10/3/2021

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Diabetes

Obesity

Metabolic Syndrome
TESTOSTERONE
Cardiovascular

Frailty

Sexual Function
JOHANNES SOEDJONO
Immune System

The Role of TMPRSS2 in Coronavirus Disease 2019 Italy : Lower TT and cFT levels enable significant discrimination between
5
SARS‐CoV‐2 patients with or without poor clinical outcomes
 Androgen stimulate androgen receptor  Italian study involving 31 male px
activity.
 TMPRSS2 transcription is upregulated by
 mean TT level of 8.8 nmol/l:
the androgen receptor  those on respiratory intensive care
 Viral S glycoproteins are activated by units having a mean level of 5 nmol/l,
TMPRSS2, which facilitates virus-cell  those on intensive care units (n=4)
membrane fusion having a mean TT level of 1.0 nmol/l,
 binding of the spike protein with  two out of every four of these men
angiotensin-converting dying.
 enzyme 2 (ACE2), which acts as a receptor  The authors concluded that low TT
Relationship between total or calculated free testosterone and
for the virus estimated probability of different clinical outcomes in and calculated free testosterone (cFT)
SARS‐CoV‐2 pneumonia patients based on T levels. The on admission predicted poor prognosis
smooth curves were carried out by locally weighted scatterplot in COVID-19 infection
smoothing (LOWESS) analysis. Abbreviations: IM = internal
medicine inpatient clinics; ICU = intensive care unit

Mollica, V., et al. Future Oncol. 2020 Jun : 10.2217/fon-2020-0571

Rastrelli G, Di Strasi, Inglese F, et al. Low testosterone levels predict clinical doi: 10.1111/andr.12821

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Double-sided role of testosterone in COVID-19

Germany : COVID-19 is associated with a fall in testosterone levels 8
infection related to male age and clinical course
• Study from Germany
• 45 px (35 male, 10
female)
• 54% male :
TT <4.9nmol/l,
• 25.7% male :
TT < 3nmol/l

 Critically ill male COVID-19 patients suffer from severe testosterone and dihydrotestosterone
deficiencies.
 Both androgens are required to mount antiviral immune responses to combat infection in
males.

Schroeder M, Tuku B, Jarczak D. The majority of male patients with COVID-19 present low testosterone levels on admission to Intensive
Care in Hamburg, Germany: a retrospective cohort study. medRxiv 2020. doi.org/10.1101/2020.05. 07.20073817.t
Salciccia, S., et al. Ther Adv Endocrinol Metab. 2021, Vol. 12: 1–8

9 10

Patients with metastatic hormone-sensitive PC

 SARS-CoV-2-infected men have a worse clinical outcome than women. and metastatic castration-resistant PC (mCRPC)
 Cancer patients have an increased risk of SARS-CoV-2 infection. on ADT displayed a higher lethality from SARS-
 Prostate cancer patients receiving androgen-deprivation therapies appear to be
partially protected from the infection.
CoV 2

Microbes can increase or inhibit sex steroid

Hormones affect host immune responses to microbes 11 hormone signaling in mammalian hosts 12

vom Steeg, LG and KleinHorm, SL. Behav. 2017 February ; 88: 45–51 vom Steeg, LG and KleinHorm, SL. Behav. 2017 February ; 88: 45–51

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.
Bidirectional communication between the neuroendocrine
•.

Bidirectional communication between the neuroendocrine system

system and immune system 13 14
(hypothalamus, pituitary) and the immune system

ThyagaRajan, S and Priyanka, HP. Ann Neurosci.2012 Jan;19(1):40-6 Krishnan, N and Buckley, AR. In Immunoendocrinology in Health and Disease. Eds. Geenen,V
and Crousos, G. Marcel and Dekker. 2005: 21-80

The HPA axis and factors controlling the neuro-endocrine

Interaction between viral infection and the immune– 15
neuroendocrine system
Hypothalamic–pituitary–gonadal axis
Hypothalamic–pituitary–thyroid axis
Hypothalamic–pituitary–gonadal axis
Hypothalamic–pituitary–aprolactin axis
response to stress 16
• The first axis that is activated after a viral
infection and stress situation is the HPA axis. The
pro inflammatory cytokines released by this viral
infection cross the BBB, arrive at the
hypothalamus, activating neurons of the organum
vasculosum of the laminae terminalis (OLVT) and
of the paraventricular nucleus (PVN), stimulating
the release of the corticotrophin-releasing
hormone (CRH), activating the anterior pituitary
gland and consequently releasing the
adrenocorticotropic hormone (ACTH), ending with
the release of corticoids by the adrenal glands
• These corticoids yield negative feedback on
immune cells, which suppress the synthesis and
release of the cytokines TNF-α, IL-1β, and IL-6

