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We first investigated testosterone production after 24 and 48 h of ibuprofen exposure to assess its effects on Leydig cell steroidogenesis. Inhibition of testosterone levels was significant and dose-dependent (β = −0.405, P = 0.01 at 24 h and β = −0.664, P < 0.0001 at 48 h) (Fig. 2A) and was augmented over time

The AMH data show that the hypogonadism affected not only Leydig cells but also Sertoli cells and also occurred as early as 14 d of administration

Sertoli cell activity showed that AMH levels decreased significantly with ibuprofen administration, by 9% (P = 0.02) after 14 d (Fig. 1B) and by 7% (P = 0.05) after 44 d compared with the placebo group

Examination of the effect of ibuprofen exposure on both the ∆4 and ∆5 steroid pathways (Fig. 2B) showed that it generally inhibited all steroids from pregnenolone down to testosterone and 17β-estradiol; the production of each steroid measured decreased at doses of 10−5–10−4 M. Under control conditions, production of androstenediol and dehydroepiandrosterone (DHEA) was below the limit of detection except in one experiment with DHEA

Measuring the mRNA expression of genes involved in steroidogenesis in vitro showed that ibuprofen had a profound inhibitory effect on the expression of these genes (Fig. 3 B–D), consistent with that seen above in our ex vivo organ model. Taken together, these data examining effects on the endocrine cells confirm that ibuprofen-induced changes in the transcriptional machinery were the likely reason for the inhibition of steroidogenesis.

Suppression of gene expression concerned the initial conversion of cholesterol to the final testosterone synthesis. Hence, expression of genes involved in cholesterol transport to the Leydig cell mitochondria was impaired

A previous study reported androsterone levels decreased by 63% among men receiving 400 mg of ibuprofen every 6 h for 4 wk

We next examined the gene expression involved in testicular steroidogenesis ex vivo and found that levels of expression of every gene that we studied except CYP19A1 decreased after exposure for 48 h compared with controls

the changes in gene expression indicate that the transcriptional machinery behind the endocrine action of Leydig cells was most likely impaired by ibuprofen exposure.

Together, these data show that ibuprofen also directly impairs Sertoli cell function ex vivo by inhibiting transcription

ibuprofen use in men led to (i) elevation of LH; (ii) a decreased testosterone/LH ratio and, to a lesser degree, a decreased inhibin B/FSH ratio; and (iii) a reduction in the levels of the Sertoli cell hormone AMH

The decrease in the free testosterone/LH ratio resulted primarily from the increased LH levels, revealing that testicular responsiveness to gonadotropins likely declined during the ibuprofen exposure. Our data from the ex vivo experiments support this notion, indicating that the observed elevation in LH resulted from ibuprofen’s direct antiandrogenic action

AMH levels were consistently suppressed by ibuprofen both in vivo and ex vivo, indicating that this hormone is uncoupled from gonadotropins in adult men. The ibuprofen suppression of AMH further demonstrated that the analgesic targeted not only the Leydig cells but also the Sertoli cells, a feature encountered not only in the human adult testis but also in the fetal testis

ibuprofen displayed broad transcription-repression abilities involving steroidogenesis, peptide hormones, and prostaglandin synthesis

a chemical compound, through its effects on the signaling compounds, can result in changes in the testis at gene level, resulting in perturbations at higher physiological levels in the adult human

The analgesics acetaminophen/paracetamol and ibuprofen have previously been shown to inhibit the postexercise response in muscles by repressing transcription

Previous ex vivo studies on adult testis have indeed pointed to an antiandrogenicity, only on Leydig cells, of phthalates (41), aspirin, indomethacin (42), and bisphenol A (BPA) and its analogs

ibuprofen’s effects were not restricted to Leydig and Sertoli cells, as data showed that the expression of genes in peritubular cells was also affected

short-term exposure

In the clinical setting, compromised Leydig cell function resulting in increased insensitivity to LH is defined as compensated hypogonadism (4), an entity associated with all-cause mortality

compensated hypogonadic men present with an increased likelihood of reproductive, cognitive, and physical symptoms

an inverse relationship was recently reported between endurance exercise training and male sexual libido

AMH concentrations are lower in seminal plasma from patients with azoospermia than from men with normal sperm levels

inhibin B is a key clinical marker of reproductive health (32). The function of AMH, also secreted by Sertoli cells, and its regulation through FSH remain unclear in men

the striking dual effect of ibuprofen observed here on both Leydig and Sertoli cells makes this NSAID the chemical compound, of all the chemical classes considered, with the broadest endocrine-disturbing properties identified so far in men.

