Sage Journals: Discover world-class research

Abstract

Despite similar infection rates due to COVID-19 (SARS CoV-2) between men and women, male patients have twice the mortality rate across older age groups compared with women. Studies from China, Germany, and Italy suggest that there is a severe primary hypogonadism associated with acute infection and that the more severe the drop in testosterone, the higher the mortality. The co-morbidities associated with increased mortality, namely age, obesity, type 2 diabetes, chronic obstructive pulmonary disease, and chronic kidney disease are all associated with lower rates of testosterone in the general population. Longitudinal studies of testosterone therapy in these conditions have shown reduced all cause mortality. These findings suggest that screening for low testosterone and treating low levels might reduce all-cause mortality including COVID-19. Paradoxically, some observational studies in prostate cancer patients have reported lower mortality rates in those receiving androgen deprivation therapy (ADT). This has led to studies of ADT to reduce mortality associated with COVID-19 infection and suggestions that testosterone replacement therapy (TRT) should be stopped. This seems ill advised as recent publications suggest that TRT can reverse progression to type 2 diabetes and even lead to complete regression, as well as reducing all-cause mortality. In contrast, ADT has been repeatedly shown to have adverse cardio-metabolic effects with increased rates of depression, suicide and reduced quality of life. We also suggest a potentially important role for daily PDE5 inhibitors based on their established beneficial effect on endothelial dysfunction, pulmonary hypertension, insulin resistance, inflammation and cellular apoptosis.

Introduction

Published mortality data consistent shows that two-thirds of ∼45,000 U.K. COVID-19 (SARS CoV-2) deaths are in men with rates under age 85 years of 50.6 of 100,000 for men in the United Kingdom, vs. 25.5 of 100,000 in women.^1,2 Over the age of 85 years, men only make up 30% of the population, meaning that female deaths predominate in this group. Corresponding figures for the United States are 43 of 100,000 in men and 23 of 100,000 in women.² After adjustment for age, the increased risk for Afro-Caribbean men is 1.9 and that for South Asian men is 1.8. Comorbidities such as age, obesity, type 2 diabetes, chronic kidney disease (CKD), hypertension, heart failure, and chronic obstructive pulmonary disease (COPD) increase the risk.¹ In this article, we address the role of testosterone in the acute and chronic phases of COVID-19 as assess strategies for future treatment and prevention.

What Is Currently Known About Testosterone and Cardiovascular and All-Cause Mortality?

Several age-related conditions are associated with increased rates of hypogonadism, notably, type 2 diabetes mellitus (T2DM), obesity, chronic heart disease (CHD), heart failure, CKD, COPD, HIV, and men on long-term opiates. Within these groups, secondary hypogonadism has been shown to be associated with increased all-cause mortality.^3–6 Recently, the American Urological Association (AUA) recommended that all men with low testosterone should be strongly counseled that they are increased cardiovascular risk.⁷

South Asian men have two to threefold risk of T2DM, with associated increased rates of secondary hypogonadism.^8,9 This increased risk is associated with genetic factors combined with diet and lifestyle.⁸ Afro-Caribbean men have been shown to have a steeper decline in testosterone level with age and a lower number of cytosine, adenine, guanine (CAG) repeats on the androgen receptor that may also be associated with increased prostate cancer risk.¹⁰ They also have more severe hypertension and are resistant to first-line hypertension therapies such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).¹¹ Certain occupations such as taxi drivers and security workers found to have increased risk may be associated with obesity, unhealthy diets, and lack of exercise as shown in multiple studies. Such occupations often include a disproportionate number of higher risk ethnic populations.¹² Much media focus on the socioeconomic and cultural factors rather than established medical evidence may prove to be divisive and unhelpful.

