The multifaceted investigation of DHEAS level in COVID-19 disease: Insights into disease severity, gender, age, comorbidities, and implications for tailored management

doi:10.21203/rs.3.rs-4553372/v1

COVID-19 is a viral disease caused by SARS-CoV-2 that has affected millions of people worldwide. DHEAS (dehydroepiandrosterone sulfate), a steroid hormone produced by the adrenal glands, has been found to play a crucial role in the immune system, and its levels have been linked to various health outcomes. The study aims to unravel the multifaceted role of DHEAS in COVID-19, focusing on disease status, temporal patterns, gender-specific trends, and the influence of age and comorbidities (hypertension (HT), heart disease (HD), and diabetes mellitus (DM)).

DHEAS was quantified using ELISA in COVID-19 patients. We conducted a longitudinal analysis, tracking DHEAS concentration over different days. Gender-specific comparisons were performed. Furthermore, we analyzed DHEAS levels in both inpatients and outpatients, considering comorbidities. COVID-19 patients, especially inpatients, have lower levels of DHEAS compared to controls. However, DHEAS was not strongly associated with mortality or the need for intensive care. Findings unveiled a dynamic pattern of DHEAS levels during COVID-19 disease, marked by an initial decline followed by recovery. Notably, the scatter plot analysis suggested that COVID-19 could increase the conventional age-related decline in DHEAS levels among males, hinting at a potential gender-specific effect. Comorbidities including HP, HD, and DM, were prevalent among COVID-19 patients and correlated with disease severity. Hypertension appeared to moderate the relationship between hospitalization and DHEAS levels, particularly in females.

DHEAS emerges as a biomarker for measuring COVID-19 severity, with distinct temporal dynamics. COVID-19's potential to increase the age-related decline in DHEAS levels, especially in male patients, underscores its intricate relationship with age. The influence of comorbidities adds another layer of complexity to COVID-19 outcomes. The influence of hypertension on DHEAS levels suggests a gender-specific effect, highlighting the need for tailored approaches in managing COVID-19 patients. These findings provide valuable insights into the multifaceted aspects of COVID-19 and its interaction with hormonal and demographic factors.

Biological sciences/Biochemistry

Health sciences/Biomarkers

Health sciences/Health care

COVID-19

DHEAS

inpatients

outpatients

comorbidity diseases

The emergence of a new coronavirus at the end of 2019, introduced as severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), created a great challenge in the field of health worldwide, the ongoing coronavirus disease 2019 (COVID-19)¹. High infectivity, and rapid transmission even in the asymptomatic phase made this virus a global threat and eventually led to a pandemic. As of this moment on 10 October 2023, the infection has spread to most countries across the world, infecting more than 696,304,257 million people and killing more than 6,923,898 million people ².

A significant number of patients with COVID-19 already have one of the underlying diseases such as cardiovascular diseases (CVDs), hypertension (HTN), diabetes mellitus (DM) and others ^3,4. CVD along with other underlying diseases is effective in the exacerbation and recurrence of respiratory viral infections. Evidence has shown that COVID-19 is associated with CVD and hypertension, although the specific interaction between the two has not been established. CVD and hypertension in patients with covid-19 are at higher risk of mortality ^5–7. However, the question is whether the underlying CVD and hypertension are the independent risks or other factors such as genetic, age, gender, etc. have an effect on their role. Evidence suggests that an important risk factor for CVD is low dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) levels. DHEA and DHEAS are the most abundant circulating steroid present in mammals, derived from cholesterol synthesized by the adrenal glands. They are precursors of the sex hormones, androgens in men and estrogens in women ⁸. Epidemiological studies have found that DHEA(S) is associated with reduced mortality in women and men while low serum levels are associated with a higher risk of diabetes, coronary heart disease, and lower physical vitality and function. Furthermore, it shows a significant decrease with age in both sexes ⁹.

Reports support the role of DHEAS in various physiologic or pathophysiologic conditions to reduce aging, oxidative stress, inflammation, diabetes, chronic heart failure, reverse vascular remodeling in pulmonary arterial hypertension and enhance vascular endothelial cell function ^10–12. In viral infections, DHEAS has an important role in immune modulation. Decreased DHEAS exacerbate the pro-inflammatory state and impair the immune defense response in the host.

Therefore, a study was conducted to investigate the serum level of DHEAS in different Iranian covid-19 patients with underlying heart disease and hypertension depending on disease status, sex, and age. Our aim was to explore the relationship between DHEAS level with covid-19 disease status and patient conditions.

2-1- The comparison of Covid-19 patients and control group:

The serum level of DHEAS in Covid-19 patients based on disease status: According to the results (Table 1), the concentration of DHEAS in COVID-19 patients was significantly lower than that in control samples. The lower DHEAS level in the inpatients was obvious in comparison of outpatients and the control group while the results showed no difference in DHEAS level between outpatients and the control group. Our results exhibited no significant difference between the DHEAS of those who died or survived in inpatient group. No significant difference was seen between inpatients based on the need or lack of need for intensive care. Of the intubated patients in ICU, DHEAS levels did not differ between patients who died and patients who survived.

Table 1
Comparison of DHEAS and age in COVID-19 patients, healthy participants (control), and different groups of patients.
			DHEAS (µg/dL)
			N	Mean ± SD	Median		Q1	Q3	p.value1	p.value2
Groups		patients	694	100.18 ± 87.57	78.25		35.80	137.00
		Control	211	127.00 ± 98.96	99.60		52.40	186.00	0.000
Groups	Inpatient		388	83.50 ± 79.73		57.50	27.05	110.00
	Outpatient		306	121.35 ± 92.49		104.00	53.80	165.00	< 0.001
	Control		211	127.00 ± 98.96		99.60	52.40	186.00	< 0.001		0.507
	No ICU Care		350	82.18 ± 79.25		57.15	27.00	107.00
Inpatient	ICU Care		38	95.64 ± 84.18		77.65	28.70	137.00	0.323
	Expire		35	83.08 ± 81.72		56.40	23.70	127.00
	Alive		353	83.54 ± 79.65		57.60	28.70	108.00	0.974
			Age (years)
			N	Mean ± SD	Median		Q1	Q3	p.value1	p.value2
Groups		patients	686	50.72 ± 16.35	50.00		38.00	61.00
		Control	209	46.68 ± 13.49	36.00		36.00	57.00	0.001
Groups	Inpatient		384	56.00 ± 16.00		55.00	44.00	68.00
	Outpatient		302	44.00 ± 14.00		43.00	33.00	54.00	0.000
	Control		209	47.00 ± 13.00		50.00	36.00	57.00	0.000		0.080
	No ICU Care		346	55.20 ± 16.06		54.00	44.00	67.00
Inpatient	ICU Care		38	59.53 ± 18.08		62.00	49.00	72.00	0.121
	Expire		34	67.21 ± 15.13		68.0	52.00	78.00
	Alive		350	54.51 ± 15.98		54.60	43.00	67.00	0.000
P-value1 compares Covid-19 patients with control group, inpatients with outpatients and control, No ICU Care and ICU Care, Expire and Alive. P-value of ≤ 0.05 is considered significant. P-value < = 0.05 is significant.