after administration of 600 mg of ibuprofen to healthy volunteers

14 d or at the last day of administration at 44 d

proportionally associated with disease severity and survival

nonthyroidal illness syndrome

Patients with persistent deterioration of hormone levels (T3, T4) during the study period had higher mortality than those who normalized the function of the thyroid axis

LT3S in patients with septic shock is part of the pathophysiology of this disease and/or an associated organ (endocrine-metabolic) failure and not just an adaptive phenomenon

substitution treatment with synthetic thyroid hormones could modify the hemodynamic symptoms of septic patients, contributing in part to the decrease in their morbidity and mortality

NETosis is a special form of programmed cell death in neutrophils, which is characterized by the extrusion of DNA, histones, and antimicrobial proteins in a web-like structure known as neutrophil extracellular traps (NETs)

increased generation of reactive oxygen species (ROS) is a crucial intracellular process that causes NETosis

NETs are important for preventing pathogen invasion, their excessive formation can result in a slew of negative consequences, such as autoimmune inflammation and tissue damage

When NETs are activated in the circulation, they can also induce hypercoagulability and thrombosis

In COVID-19, major NET protein cargos of NETs (i.e., NE, MPO, and histones) are significantly elevated.

SARS-CoV-2 can also infect host cells through noncanonical receptors such as C-type lectin receptors

Immunopathological manifestations, including cytokine storms and impaired adaptive immunity, are the primary drivers behind COVID-19, with neutrophil infiltration being suggested as a significant cause

NETosis, leading to aberrant immunity such as cytokine storms, autoimmune disorders, and immunosuppression.

SARS-CoV-2 and its components (e.g., spike proteins and viral RNA) attach to platelets and increase their activation and aggregation in COVID-19, resulting in vascular injury and thrombosis, both of which are linked to NET formation

NET formation may be caused by activated platelets rather than SARS-CoV-2 itself

NETosis and NETs are increasingly recognized as causes of vascular injury

early bacterial coinfections were more prevalent in COVID-19 patients than those infected with other viruses

NETosis and NETs may also have a role in the development of post COVID-19 syndromes, including lung fibrosis, neurological disorders, tumor growth, and worsening of concomitant disease

NETs and other by-products of NETosis have been shown to act as direct inflammation amplifiers. Hyperinflammation

“cytokine storm”

SARS-CoV-2 drives NETosis and NET formation to allow for the release of free DNA and by-products (e.g., elastases and histones). This may trigger surrounding macrophages and endothelial cells to secrete excessive proinflammatory cytokines and chemokines, which, in turn, enhance NET formation and form a positive feedback of cytokine storms in COVID-19

NET release enables self-antigen exposure and autoantibody production, thereby increasing the autoinflammatory response

patients with COVID-19 who have higher anti-NET antibodies are more likely to be detected with positive autoantibodies [e.g., antinuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA)]

can enhance this process by interacting with neutrophils through toll-like receptor 4 (TLR4), platelet factor 4 (PF4), and extracellular vesicle-dependent processes

have weakened adaptive immunity as well as a high level of inflammation

tumor-associated NETosis and NETs promote an immunosuppressive environment in which anti-tumor immunity is compromised

NETs have also been shown to enhance macrophage pyroptosis in sepsis

facilitating an immunosuppressive microenvironment

persistent immunosuppression may result in bacterial co-infection or secondary infection

COVID-19 NETs may act as potential inducers for autoimmune responses

NET-induced immunosuppression in COVID-19 in the context of co-existing bacterial infection

Following initial onset of COVID-19, an estimated 50% or more of COVID-19 survivors may develop multi-organ problems (e.g., pulmonary dysfunction and neurologic impairment) or have worsening concomitant chronic illness

NETs in the bronchoalveolar lavage fluid of severe COVID-19 patients cause EMT in lung epithelial cells

decreased E-cadherin (an epithelial marker) expression

COVID-19 also has a long-term influence on tumor progression

Patients with tumors have been shown to be more vulnerable to SARS-CoV-2 infection and subsequent development of severe COVID-19

patients who have recovered from COVID-19 may have an increased risk of developing cancer or of cancer progression and metastasis

awaken cancer cells

NETs have been shown to change the tumor microenvironment

enhance tumor progression and metastasis

vitamin C has been tested in phase 2 clinical trials aimed at reducing COVID-19-associated mortality by reducing excessive activation of the inflammatory response

vitamin C is an antioxidant that significantly attenuates PMA-induced NETosis in healthy neutrophils by scavenging ROS

vitamin C may also inhibit NETosis and NET production in COVID-19

Metformin

Vitamin C