Low total and free testosterone have been shown in multiple studies to increase the risk of diabetes three to fourfold, especially in men with body mass index (BMI) 30 kg/m² and two to three components of metabolic syndrome.¹³ The association between testosterone and T2DM is considered bidirectional, often being considered as “functional hypogonadism” with low testosterone being seen merely as a “marker” of chronic ill health.^6,13 The American Diabetes Association,¹⁴ American Academy of Clinical Endocrinologists,¹⁵ American Urology Association,⁷ and British Society for Sexual Medicine¹⁶ all currently recommend screening for all men with T2DM, erectile dysfunction (ER), or obesity (BMI >30 kg/m²), for hypogonadism the current prevalence is ∼40%, more than double the general population.¹⁷

Several publications where patients have been treated with testosterone replacement therapy (TRT) to restore testosterone levels to normal have shown significant reduction in hospitalization and all-cause mortality, in men with CHD,¹⁸ T2DM,^5,19 heart failure,²⁰ CKD,²¹ COPD,²² and opiate use.²³ Other articles have shown reversal of T2DM with TRT in a third of patients and reversal of prediabetes to normoglycemia compared with a control group.²⁴ A recent meta-analysis concluded that “low testosterone levels in men with T2DM are associated with increased cardiovascular mortality” and that “testosterone therapy is associated with a reduction in all-cause mortality and cardiovascular events.”²⁵

Recently a large multicenter randomized controlled trial (RCT) from Australia has been published. The authors found that obese men with prediabetes and baseline total testosterone (TT) <14 nmol/L treated with diet plus either testosterone undecanoate (TU) injection of placebo for 2 years reported a 40% reduction in progression to T2DM in the TU group. Significant benefits were seen compared with diet alone in terms of reduced visceral fat, increased lean muscle mass, and improved sexual function. The effect was independent of baseline testosterone level.²⁶ This well-conducted long-term study is likely to change clinical practice. Increased hematocrit >54% on two consecutive occasions occurred in 25 of 504 (6%) patients, necessitating withdrawal versus 6 of 503 patients in the control group. An additional 30 patients in the treated group had a single isolated raised hematocrit that returned to normal on repeat testing 2 weeks later. Overall, 104 of 503 (20.6%) in the placebo group versus only 65 of 504 (12.6%) in the active group withdrew over 2 years. A large RCT of men with established T2DM showed improvements in HbA1c of 0.4% after 6 months and 0.87 at 18 months.²⁷

A recent review by Hackett²⁸ demonstrated that studies recruiting men with T2DM and confirmed insulin resistance (IR), treated to target testosterone levels for periods of >6 months, showed consistent improvement in glycemic parameters. In contrast, studies involving well-controlled patients, with minimal IR, showed mixed results, conclusions were consistent with a meta-analysis by Corona et al.²⁹ (Table 1).^24,30–39

Table 1.

Review of Randomized Controlled Trials and Longitudinal and Registry Studies of Insulin Levels (mU/mL), Insulin Sensitivity, and HbA1c (%) with Testosterone Therapy, 2007–2020