The serum level of DHEAS in different groups of Covid-19 patients based on gender: Based on Table 1S, the evaluation of the DHEAS level in samples received on the first day exhibited that the level of DHEAS in female was significantly lower than males in both patients and control groups. Additionally, the difference in DHEAS level between male and female inpatients was significant. No significance difference was seen between inpatients admitted to ICU care. In addition, although there was no significant difference in the level of DHEAS between the females of the control group and the patients, the comparison between the males of the two groups exhibited a significant difference. However, the mean DHEAS concentration of both males and females in inpatient group was significantly lower than those of outpatient group.

DHEAS trending in Covid-19 patients: Fig. 1 shows the results of DHEAS levels in all COVID-19 patients in the study on different days compared to the first day. We also considered outcomes in inpatients and outpatients. As is obvious, the amount of hormone has a significant decreasing trend until the third day. From the seventh day of the disease, its amount increased, however, its increase was significant after one month. This increasing trend of DHEAS continued until the second month, but this increase was not significant (not shown in Fig. 1). As observed in Fig. 1, inpatients up to the 14th day of illness exhibit a decrease in DHEAS levels, and the recovery of DHEAS in these patients is slow. While in outpatients, the DHEAS levels keep increasing.

Figure 1.

Consideration of the age of Covid-19 patients based on disease status: Based on the results presented in table.1, there was a significant difference between the average age of covid-19 patients and control samples. The average age of inpatients was significantly higher than that of outpatients. In addition, Inpatients were older than control group. The mean ages of inpatients who needed intensive care were not significantly different from that of those with no need for intensive care. However, the mean ages of inpatients who died were significantly greater than that of inpatients who survived.

Consideration of the age of Covid-19 patients based on gender: There was no significant difference between the age of males and females in patients and also in control samples. In different subgroups of the disease, including inpatients, outpatients, and ICU-care inpatients, comparing the age of both sexes displayed no significant difference. Furthermore, the mean age of both males and females in the patient group was significantly more than those of the control group. The same result was clearly seen in the comparison of the same sexes of hospitalized and non-hospitalized groups (table. 1S).

The correlation between DHEAS and age: The scatter plot presented in Fig. 2A elucidates the correlation between DHEAS and age within the control and COVID-19 patient groups. In this plot, the dependence of DHEAS on age is obvious among patients, similar to that observed in the control group, but with a lower slope. A comparison of the graph in females of both groups (Fig. 2B) showed the relationship between DHEAS with age with the same slope, however, the plot of the male subgroups (Fig. 2C) revealed a distinct difference in the relationship between DHEAS and age, with the male patient group exhibiting a less intense slope compared to the control group. Importantly, the slope related to the male plot is more pronounced and significant than that observed in the female plot for both groups.

2-2- Evaluating the hospitalization rate of COVID-19 patients with underlying disease:

As seen in Fig. 3, hospitalization rates for HTN, DM, and HD among COVID-19 patients were significantly higher compared to outpatients.

Figure 3.

2-3- Evaluating the impact of Hypertension (HTN):

The serum level of DHEAS based on disease status: According to Table 2, the DHEAS level in HTN-positive Covid-19 patients was remarkably lower than HTN-negative Covid-19 patients on the first day of the study. The DHEAS level in HTN-positive outpatients was lower than HTN-negative Covid-19 patients. In addition, the evidence supported a difference in the level of this hormone between HTN negative inpatients and HTN negative outpatients and controls.

Table 2

Comparison of DHEAS levels between different groups of COVID-19 patients with and without hypertension and healthy participants (control).
				DHEAS (µg/dL)
					N		Mean ± SD	Median		Q1		Q3		p.value1	p.value2		p.value3	p.value4
		1- HTN Positive/ Patient			158		77.23 ± 72.28	53.90		20.70		104.00
Groups		2- HTN Negative / Patient			443		110.02 ± 90.10	87.00		44.00		150.00		0.000
		3- HTN Negative / Control			65		118.20 ± 103.35	79.40		48.20		165.00		0.001	0.503
Groups	1		HTN ‎Positive / Inpatient		120	74.82 ± 71.90			48.00		20.80	103.00
	2		HTN ‎Positive / Outpatient		38	84.86 ± 73.91			71.95		19.50	122.00	0.457
	3		HTN Negative / Inpatient		229		87.39 ± 76.47		65.10		33.40	115.00	0.137		0.849
	4		HTN Negative / Outpatient		214		134.23 ± 97.19		115.00		62.80	186.00	0.000		0.003	0.000
	5		HTN Negative / Control		65		118.20 ± 103.35		79.40		48.20	165.00	0.000		0.084	0.009		0.252
Groups	1		HTN ‎Positive / patient	Female	88		60.08 ± 61.74		29.25		15.60	72.15
	1		HTN ‎Positive / patient	male	70		98.79 ± 78.95		79.00		41.70	130.00	0.001
	2		HTN ‎ Negative / patient	Female	167		84.99 ± 74.40		67.80		36.80	116.00
	2		HTN ‎ Negative / patient	male	276		125.16 ± 95.37		103.50		52.10	174.00	0.000
	3		HTN Negative / Control	Female	24		68.70 ± 52.86		56.85		24.80	88.70
	3		HTN Negative / Control	male	41		147.17 ± 114.69		99.60		54.80	222.00	0.002
P-value 1 compares group1 with other groups and p-value 2 compares group 2 with other groups. P-value 3 compares group 3 with other groups. P-value 4 compares group 4 with group 5. P-value < = 0.05 is significant.

The serum level of DHEAS based on gender: According to table. 2., the serum level of DHEAS was significantly higher in males than in females in HTN positive/negative patients and HTN negative control. Between inpatients and outpatients in both males and females without HTN (Table 2S), the mean DHEAS concentrations were significantly higher than those in patients with HTN. Among female patients with HTN, the mean DHEAS concentration was lower for outpatients compared to inpatients, but it was not significant. Among male patients with HTN, the mean DHEAS concentration was significantly higher for outpatients compared to inpatients. The higher DHEAS level in patients with HTN compared to those without HTN was significant only in female outpatients.