Jara, Lj., et l., Autoimmun Rev. 2021 Sep 10;102946. Oyola, MG and Handa, RJ. Stress. 2017 September ; 20(5): 476–494

This evidence indicates the involvement of COVID-19

COVID-19 has a devastating effect on the hypothalamic– 17 infection with the HPG axis 18
pituitary–adrenal axis • The gonadotropin releasing hormone
(GnRH),produced by immune cells;
estrogens stimulate the immune
response, and androgens inhibit this
• COVID-19 infection alters the stress response system, and this alteration
response
contributes to the worsening of elderly patients or those with an autoimmune • The hypothalamic–pituitary–gonadal
disease. Patients severely infected with COVID-19 exhibited significantly lower axis can be directly affected by COVID-
cortisol levels than severely infected non-COVID-19 patients (Mao Y, et al. Front 19, destroying Sertoli cells and Leydig
Endocrinol (Lausanne) 2021; 11:593179) cells, causing a worsening of
spermatogenesis and a decrease in
• Inadequate response of the HPA axis (Alzahrani, AS, et al. Endocr Pract
testosterone levels
2021;27(2):83–9)

Oyola, MG and Handa, RJ. Stress. 2017 September ; 20(5): 476–494

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The reciprocal interaction between the HPA and HPG axes Effects of testosterone (T) and its metabolites on HPA
19 axis and behavioral stress responses 20

Correspondingly, crosstalk between the

hypothalamic–pituitary–gonadal (HPG) and
HPA axes could lead to abnormalities of stress
responses

Oyola, MG and Handa, RJ. Stress. 2017 September ; 20(5): 476–494 Zuloaga et al. Biology of Sex Differences (2020) 11:44

Putative mechanisms leading to poor prognosis or death in men and 21 22

their relationship with circulating levels of serum testosterone

Conditions predisposing to Hypothesized mechanisms Supposed serum T Thrombotic risk Endothelial dysfunction5 Low
worse prognosis circulating levels Platelet activation6 Low

SARS-CoV-2 internalization in host's Increased expression of TMPRSS21 Normal Decreased tissue plasminogen activator7 Low
cells activity

Increased expression of ACE22 Low Raised plasminogen activator inhibitor-1 Low

activity7
Baseline patients’ characteristics Aging3 Low
Immune system dysfunction Cytokines storm (IL-6, IL-1beta, TNF-alpha) Low
Cardiovascular diseases3 Low
Decline in IL-10 levels and blunted T-reg Low
Pulmonary diseases3 Low response
Diabetes mellitus3 Normal/low Impaired B-cells activity Normal

Obesity3 Normal/low

Direct testicle involvement (primary SARS-CoV-2 infection Low (high

hypogonadism) gonadotropins) 5 Poredos P, Jezovnik MK. Angiology. 2018;69(7):564-567
6 Carlioglu A,et al. Blood Coagul Fibrinolysis. 2015;26(7):811-815
1 Asselta 7 Glueck CJ, et al. J Lab Clin Med. 1993;122(4):412-420.
R, et al. medRxiv. 2020. https://doi.org/10.1101/2020.03.30.20047878
2 Walls AC, et al.. Cell. 2020;181(2):281-292
3 Shi S, Qin M, Shen B, et al.. JAMA Cardiol. 2020. https://doi.org/10.1001/jamac ardio.2020.0950

Molecular mechanisms of androgen action

23 AR can act directly on immune cells by 24
influencing the transcription of immune-
regulatory genes through DNA-binding-
dependent and -independent mechanisms

AR are expressed in a wide variety of innate and

adaptive immune cells including neutrophils,
macrophages, mast cells, monocytes,
megakaryocytes, B cells, and T cells

McGrath, et al. Vasc Health and Risk Management 2008:4(1) 11–21 Batalla, IB., et al. Front Immunol. 2020; 11: 1184.

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Classification of COVID-19 disease states and potential

Cytokine Storm 25 therapeutic targets 26

Testosterone-replacement therapy is associated with a reduction or

complete abrogation of spontaneous ex vivo production of IL-1, IL-6
and TNF by APCs

Fajgenbaum,DC.and June,CH. N Engl J Med 2020;383:2255-73 Siddiqi, HK and Mehra, MR. J Heart Lung Transplant . 2020 May;39(5):405-407

Proposed management of COVID-19 patients according

to testosterone levels and stage of disease 27 Take Home Message 28

 SARS-CoV-2 infection alters the mechanisms of response to stress by the

direct action of the virus in the effector organs of the immune–
neuroendocrine system and through a hyperinflammatory response with
a devastator effect on the immune–neuroendocrine system
 Knowing the effect of the COVID-19 infection on the immune–
neuroendocrine system and its response, is essential to propose novel
treatments, to improve the survival of patients infected with COVID-19.

Salciccia, S., et al. Ther Adv Endocrinol Metab. 2021, Vol. 12: 1–8