References	Glycemic parameters treatment effect	Conclusions
Kapoor et al. 2007 N = 27 RCT men with T2DM³⁰	HOMA-IR 4.2–3.5 (p = 0.02) Insulin 13.68–11.76 HbA1c 7.28–6.91 (p = 0.03)	TTh significantly improved insulin sensitivity, HbA1c, and insulin levels.
Kalinchenko et al. 2010. N = 184 RCT TU vs. placebo. Obese men with and without T2DM. 30 weeks³¹	HOMA-IR 5.4–4.3 (p = 0.04) Insulin 18.9–15.6 (p = 0.07)	TTh significantly improves insulin sensitivity, lowers insulin levels, CRP, and IL-6 and reduces BMI and waist circumference.
Jones et al. 2011. N = 220. RCT. Men with T2DM and MetS. 2% gel³²	HOMA-IR 5.9–4.93. Not powered for HbA1c as well-controlled T2DM	TTh improves insulin sensitivity, reduces lipoprotein-A. Improved sexual function.
Hackett et al. 2013 N = 200, RCT. TU vs. placebo Men with T2DM. 30 weeks plus 52 weeks open label³³	HOMA-IR 3.52–2.48 (after 82 weeks) HbA1c 8.85–8.42 in poorly controlled T2DM	TTh significantly reduced HbA1c, HOMA-IR, BMI, waist circumference, and sexual function. All responses reduced in men with baseline depression.
Francomano et al. 2014 N = 20 TU vs. control. 5-year follow-up, men with T2DM³⁴	HOMA-IR 4.25–1.4 (p = 0.0001) HbA1c 7.7–6.1 (p = 0.0001)	TTh significantly improved insulin sensitivity, HbA1c, British Medical Association, waist circumference, and metabolic and endothelial markers.
Gianetti et al. 2014 N = 88. 40 weeks RCT. TU vs. placebo. Men with T2DM³⁵	HOMA-IR 2.11–1.75 (p = 0.08) HbA1c 6.8–7.1 (p = 0.05)	No improvement in insulin sensitivity or HbA1c in men with essentially well-controlled T2DM.
Dhindsa et al. 2016 N = 44 (20 active vs. 14 placebo). 24 weeks. Testosterone injection 250 mg per week vs. placebo. Men with T2DM³⁶	Insulin 13.6–9.9 (p = 0.04) HbA1c 6.8–7.2 (p = 0.27) (short duration and well-controlled T2DM)	TTh in men with T2DM and HH increases insulin sensitivity, lean muscle mass, and decreases subcutaneous fat.
Grotti et al. 2018 N = 55. RCT TU vs. placebo. 12-month follow-up. Obese men with T2DM³⁷	Insulin 26.03–17.51 (p < 0.001) HOMA-IR 11.45–6.81 (p < 0.001) HbA1c 8.12–7.18 (p < 0.001)	Reduced insulin levels, improved insulin sensitivity. Improved HbA1c. Improved flow-mediated dilatation (p = 0.005).
Mohler et al. 2018 N = 788. Placebo controlled RCT. 1% gel. 12-month follow-up. Men >55 years with HG. 37.6% with T2DM³⁸	Insulin 19.6–17.9 (p = 0.02) HOMA-IR 5.8–5.5 (p = 0.03) HbA1c 6.3–6.3. (NS)	Improved insulin sensitivity but not HbA1c (well controlled—only 30% with T2DM). No effect on men without T2DM medication suggesting greater effect in men with T2DM.
Yassin et al. and Haider et al. N = 316, control = 87. 9–11-year follow-up. Registry study. Single center^24,39	HOMA-IR 8.7–1.8 HbA1c 7.8–5.4	Improvement in HOMA-IR and HbA1c. Remission in T2DM is reduced by 34.3% with 40% reduction in progression from prediabetes to frank diabetes.
Wittert et al. (T4DM) 2020 Double-blind RCT 2 years. TU vs. placebo in obese men with prediabetes (N = 1007, combined with aggressive diet and exercise intervention)²⁶	2 h postprandial glucose reduced by 1.70 vs. 0.95 nmol/L (p < 0.001)	A 40% reduction in progression to type 2 diabetes, reduced waist circumference, reduced total and abdominal fat, increased lean muscle mass, grip strength, and improved sexual symptoms (all p < 0.001).

BMI, body mass index; CRP, C-reactive protein; HBA1c, hemoglobin A1c; HG, hypogonadism; HH, hypogonadatrophic hypogonadism; HOMA-IR, homeostatic model assessment of insulin resistance; IL, interleukin; MetS, metabolic syndrome; NS, not significant; RCT, randomized controlled trial; T2DM, type 2 diabetes mellitus; TTh, testosterone therapy; TU, testosterone undecanoate.