About the effect of age: Our data in table. 3 illuminated that the age of patients with HTN was significantly higher than patients without HTN in general and also in comparisons between inpatients, outpatients, and between inpatients and outpatients.

Results revealed a significant difference in mean age between males and females only in patients without HTN but not in patients with HTN and control group (table. 3).

2-4- Evaluating the impact of Heart Disease (HD):

The serum level of DHEAS based on disease status: Based on Table 4, the serum level of DHEAS was significantly lower in patients with underlying heart disease compared to patients without heart disease. Between outpatients, the level of DHEAS in both subgroups with and without HD was significant such that outpatients having HD experienced more deficiency of DHEAS. In addition, comparing inpatients and outpatients showed that inpatients without heart problem had lower DHEAS than heart disease-negative outpatients and controls.

Table 3- Comparison of age between different groups of COVID-19 patients with and without hypertension and healthy participants (control),

				Age (years)
					N		Mean ± SD	Median	Q1		Q3		p.value1	p.value2		p.value3	p.value4
		1-HTN Positive/ Patient			158		63±13	62	54		73
Group		2-HTN Negative / Patient			440		45±15	44	34		54		0.000
		3-HTN Negative / Control			64		46±14	49	35		56		0.000	0.711
Group	1		HTN ‎Positive / Inpatient		120	65±14		66		55	74
	2		HTN ‎Positive / Outpatient		38	60±12		58		51	69	0.048
	3		HTN Negative / Inpatient		226		50±16	49		38	61	0.000		0.001
	4		HTN Negative /Outpatient		214		40±12	38		31	49	0.000		0.000	0.000
	5		HTN Negative / Control		64		46±14	49		35	56	0.000		0.000	0.047		0.001
Group	1		HTN ‎Positive / patient	Female	88		64±13	64		55	75
				male	70		63±14	61		53	70	0.486
	2		HTN ‎ Negative / patient	Female	167		43±14	41		32	53
				male	273		47±15	46		35	56	0.012
	3		HTN Negative / Control	Female	24		47±14	49		36	57
				male	40		45±15	47		34	55	0.584

P-value 1 compares group1 with other groups and p-value 2 compares group 2 with other groups. P-value 3 compares group 3 with other groups. P-value 4 compares group 4 with group 5. P-value<=0.05 is significant.

Table 4

Comparison of DHEAS levels between different groups of COVID-19 patients with and without heart disease and healthy participants (control).
			DHEAS (µg/dL)
				N		Mean ± SD	Median		Q1		Q3		p.value1		p.value2		p.value3	p.value4
		1-HD Positive/ Patient		84		71.95 ± 70.61	47.50		15.90		95.25
Group		2-HD Negative / Patient		517		106.19 ± 88.42	82.60		41.00		143.00		0.001
		3-HD Negative / Control		71		116.73 ± 99.84	87.00		48.20		165.00		0.001		0.354
Group	1	HD ‎Positive / Inpatient		71	71.78 ± 71.85			47.20		15.00	92.60
	2	HD ‎Positive / Outpatient		13	72.85 ± 66.12			62.10		19.10	107.00	0.961
	3	HD Negative / Inpatient		278		85.95 ± 75.72		64.80		31.50	115.00	0.156			0.540
	4	HD Negative / Outpatient		239		129.72 ± 96.15		107.00		60.20	178.00	0.001			0.036	0.001
	5	HD Negative / Control		71		116.73 ± 99.84		87.00		48.20	165.00	0.003			0.132	0.005		0.322
Group	1	HD ‎Positive / patient	Female	37		56.97 ± 66.57		22.30		15.00	66.40
	1	HD ‎Positive / patient	male	47		83.74 ± 72.16		65.00		33.50	104.00		0.085
	2	HD ‎ Negative / patient	Female	218		79.69 ± 71.53		63.05		28.70	112.00
	2	HD ‎ Negative / patient	male	299		125.50 ± 94.47		104.00		53.00	172.00			0.001
	3	HD Negative/ Control	Female	28		69.89 ± 50.43		59.55		24.80	91.65
	3	HD Negative/ Control	male	43		147.23 ± 112.09		107.00		54.80	222.00			0.001
P-value 1 compares group1 with other groups and p-value 2 compares group 2 with other groups. P-value 3 compares group 3 with other groups. P-value 4 compares group 4 with group 5. P-value < = 0.05 is significant.

Among the heart-positive covid-19 patients, no significant difference was observed in DHEAS serum levels between male and female patients. However, in heart-negative covid-19 patients as well as in the control group, DHEAS levels in females were significantly lower than in males (table. 4).

About the effect of age: According to the results in Table 5, covid-19 patients with HD were significantly older than those without heart disease. Comparing heart-negative inpatients with heart-positive inpatients and also heart-negative control, the remarkable differences were confirmed. The same results were also seen in the comparison of different subgroups of outpatients.

Table 5

Comparison of age between different groups of COVID-19 patients with and without heart disease and healthy participants (control).
				Age (years)
					N		Mean ± SD	Median	Q1		Q3		p.value1	p.value2		p.value3	p.value4
		1-HD Positive/ Patient			84		64 ± 13	65	55		75
Groups		2-HD Negative / Patient			514		48 ± 16	46	35		58		0.000
		3-HD Negative / Control			70		47 ± 14	50	35		57		0.000	0.544
Groups	1		HD ‎Positive / Inpatient		71	65 ± 14		67		55	78
	2		HD ‎Positive / Outpatient		13	62 ± 11		59		52	70	0.408
	3		HD Negative / Inpatient		275		53 ± 16	51		40	65	0.000		0.054
	4		HD Negative / Outpatient		239		42 ± 13	40		32	52	0.000		0.000	0.000
	5		HD Negative / Control		70		47 ± 14	50		35	57	0.000		0.000	0.003		0.011
Groups	1		HD ‎Positive / patient	Female	37		64 ± 14	66		53	75
	1		HD ‎Positive / patient	male	47		65 ± 13	64		55	78		0.651
	2		HD Negative / patient	Female	218		48 ± 16	46		35	60
	2		HD Negative / patient	male	296		48 ± 16	46		36	58		0.747
	3		HD Negative/ Control	Female	28		48 ± 13	53		38	58
	3		HD Negative/ Control	male	42		45 ± 14	47		35	55		0.373
P-value 1 compares group1 with other groups and p-value 2 compares group 2 with other groups. P-value 3 compares group 3 with other groups. P-value 4 compares group 4 with group 5. P-value < = 0.05 is significant.

