critically ill male (blue columns) and female (red columns) COVID-19 or non-COVID-19 patients are displayed in dependency of disease severity as assessed by SOFA scores (a–c). Male COVID-19 patients were subdivided into patients requiring ECMO therapy (+ECMO) and patients not requiring ECMO therapy (-ECMO) (d). Percentile boxplots represent 25–75% of values, with the median value indicated by a crossline, and mean values by a plus icon. The laboratory assessed hormone reference ranges are indicated in grey. Values are shown as median and interquartile ranges. Statistical significance in males was assessed by NON-parametric tests (Kruskal–Wallis test and Dunn’s test for multiple comparisons). Statistical significance in females was evaluated by unpaired, two-tailed NON-parametric Student’s t-test (Mann–Whitney test).

Figure 3. Chemokine and cytokine responses in COVID-19 patients. Cytokine and chemokines were measured in plasma obtained from critically ill male (a–e) and female (f and g) COVID-19 patients using a 27-plex immunoassay. Those with significant differences are shown. Cytokine and chemokine levels of male and female COVID-19 patients are displayed in dependency of disease severity as assessed by SOFA scores (2–3; 4–7; 8–11).

Figure 4. Correlation of IFN-γ levels in male and female COVID-19 patients to estradiol levels. Estradiol levels measured in plasma of critically ill male and female COVID-19 patients were plotted against the expression levels of all cytokines and chemokines assessed. Here, only IFN-γ is displayed, which showed a significant correlation to estradiol levels. Statistical significance was assessed by generalized linear regression.