Venous thrombotic embolism and testosterone

Administration of exogenous testosterone can raise hematocrit values and potentially blood viscosity, along with platelet and thromboxane A2 concentrations, thereby enhancing the risk of venous thromboembolism.⁴⁰ Potentially this might increase risk in association with the severe endothelial dysfunction induced by COVID-19 infection. Walker et al.⁴¹ reported recorded episodes of venous thrombotic embolism (VTE) after recorded testosterone prescriptions and recorded short-term coded VTE with the prior 6 months in 3110 men, coded as “hypogonadism.” They described an odds ratio (OR) of 1.68 for younger men and 2.02 for older men, suggesting increased relative risk in younger men, even though the p-value was not significant at 0.14. As the reported prevalence of VTE in men <60 years is less than 1 event per 1000 patient years, this study was severely underpowered. In addition, there was no data on evidence of blood testing to confirm diagnosis of hypogonadism, no confirmation of VTE diagnosis, and no follow-up levels and no evidence that prescriptions were taken as we know that compliance is at best 50% for newly initiated prescriptions. Baillargeon et al.⁴² reviewed a health care database of 30,572 men and found no association between incident VTE and testosterone medication in the previous 14 days. Two meta-analyses^43,44 reported no association between VTE and TRT and Salter and Mulhall⁴⁵ analyzed the recommendations of six leading medical societies and all concluded that there was no association between TRT and VTE. Rather than considering an increase in hematocrit to be a cause for concern, the T trial⁴⁶ also found no increase in VTE but found that 126 of 788 men were anemic at baseline and 58% were normalized with TRT by 12 months. Lest we forget, anemia is an independent risk factor for cardiovascular disease (CVD).⁴⁷

The Role of Sex Hormones in the COVID-19 Pandemic

Common explanations for the gender differences are increased smoking by men, although this does not seem to be relevant in recent studies.⁴⁸ In fact, women are at 50% greater risk of COPD associated with smoking.⁴⁸ Men are more prone to “risky behavior,” less frequent hand washing, and later presentation,^1,2 and even baldness⁴⁹ is now suggested as a risk factor, even though there is no link with serum testosterone levels within the normal range.⁵⁰ A protective effect of estrogen is suggested in women, that is diminished after menopause.⁵¹

Several recent studies point to an important role for hormones, particularly testosterone, during the acute phase of the illness.⁵² A RCT reported an improvement in peak oxygen consumption in men receiving testosterone replacement therapy.⁵³ SARS–CoV-2 infects lung alveolar epithelial cells using angiotensin-converting enzyme II (ACE2) as an entry receptor. ACE2 plays a role in lung protection and, therefore, viral binding to this receptor may deregulate a lung protective pathway.⁵² Interestingly, studies showed that ACE2 is a constitutive product of adult-type Leydig cells, thus implying a role in testicular function and suggesting a possible involvement of testicle in SARS-CoV-2 infected patients, a factor that may affect testosterone secretion.⁵² Several studies carried out both in animals and in humans showed that hypogonadism is associated with increased proinflammatory cytokines and that testosterone treatment reduces interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α.⁵² Furthermore, the association between an increased proinflammatory state and decline in testosterone is often observed in aging men and in men with stable coronary artery disease.^4,6

Endothelial dysfunction with additional thrombotic risk has been flagged up multiple times as an important risk factor for CVD and is frequently present in men with erectile dysfunction and testosterone deficiency.⁶ It appears the SARS-CoV-2 infection facilitates the induction of endothelial dysfunction in many organs but especially in the vascular tree.⁵² In hepatitis B virus (HBV) and C (HBC) virus infections, androgens can directly interact with HBV genome integrated into the cell nucleus and activate transcription of HBV oncoproteins. Conversely, estrogen receptors protect liver cells from inflammatory damage, apoptosis, and oxidative stress, which contribute to fibrosis and malignant transformation.⁵⁴

Lessons from Recent COVID-19 Studies?