There was no significant difference in age between males and females in both covid-19 subgroups with or without HD (table. 5).

2-5- Evaluating the impact of Diabetes Mellitus (DM):

The serum level of DHEAS based on disease status: As table. 6 shows, the level of DHEAS in patients with underlying DM was significantly lower compared to DM-negative patients and control. In both outpatient and inpatient groups, DM patients experienced a greater deficiency of DHEAS than DM negative patients. Furthermore, it was observed that inpatients without DM had lower DHEAS levels compared to DM-negative outpatients. Notably, a significant difference was found between controls and DM-negative inpatients.

Among COVID-19 patients with DM, no significant variance was observed in serum DHEAS levels between males and females. Nevertheless, in non-DM COVID-19 patients and in the control group, females showed significantly lower DHEAS levels than males (Table. 6).

About the effect of age: According to Table 7, the results indicate that COVID-19 patients with DM are significantly older compared to those without DM disease and the control group. Noteworthy differences were observed when comparing DM-negative inpatients with DM-positive inpatients and DM-negative controls. Similar findings were observed when analyzing different subgroups of outpatients. Furthermore, there was no significant difference between the age of DM-positive inpatients and outpatients.

Table 6- Comparison of DHEAS levels between different groups of COVID-19 patients with and without DM and healthy participants (control).

			DHEAS ((μg/dL)
				N	Mean ± SD	Median		Q1		Q3	p.value1	p.value2		p.value3	p.value4
		1-DM Positive/ Patient		131	73.17±63.93	56.40		22.60		89.50
Group		2-DM Negative / Patient		470	109.27±90.82	88.05		41.20		145.00	0.001
		3-DM Negative / Control		65	121.67±102.25	87.00		52.80		176.00	0.001	0.310
Group	1	DM ‎Positive /Inpatient		100	68.09±59.88		49.45		21.00	85.60
	2	DM ‎Positive/Outpatient		31	89.56±74.26		65.10		30.10	141.00	0.103
	3	DM Negative / Inpatient		249	89.09±79.68		65.40		30.20	116.00	0.018	0.975
	4	DM Negative / Outpatient		221	132.01±97.19		114.00		62.80	183.00	0.001	0.020	0.001
	5	DM Negative / Control		65	121.67±102.25		87.00		52.80	176.00	0.001	0.006	0.122		0.457
Group	1	DM ‎Positive / patient	Female	69	65.58±60.49		45.50		16.70	82.30
			male	62	81.62±67.03		60.50		32.10	127.00	0.152
	2	DM Negative / patient	Female	186	80.41±74.48		60.90		25.40	115.00
			male	284	128.17±95.59		104.00		56.60	176.50	0.001
	3	DM Negative/ Control	Female	23	81.28±72.71		59.40		30.60	94.30
			male	42	150.01±110.79		108.50		56.90	223.00	0.001

P-value 1 compares group1 with other groups and p-value 2 compares group 2 with other groups. P-value 3 compares group 3 with other groups. P-value 4 compares group 4 with group 5. P-value<=0.05 is significant.

Table 7

Comparison of age between different groups of COVID-19 patients with and without heart disease and healthy participants (control).
			Age (years)
				N	Mean ± SD	Median		Q1		Q3		p.value1		p.value2		p.value3	p.value4
		1-DM Positive/ Patient		131	61 ± 13	60		52		70
Group		2-DM Negative / Patient		467	47 ± 16	45		34		58		0.000
		3-DM Negative / Control		64	45 ± 14	46		35		56		0.000		0.374
Group	1	DM ‎Positive /Inpatient		100	62 ± 12		61		53	70
	2	DM ‎Positive/Outpatient		31	57 ± 14		56		50	66	0.087
	3	DM Negative / Inpatient		246	53 ± 17		50		39	66	0.000			0.144
	4	DM Negative / Outpatient		221	41 ± 13		38		31	50	0.000			0.000	0.000
	5	DM Negative / Control		64	45 ± 14		46		35	56	0.000			0.000	0.001		0.019
Group	1	DM ‎Positive / patient	Female	69	60 ± 13		60		52	69
	1	DM ‎Positive / patient	male	62	62 ± 12		60		54	70		0.337
	2	DM Negative / patient	Female	186	47 ± 16		45		33	59
	2	DM Negative / patient	male	281	47 ± 16		45		35	57			0.728
	3	DM Negative/ Control	Female	24	41 ± 12		41		32	53
	3	DM Negative/ Control	male	40	44 ± 14		42		33	55			0.303
P-value 1 compares group1 with other groups and p-value 2 compares group 2 with other groups. P-value 3 compares group 3 with other groups. P-value 4 compares group 4 with group 5. P-value < = 0.05 is significant.

There was no significant age difference between males and females in both subgroups of COVID-19, regardless of the presence of DM (Table. 7).

2-5- Multiple regression analysis

In Table 8, the simultaneous relationship between HTN-DHEAS and COVID-19 severity has been investigated. The interaction of these two factors showed a significant relationship with the severity of the disease with p-value of 0.035. There is no significant simultaneous relationship between HD-DHEAS or DM-DHEAS and COVID-19 severity (p-value of 0.255 and 0.106) (Table 3S).

Table 8

Regression analysis of the relationship of DHEA, hypertension, and Covid-19 severity.
Coefficients^a
Model		Unstandardized Coefficients		Standardized Coefficients	t	Sig.
Model		B	Std. Error	Beta	t	Sig.
1	(Constant)	134.231	5.708		23.517	0.000
	Reg_IN_OUT	-46.837	7.939	-0.266	-5.900	0.000
	HTN	-49.370	14.699	-0.250	-3.359	0.001
	Reg_inpoutp_HTN	36.792	17.453	0.169	2.108	0.035
a. Dependent Variable: DHEAS
P-value < = 0.05 is significant.

Our study discovered a significant difference in DHEAS levels between COVID-19 patients and controls, reaffirming our earlier findings ¹³. In contrast to our previous study, which focused solely on samples from Tehran, the current longitudinal study expanded its sample selection to include COVID-19 patients from various provinces in Iran, offering a more comprehensive representation and a better understanding of temporal dynamics and potential trends of the diseases. Additionally, we considered gender as an important factor during our analysis, recognizing potential variations in DHEAS levels based on the participants' sex. Moreover, we explored the relationship between DHEAS levels and comorbidities, seeking to identify any correlations between DHEAS and other health conditions in COVID-19 patients, contributing to a broader understanding of the complexities of this disease.

Our data suggest that DHEAS levels may decrease under the influence of COVID-19 infection, especially in hospitalized subjects. This viral infection presumably exerts a notable influence on DHEAS levels in those individuals who require hospitalization for the management and treatment of their illness. However DHEAS does not appear to be strongly associated with mortality, or the need for intensive care. Indeed, our data suggests that although DHEAS levels correlate with disease severity, the association between DHEAS levels and disease severity may be attenuated or modified in the ICU setting. Factors specific to the intensive care environment, such as the severity of illness, interventions, or treatments, may contribute to this observed difference. According to Das et al's study, individuals with moderate to severe COVID-19 displayed a greater incidence of hypocortisolism and lower levels of DHEAS in comparison to those with mild disease ¹⁴. Further research is warranted to explore the underlying mechanisms and potential implications of this finding, shedding light on the relationship between DHEAS levels, disease severity, and the impact of ICU care on DHEAS dynamics. However, a report rejected a direct effect of COVID-19 on the HPA axis or the adrenal cortex because of the absence of variations in the circulating levels of ACTH, aldosterone, and DHEA between COVID-19 patients and controls ¹⁵.

In general, women have significantly lower levels of DHEAS compared to men. This difference in DHEAS levels between genders is primarily attributed to the influence of sex hormones, such as testosterone and estrogen, which regulate the production of DHEAS ¹⁶. Our evaluation of DHEAS levels in affected and control males and females demonstrated a significant gender disparity in DHEAS levels, with females exhibiting significantly lower levels compared to males. Furthermore, the analysis revealed a clear and significant difference in DHEAS levels between male and female inpatients. However, this significant difference was not observed among inpatients admitted to ICU care, suggesting that ICU care may have influenced the DHEAS levels in both males and females. To accurately assess the disparity in DHEAS levels between control individuals and patients, as well as between inpatients and outpatients, it is imperative to conduct gender-specific comparisons by matching females with females and males with males. While no significant difference in DHEAS levels was found between the females of the control group and the patients, a significant decrease was observed in males of the patients than control. This indicates that DHEAS levels may be used as a biomarker and play a role in differentiating between male patients and control males. Therefore, our findings highlight gender-based variations in DHEAS levels and suggest that DHEAS levels may have implications for disease progression and severity in COVID-19 patients, particularly among males.

Hormonal deficiencies related to age, particularly in DHEA, could potentially have a substantial impact on morbidity and mortality among older individuals ¹⁷. Increased secretion of DHEA/DHEAS has been associated with better health outcomes in individuals and greater longevity in males ¹⁸. Typically, DHEAS levels exhibit a certain pattern with age, where they tend to decrease gradually as individuals grow older. Our scatter plot providing insights into the correlation between DHEAS and age shows a potential deviation from this expected pattern in the case of male patients with COVID-19, so that the slope of DHEAS changes versus age is slower. It suggests that the presence of the virus may alter the typical age-related decline in DHEAS levels in males. This gender-specific impact on the relationship between DHEAS levels, age, and COVID-19 necessitates further investigation to better understand the underlying mechanisms at play.

Additionally, we suggest a dynamic pattern in DHEAS levels throughout the course of COVID-19, with a significant decline early in the disease progression followed by a subsequent recovery towards normal levels. The initial significant decline in DHEAS levels during the early stages of COVID-19 could be attributed to various factors. It is well-established that viral infections, including COVID-19, can induce an acute stress response in the body, leading to alterations in hormonal regulation ^19,20. This acute stress response may contribute to the temporary suppression of DHEAS production. As the disease progresses and the immune system mounts a response to combat the infection, we observe a subsequent recovery in DHEAS levels. This recovery phase may signify the restoration of hormonal balance as the body recovers from the acute stress response and the immune response starts to normalize. The recovery of DHEAS levels towards the normal range could indicate a positive prognostic factor, suggesting a favorable response to the infection. The dynamic nature of DHEAS levels during COVID-19 highlights the complexity of the disease and its impact on hormonal regulation. According to our findings, the inpatients experienced a prolonged decrease in DHEAS levels for up to 14 days, suggesting a gradual decline that might be associated with the severity of their condition or other factors related to hospitalization. In contrast, outpatients initially exhibited a decline in DHEAS concentration during the first three days, after which there was a noticeable and relatively rapid increase that eventually recovered to the control level. Indeed, the rate of change in DHEAS concentration for inpatients was notably slower than that observed in outpatients, indicating distinct physiological responses between these two groups. Therefore, DHEAS therapy may be a consideration for inpatients; however, a comprehensive evaluation of individual patient factors is essential before making any recommendations.

There was a statistically significant difference observed between the average age of COVID-19 patients and the control samples, indicating that age plays a role in the susceptibility to the disease. Furthermore, among the COVID-19 patients, the average age of inpatients was significantly higher compared to both outpatients and the control group. Therefore, advanced age is associated with a higher likelihood of experiencing more severe symptoms or complications. Several studies have explored the strong association between patients' age and the outcome of COVID-19 ²¹. No significant difference was seen between the mean ages of inpatients with and without the need for intensive care. Accordingly, other factors than age such as comorbidities may also contribute to the decision for intensive care admission. However, the mean ages of inpatients who passed away were significantly higher than those who survived. Thus, the advanced age may be associated with increased mortality risk among COVID-19 inpatients.

Generally, The influence of social parameters and disparities between genders on disease incidence and severity is widely recognized ²². Gender-constructed behaviors in both men and women, along with sociocultural factors, have an impact on the likelihood of exposure to infections and the subsequent outcomes ²³. Based on the current results there was no significant difference in age between males and females among both the patient and control samples. This lack of significant difference in age was observed consistently across different subgroups of the disease, including inpatients, outpatients, and ICU-care inpatients. Therefore, it is important to note that age does not play a significant role in the distribution of the disease across gender. The absence of a significant age difference between males and females across different disease subgroups suggests that other factors, such as comorbidities, genetic predisposition, environmental exposure, or lifestyle choices may play more prominent roles in the disease's onset and severity. However, the overall findings still underscore the significance of age in relation to disease severity, mortality, and its impact on COVID-19 patients.

However, we observed significant age discrepancies between males in both control and patient groups, but not between females. This age disparity was also evident when comparing the same sexes within the hospitalized and non-hospitalized groups. It seems essential to engage in gender-specific comparisons when conducting age-related analyses, especially when assessing control individuals versus patients or inpatients versus outpatients. By conducting gender-specific comparisons, researchers can mitigate confounding factors and gain a comprehensive understanding and meaningful interpretations of the influence of age on biological and physiological differences within distinct gender groups.