In a recent study from Germany involving 45 acute SARS CoV-2 admissions (35 male, 10 female), 54% of male patients had TT <4.9 nmol/L, with 25.7% <3 nmol/L on admission. They considered 6.68 nmol/L as normal based on local reference ranges. Luteinising hormone (LH) was raised in 31.4%, and estradiol was raised in 31.4% and was associated with increased inflammatory markers, especially IL-6. The authors concluded that critically ill male COVID-19 patients suffer from severe testosterone and dihydrotestosterone deficiencies.⁵⁵ Both androgens are required to mount antiviral immune responses to combat infection in men.⁶

In an Italian study involving 31 male patients, those managed routinely on medical wards had mean TT 8.8 nmol/L, those on respiratory ICU had mean TT 5 nmol/L, and those on ICU (n = 4) had mean TT 1.0 nmol/L, with 2 of 4 dying. The authors concluded that low TT and calculated free testosterone on admission predicted poor prognosis in COVID-19 infection.⁵⁶

A study of 81 admissions with COVID-19 from Wuhan, China, mean age 38 years, showed reduced TT levels and raised LH, suggestive of a compensated primary hypogonadism.⁵⁷

In a prepublication study, the time to clearance of the virus in symptomatic patients was investigated by serial oropharyngeal/nasopharyngeal swabs followed by real time-polymerase chain reaction (PCR). A total of 68 Indian subjects with median age of 37 years (range 3–75) were examined and included 48 (71%) males and 20 (29%) females. Female patients were able to achieve viral clearance significantly earlier than males, with a median difference of 2 days in achieving a negative PCR result (p = 0.038). The researchers studied expression patterns of the SARS-CoV-2 receptor, ACE2, in tissue-specific repositories. The testis was one of the highest sites of ACE2 expression in three independent RNA expression databases (Human Protein Atlas, FAMTOM5, and GETx). ACE2 was also determined to be highly expressed in testicular cells at the protein levels. In contrast, very little expression of ACE2 was seen in ovarian tissue. High expression of ACE2 in testes raises the possibility that testicular viral reservoirs may play a role in viral persistence in males, requiring further research. Serum testosterone levels may also be adversely affected and impact on recovery, suggesting that levels should be investigated in these men affected by COVID-19 because of the adverse impact of testosterone deficiency on cardiovascular mortality and heart failure.⁵⁸

In the United States, a trial involving estrogen administration to acute male cases has begun.⁵⁹ This seems illogical based on the findings of raised estradiol levels, which were associated with raised inflammatory markers in the study from Germany.⁶⁰

Is High Testosterone a Promoter of COVID-19 Infection?

Data by Pozzilli and Lenzi⁵² from Italy reveal 58% of SARS-CoV-2 infection was in males.^1–3 The difference in the number of cases reported by gender increased progressively in favor of male subjects up to the age group ≥60–69 years (66.6%) and ≥70–79 years (66.1%), with the exception of the 20–29 and 30–39 years group in which the number of female subjects was slightly higher. Mortality was higher in male subjects in all age groups. Deaths among 30–39 years were 82.4% males, deaths among 40–49 years are 73.1% males, deaths among 50–59 years are 78.5% males, deaths among 60–69 years are 79.7% males, deaths among 70–79 years are 79.6% males, and deaths among 80–89 years are 66.9% males. As men <40 years are known to have higher testosterone levels that decline with age,³ this suggests a possible protective effect of testosterone in younger men in terms of rates of infection, which is lost with age, but once infected, there is no protective effect from testosterone. Treating low testosterone levels linked to medical conditions associated with aging might be important in terms of reducing infection risk, but that, once infected, alternative hormonal strategies might be required. To date, no publications have associated COVID-19 infection rates and outcome to baseline testosterone levels.