Chronic non-communicable diseases have been identified as noteworthy predisposing factors for SARS-CoV-2 infection, while also serving as prognostic indicators for severe COVID-19 and unfavorable outcomes, including the need for intensive care unit admission or mortality ^24–26. Hypertension, HD, and DM stand out as a prevalent condition affecting a substantial number of individuals worldwide ^27–32. However, the specific association between these diseases and the increased risk of acquiring SARS-CoV-2 infection, as well as the potential impact on the severity of COVID-19, remains unclear. Our data underscores the significant association between these diseases specially HTN, HD, and DM with the risk of SARS-CoV-2 infection and disease severity. Additionally, we sought to examine the impact of HTN, HD and DM on various factors, including DHEAS.

Among the patients included in our study, about 24.7% of patients in our study were identified as HTN positive, around 20.7% of patients suffered from DM, while some patients (12.9%) had a pre-existing HD. Furthermore, we observed a higher occurrence of HTN and DM among hospitalized patients compared to those treated as outpatients (2.27 and 2.33 times, respectively). This suggests that individuals with HTN and DM may be more prone to experiencing severe manifestations of the disease. In the case of pre-existing HD, a more significant number of inpatients had this condition, while a smaller percentage of outpatients had a history of HD (3.90 times).

A study mentioned that endogenous DHEAS levels are positively related to blood pressure levels and hypertension status [29]. Barbagallo et al. discovered evidence indicating that DHEAS has a direct impact on blood vessels, suggesting its ability to modulate intracellular calcium metabolism [30]. This finding implies that DHEAS may play a role in regulating vascular responsiveness to various hormonal stimuli that cause depolarization and constriction. The mechanism through which DHEAS exerts its effects on vascular function is not fully understood, but it has been suggested that it triggers the production of NO by endothelial nitric oxide synthase (eNOS) and stimulates the release of nitric oxide (NO) from vascular endothelial cells. NO is a key regulator of vascular function, and its release is associated with improved vascular function [31].

DHEA may act as a cardioprotective agent ³³ and modulate cardiovascular signaling pathways, exert anti-inflammatory properties and help reduce inflammation in the cardiovascular system ³⁴. However, studies on the link between DHEA and cardiovascular disease (CVD) have yielded inconsistent results, leading to debate and controversy. According to some meta-analyses, the average DHEAS levels in coronary heart disease (CHD) cases were significantly lower than those in controls. However, there was no significant association between DHEA levels and CHD risk, indicating a more modest connection than previously believed ^35,36. Other studies have indicated that low serum levels of DHEA in men may raise the risk of CHD, though the connection between DHEAS and CHD is conflicting ^37–39. In women, the associations of DHEA and DHEAS with CVD have also yielded inconsistent findings ^40,41.

The relationship between endogenous DHEA and DM is a complex and still not fully understood topic. Decreased levels of DHEA have been linked to diabetes, impaired glucose tolerance, hyperglycemia, and insulin resistance ⁴². Additionally, in a study, higher serum DHEA levels were associated with a lower risk of type 2 diabetes ⁴³. Based on a previous study, in men, lower DHEAS levels were associated with an increased risk of diabetes ⁴⁴. However, plasma DHEAS was not found to be associated with incident type 2 diabetes in women ⁴⁵. Another study reported that obese patients with diabetes had low or undetectable levels of urine DHEA ⁴⁶. While DHEA has been cross-sectionally associated with impaired fasting glucose in postmenopausal women, no significant association with type 2 diabetes was observed ⁴⁷.

Our findings underscore significantly decreased levels of DHEAS in COVID-19 patients with HTN, HD, and DM. Furthermore, these comorbidities played a substantial role in disrupting hormonal balance and decreasing DHEAS concentration particularly among outpatients. The immune system response to COVID-19, stress, and the presence of disease might collectively contribute to this decrease in DHEAS which require further investigation.

The severity of COVID-19 and/or the hospitalization could also override the influence of these comorbidities on DHEAS levels. COVID-19 inpatients often experience significant stress, inflammation, and receive various medications which can impact hormone levels ⁴⁸. Additionally, the severity of the disease and the treatments given may dominate any influence that HTN, HD or DM alone might have on DHEAS levels which require further research.

However, our comprehensive analysis of the effects of HTN, DM, and HD on DHEAS levels in COVID-19 patients has revealed intriguing insights. We found that the interaction of HTN and changing in DHEAS level has a notable influence on disease severity. In contrast, our analysis did not reveal a similar conclusion for DM or HD. These findings underscore the distinct role of HTN as a moderator in the correlation of DHEAS and severity in the context of COVID-19 and suggest that the influence of this comorbidity on hormonal profiles may vary across different conditions.

Our result indicated a gender-specific difference in the hormonal response to COVID-19 among patients with hypertension. In males and females with HTN, the mean DHEAS concentrations were found to be similar between inpatients and outpatients especially in females. This suggests that hospitalization status does not influence DHEAS levels in these groups. However, among female patients without HTN, a notable difference was observed. The mean DHEAS concentration was lower for inpatients compared to outpatients. Among male patients without HTN, a same trend emerged that was not significant.

Additionally, the comparison between females without HTN and with HTN who received outpatient care showed a significant difference in DHEAS concentration. This suggests that the presence of HTN has a notable impact on DHEAS levels in female outpatients specifically. However, hypertension is known to be associated with various physiological changes in the body, including alterations in hormone production and regulation ^49,50. It is possible that hypertension, particularly in female outpatients, may disrupt the normal production or metabolism of DHEAS, leading to lower DHEAS concentrations. The specific mechanisms through which hypertension affects DHEAS levels would require further investigation. Based on the information provided, there are distinct patterns in DHEAS concentrations between inpatients and outpatients, stratified by gender and the presence of hypertension. According to these findings, it is reasonable to suggest that HTN may act as a moderator in the relationship between hospitalization status and DHEAS levels, but this effect is more pronounced among female patients.

Based on the current research and in agreement with our previous study, the severity of the COVID-19 disease can emerge as an essential factor in alterations in DHEAS levels. Our findings suggest a complex relationship between DHEAS levels, COVID-19 severity, comorbidities (HTN, HD, DM), and demographic factors (age and gender). The trend of DHEAS reduction in hospitalized patients was different from outpatients, emphasizing the significance of this hormone in clinical decision-making. DHEAS can be considered as a potential biomarker for disease progression, severity, and recovery, providing valuable insights into the underlying pathophysiological processes. However, further research is required to uncover the underlying mechanisms and clinical implications.

5-1-Study design and participants

This is an observational cohort study of 686 covid-19 patients and 209 controls with no evidence of SARS-CoV-2 infection in Iran ¹³. This study cooperated with Imam Khomeini Hospital Complex and the Immunoregulation Research Center of Shahed University from February 12, 2020, to April 4, 2020. The study was approved by the National Ethics Committee on Research in Medical Sciences of the Iranian Ministry of Health (Ethical Code: IR.NIMAD. REC.1399.041) and all methods were performed in accordance with the relevant guidelines and regulations. Covid-19 patients were identified based on gender, and the status of all COVID-19 patients including disease severity (non-hospitalized (outpatient), and hospitalized (inpatient)).

Written informed consent was obtained from all the patients. In addition, the patients filled out the electronic standardized questionnaires about comorbidities associated with COVID-19, including DM, HTN, heart disease, and other diseases.

In this cohort study, various factors were investigated, but our focus in this article was the investigation of serum levels of DHEAS considering gender and age. In the following, we separated COVID-19 patients with a history of HTN, HD, or DM and compared them with COVID-19 patients and controls without underlying HTN, HD, or DM, regardless of any other underlying disease. In this study, the status of all COVID-19 patients was considered.

5-2- DHEAS analysis

Serum DHEAS were measured with Siemens Kit by IMMULITE 2000, Germany automated system.

5-3- Statistical analysis

The study used SPSS (version 26.0, IBM SPSS Co, Armonk, NY) for statistical analyses. The factors were investigated as mean ± standard deviation and compared between groups using the Welch corrected t-test and Tukey post hoc pairwise comparison. The correlation of laboratory parameters with each other was studied using the Spearman rank correlation coefficient. A linear regression analysis was done. The P-value of less than 0.05 was considered significant.

Author Contribution

A.Tahereh Jamali1, B.Sussan Kaboudanian Ardestani, C.Mohammad-Reza Vaez-Mahdavi, D. Arezou Rezaei, E. Fatemeh Tuserkani, F. HosseinAli Khazaei, G. Ali Khodadadi, H. Bahman Khazaei, I. Keivan Latifi, J. Tooba Ghazanfari1*A . wrote the main manuscript text, prepared figures, and considered the data scientifically.B.J. supervised the research and considered the data.B.C.J.C. designed the researchD. considered the manuscript scientifically and edited it.E. performed the statistical analysis.F-I. did the experiments.All authors reviewed the manuscript.

Data Availability

The datasets analyzed during the current study are not publicly available due our institutes's policy but are available from the corresponding author on reasonable request.