The mentioned figures provide evidence to support the testosterone-driven COVID-19 hypothesis.⁵² Androgen receptor activity has been considered a requirement for the transcription of TMPRSS2 gene as no other known TMPRSS2 gene promoter has been reported to exert the same action in humans. TMPRSS2 is both the most frequently altered gene in primary prostate cancer and a critical factor enabling cellular infection by SARS-CoV-2. The hyperandrogenic phenotype could explain the severe attacks of COVID-19 occasionally in younger men, possibly associated with androgen receptor polymorphism with shorter CAG repeats. These patients are at greater risk of prostate cancer, and this mechanism might be the link between higher rates of prostate cancer and increased morbidity and mortality in men of Afro-Caribbean origin. Since TMPRSS2 is expressed also at pulmonary level, the use of TMPRSS2 inhibitors, currently used for prostate cancer, represents an appealing target for prevention or treatment of COVID-19 pneumonia.⁵²

Androgen deprivation therapy has been suggested on the basis of a reported improved survival from COVID-19 in men with prostate cancer. Montopoli et al.⁶¹ with only 5 of 5273 men with prostate cancer on androgen deprivation therapy (ADT) developed proven COVID-19 and none died. Among patients with cancer, 67.9% (n = 292) were hospitalized and 17.4% (n = 75) died. No significant differences were observed between prostate cancer patients and those affected by other types of cancers.³⁹ In support of these findings, Patel et al.⁶² identified 58 patients with prostate cancer, 22 on ADT and 36 not on ADT. The cohorts were reasonably matched apart from the ADT group and having higher incidence of metastatic disease (64% vs. 0%) and higher rates of pulmonary disease (27% vs. 6%). ADT was associated with lower rates of hospitalization and oxygen requirement. There was a reduced mortality (OR 0.37 p = 0.22) not reaching statistical significance. A potential bias of this study might be greater levels of protective isolation, associated with the presence of metastatic disease, reducing the risk of viral contact. None of these studies are supported with data on testosterone levels before, or during, admission.

The authors of these studies have suggested a preventive role for ADT. As studies from Italy and Germany suggest that COVID-19 infection is frequently associated with an acute primary hypogonadism that is associated with increased mortality, it is questionable as to whether ADT after admission would be effective. A prophylactic prevention policy for the at-risk population is highly impractical, as the adverse event profile of these drugs is likely to prove unacceptable and is frequently not reversible. As the evidence strongly suggests that the at-risk population has comorbidities associated with low testosterone levels, there would seem to be no reason to stop testosterone replacement, as there is currently no evidence to suggest that levels of testosterone within the normal range are associated with adverse outcomes.

ADTs significantly increasing the risk of T2DM by up to 30%⁶³ and are associated with sexual dysfunction, reduced quality of life, depression, and increased rates of suicide.⁶⁴A role for 5-α reductase inhibitors (5ARIs) has been suggested, but these drugs also increase the risk of T2DM by 30%⁶⁵ and are associated with often irreversible sexual dysfunction. There are mechanisms by which 5ARIs might have adverse effects on the lungs.⁶⁶ Both these strategies appear flawed in the light of the findings from Germany and Italy of extremely low testosterone and dihydrotestosterone levels in acutely ill patients.^55,56

Long-Term Prevention Strategy for Men at High Risk in the United Kingdom

Although acute therapies and vaccine development are vitally important in COVID-19 management, preventive strategies are required for high-risk groups in the event of second- and third-wave pandemics, or the emergence of new viral threats. The clearly defined risk factors of age, male gender, obesity, type 2 diabetes, CKD, COPD are all associated with high rates of hypogonadism,^4–6 as are higher risk ethnic groups.^8,9

According to 2019 U.K. figures, 56% of the 4.4 million people with T2DM are male and 44% female. Afro-Caribbean, Bangladeshi, and Indian men have two to four times greater prevalence than Caucasian men and are diagnosed ∼10 years earlier.⁶⁷ A 2016 study from Sweden found a 14.6% prevalence in men and 9.1% prevalence in women. There was no relationship with BMI but has a strong association with increased visceral fat mass.⁶⁸ Ten percent of the UK National Health Service (NHS) budget is spend on type 2 diabetes (£10 billion) per year.⁶⁹ Multiple diet and lifestyle interventions have achieved limited success as prevalence continues to increase worldwide. No specific interventions to date have targeted the specific high-risk ethnic groups of men with excessive levels of visceral fat, clearly shown to be at high all-cause and COVID-19 mortality risk.⁶⁷ To date, the vast knowledge linking low testosterone levels with increased visceral fat and the beneficial effects of TRT on visceral fat and lean muscle has been largely ignored.