Lai, C.-C., Shih, T.-P., Ko, W.-C., Tang, H.-J. & Hsueh, P.-R. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. International journal of antimicrobial agents 55, 105924 (2020).
https://covid19.who.int/
Gerc, V., Masic, I., Salihefendic, N. & Zildzic, M. Cardiovascular diseases (CVDs) in COVID-19 pandemic era. Materia socio-medica 32, 158 (2020).
Pepera, G., Tribali, M.-S., Batalik, L., Petrov, I. & Papathanasiou, J. Epidemiology, risk factors and prognosis of cardiovascular disease in the Coronavirus Disease 2019 (COVID-19) pandemic era: A systematic review. Reviews in Cardiovascular Medicine 23, 28 (2022).
Radke, R. M., Frenzel, T., Baumgartner, H. & Diller, G.-P. Adult congenital heart disease and the COVID-19 pandemic. Heart 106, 1302–1309 (2020).
Vidal-Perez, R. et al. Cardiovascular disease and COVID-19, a deadly combination: A review about direct and indirect impact of a pandemic. World Journal of Clinical Cases 10, 9556 (2022).
Cannata, A. et al. Impact of the COVID-19 pandemic on in-hospital mortality in cardiovascular disease: a meta-analysis. European journal of preventive cardiology 29, 1266–1274 (2022).
Simpson, E. R. Sources of estrogen and their importance. The Journal of steroid biochemistry and molecular biology 86, 225–230 (2003).
Yavropoulou, M. P. & Sfikakis, P. P. Cortisol and DHEAS in COVID-19. Hormones 22, 13–14 (2023).
Mannella, P., Simoncini, T., Caretto, M. & Genazzani, A. in Vitamins and hormones Vol. 108 333–353 (Elsevier, 2018).
Yamaguchi, Y. et al. Reduced serum dehydroepiandrosterone levels in diabetic patients with hyperinsulinaemia. Clinical endocrinology 49, 377–383 (1998).
Ardestani, S. K. et al. Changes in hormones, Leukocyte Telomere Length (LTL), and p16INK4a expression in SM-exposed individuals in favor of the cellular senescence. Drug and Chemical Toxicology, 1–7 (2022).
Vaez Mahdavi, M. R. et al. COVID-19 Patients Suffer From DHEA-S Deficiency. Immunoregulation 3, 135–144 (2020).
Das, L. et al. Spectrum of endocrine dysfunction and association with disease severity in patients with COVID-19: insights from a cross-sectional, observational study. Frontiers in endocrinology 12, 645787 (2021).
Yavropoulou, M. P. et al. Alterations in cortisol and interleukin-6 secretion in patients with COVID-19 suggestive of neuroendocrine-immune adaptations. Endocrine 75, 317–327 (2022). https://doi.org/10.1007/s12020-021-02968-8
Traish, A. M., Kang, H. P., Saad, F. & Guay, A. T. Dehydroepiandrosterone (DHEA)—a precursor steroid or an active hormone in human physiology (CME). The journal of sexual medicine 8, 2960–2982 (2011).
Samaras, N., Samaras, D., Frangos, E., Forster, A. & Philippe, J. A review of age-related dehydroepiandrosterone decline and its association with well-known geriatric syndromes: is treatment beneficial? Rejuvenation research 16, 285–294 (2013).
Yen, S. S. Dehydroepiandrosterone sulfate and longevity: new clues for an old friend. Proceedings of the National Academy of Sciences 98, 8167–8169 (2001).
Tomo, S. et al. Assessment of DHEAS, cortisol, and DHEAS/cortisol ratio in patients with COVID-19: a pilot study. Hormones 21, 515–518 (2022).
Pal, R. COVID-19, hypothalamo-pituitary-adrenal axis and clinical implications. Endocrine 68, 251–252 (2020).
Pawlikowski, M. & Winczyk, K. Endocrine and metabolic aspects of COVID-19. Endokrynologia Polska 72, 256–260 (2021).
Gebhard, C., Regitz-Zagrosek, V., Neuhauser, H. K., Morgan, R. & Klein, S. L. Impact of sex and gender on COVID-19 outcomes in Europe. Biology of sex differences 11, 1–13 (2020).
Mourosi, J. T., Anwar, S. & Hosen, M. J. The sex and gender dimensions of COVID-19: A narrative review of the potential underlying factors. Infection, Genetics and Evolution, 105338 (2022).
Maddaloni, E. & Buzzetti, R. Covid-19 and diabetes mellitus: unveiling the interaction of two pandemics. Diabetes/metabolism research and reviews 36, e33213321 (2020).
Wang, X. et al. Comorbid chronic diseases and acute organ injuries are strongly correlated with disease severity and mortality among COVID-19 patients: a systemic review and meta-analysis. Research (2020).
Peykari, N. et al. Non-communicable Diseases and COVID-19; a double-edged sword A Special Communication from IRAN. Journal of Diabetes & Metabolic Disorders 19, 2057–2061 (2020).
Bansal, M. Cardiovascular disease and COVID-19. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14, 247–250 (2020).
Zheng, Y.-Y., Ma, Y.-T., Zhang, J.-Y. & Xie, X. COVID-19 and the cardiovascular system. Nature reviews cardiology 17, 259–260 (2020).
Ruan, Q., Yang, K., Wang, W., Jiang, L. & Song, J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive care medicine 46, 846–848 (2020).
Yang, C. & Jin, Z. An acute respiratory infection runs into the most common noncommunicable epidemic—COVID-19 and cardiovascular diseases. JAMA cardiology 5, 743–744 (2020).
Gupta, R., Ghosh, A., Singh, A. K. & Misra, A. Clinical considerations for patients with diabetes in times of COVID-19 epidemic. Diabetes & metabolic syndrome 14, 211 (2020).
Organization, W. H. Hypertension and COVID-19: scientific brief, 17 June 2021. (World Health Organization, 2021).
Nakamura, S. et al. Possible association of heart failure status with synthetic balance between aldosterone and dehydroepiandrosterone in human heart. Circulation 110, 1787–1793 (2004).
Rutkowski, K., Sowa, P., Rutkowska-Talipska, J., Kuryliszyn-Moskal, A. & Rutkowski, R. Dehydroepiandrosterone (DHEA): hypes and hopes. Drugs 74, 1195–1207 (2014). https://doi.org/10.1007/s40265-014-0259-8
Wu, T. T., Gao, Y., Zheng, Y. Y., Ma, Y. T. & Xie, X. Association of endogenous DHEA/DHEAS with coronary heart disease: A systematic review and meta-analysis. Clin Exp Pharmacol Physiol 46, 984–994 (2019). https://doi.org/10.1111/1440-1681.13146
Wu, T., Zheng, Y. & Xie, X. GW29-e1427 The Correlations Between endogenous DHEA/DHEAS and Coronary Artery Diseases: A Systematic Review and Meta-Analysis. Journal of the American College of Cardiology 72, C246-C246 (2018).
Tivesten, Å. et al. Dehydroepiandrosterone and its sulfate predict the 5-year risk of coronary heart disease events in elderly men. Journal of the american college of cardiology 64, 1801–1810 (2014).
Jia, X. et al. Plasma dehydroepiandrosterone sulfate and cardiovascular disease risk in older men and women. The Journal of Clinical Endocrinology & Metabolism 105, e4304-e4327 (2020).
Zhang, X. et al. Low Serum Dehydroepiandrosterone and Dehydroepiandrosterone Sulfate Are Associated With Coronary Heart Disease in Men With Type 2 Diabetes Mellitus. Front Endocrinol (Lausanne) 13, 890029 (2022). https://doi.org/10.3389/fendo.2022.890029
Meun, C. et al. High androgens in postmenopausal women and the risk for atherosclerosis and cardiovascular disease: the Rotterdam study. The Journal of Clinical Endocrinology & Metabolism 103, 1622–1630 (2018).
Page, J. H. et al. Plasma dehydroepiandrosterone and risk of myocardial infarction in women. Clin Chem 54, 1190–1196 (2008). https://doi.org/10.1373/clinchem.2007.099291
Wellman, M., Shane-McWhorter, L., Orlando, P. L. & Jennings, J. P. The role of dehydroepiandrosterone in diabetes mellitus. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 19, 582–591 (1999).
Brahimaj, A. et al. Serum dehydroepiandrosterone levels are associated with lower risk of type 2 diabetes: the Rotterdam Study. Diabetologia 60, 98–106 (2017). https://doi.org/10.1007/s00125-016-4136-8
Kim, C. & Halter, J. B. Endogenous sex hormones, metabolic syndrome, and diabetes in men and women. Curr Cardiol Rep 16, 467 (2014). https://doi.org/10.1007/s11886-014-0467-6
Rasmussen, J. J. et al. Endogenous testosterone levels are associated with risk of type 2 diabetes in women without established comorbidity. Journal of the Endocrine Society 4, bvaa050 (2020).
Aoki, K. & Terauchi, Y. Effect of dehydroepiandrosterone (DHEA) on diabetes mellitus and obesity. Vitamins and hormones 108, 355–365 (2018).
Kalyani, R. R. et al. The association of endogenous sex hormones, adiposity, and insulin resistance with incident diabetes in postmenopausal women. J Clin Endocrinol Metab 94, 4127–4135 (2009). https://doi.org/10.1210/jc.2009-0910
Bajwa, S. J. S., Sharma, R. & Kurdi, M. S. The stress of COVID-19: Playing havoc with the hormones-A review. Journal of Endocrinology Research 2, 1–8 (2020).
Levanovich, P. E., Diaczok, A. & Rossi, N. F. Clinical and molecular perspectives of monogenic hypertension. Current hypertension reviews 16, 91–107 (2020).
Hester, J., Ventetuolo, C. & Lahm, T. Sex, gender, and sex hormones in pulmonary hypertension and right ventricular failure. Comprehensive Physiology 10, 125 (2019).

No competing interests reported.

supplementary.docx

The multifaceted investigation of DHEAS level in COVID-19 disease: Insights into disease severity, gender, age, comorbidities, and implications for tailored management

Status:

Version 1

Abstract

Figures

1- Introduction

2-Results

2-1- The comparison of Covid-19 patients and control group:

2-2- Evaluating the hospitalization rate of COVID-19 patients with underlying disease:

2-3- Evaluating the impact of Hypertension (HTN):

2-4- Evaluating the impact of Heart Disease (HD):

2-5- Evaluating the impact of Diabetes Mellitus (DM):

2-5- Multiple regression analysis

3-Discussion

4-Conclusion

5- Materials and Methods

5-1-Study design and participants

5-2- DHEAS analysis

5-3- Statistical analysis

Declarations

Author Contribution

Data Availability

References

Additional Declarations

Supplementary Files

Status:

Version 1