From the practical viewpoint, using drugs that improve endothelial function, such as ACE inhibitors/ARBs and statins, could be very important in these patients, although many patients will already be on these drugs as part of standard diabetes care.⁶⁹

Role of Daily Phosphodiesterase Type 5 Inhibitors in Prevention?

Daily PDE5 inhibitors such as tadalafil have been consistently shown to improve endothelial function, increase insulin sensitivity, reduce visceral fat, increase testosterone levels,⁷⁰ and even reduce rates of bowel cancer.^71,72 Santi et al.⁷⁰ conducted a meta-analysis of 12 RCTs (n = 476) of chronic PDE5 inhibitors in T2DM and concluded clear evidence of improved flow-mediated dilatation and reduction of IL-6, with high-sensitivity C-reactive protein (hs-CRP) improvement. Oral PDE5 inhibitors have been demonstrated to possess many beneficial useful additional implications with acknowledged anti-inflammatory, antioxidant, immune response regulation, and antiapoptotic properties.⁷³ These properties have been elucidated through the NO/sGC/cGMP in addition to the emerged hemeoxygenase-1 enzyme as well as hydrogen sulfide pathways.⁷⁴ PDE5 inhibitors facilitate vasoconstriction caused by AT1 receptor downregulation due to SARS-CoV-2-ACE2 binding alveolar cells, bronchial epithelium, and vascular endothelium through the NO/sGC/cGMP pathway.⁷⁴

PDE5 is expressed in high levels in the lung tissue and is highly specific for hydrolysis of cyclic guanosine monophosphate (cGMP).⁷⁵ Sildenafil and tadalafil are licensed as first-line treatment for pulmonary hypertension, primarily through their effect on endothelial function and prevention of impaired pulmonary artery relaxation.^76,77 Sildenafil citrate use has been verified to exhibit protective effects in pulmonary arterial hypertension cases by suppressing multiple cytokines involved in the neutrophil and mononuclear cell recruitment, including cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2α/β, tissue inhibitor of metalloproteinase-1, IL-1α, lipopolysaccharide-induced chemoattractant cytokines chemokine, monokine induced by gamma interferon, macrophage inflammatory protein (MIP)-1α, and MIP-3α.^78,79

Sildenafil has been shown to have positive effects in cases of acute lung injury,⁸⁰ by inhibiting the proliferation of regulatory T cells and the production of autoantibodies, proinflammatory cytokines, and modulating platelet activation, angiogenesis, and pulmonary vasoreactivity. Sildenafil use has been validated to reduce the leak of neutrophils into the lung, the release of proinflammatory mediators TNF-α, IL-8, and IL-6.⁸¹

In COPD, sildenafil use has been reported to improve pulmonary hemodynamics by inhibiting hypoxic vasoconstriction and facilitating the weaning of these patients from the ventilators due to improved respiratory parameters.⁸² In hypoxic conditions, sildenafil use was shown to increase the exercise capacity in acute normobaric hypoxia by improving arterial oxygenation.⁸³ Prophylactic treatment with an optimal dose of sildenafil citrate has been demonstrated to significantly increase lung cGMP levels, prolongs median survival, and reduces fibrin deposition and total protein content in bronchoalveolar lavage fluid.⁸⁴

PDE5 inhibitors raise the intracellular cGMP, which has intense anti-inflammatory effect by reducing the effects of proinflammatory kinins, IL-1beta and TNF-α, and increasing the expression of the anti-inflammatory IL-10.⁸⁵

PDE5 inhibitors are highly protective agents against lung and kidney damage due to sepsis by the maintenance of the oxidant–antioxidant status of TNF-α⁸⁶ and produce a sustained reduction of fibrinogen hs-CRP and hsIL-6.⁸⁷ They behave as antioxidants by inhibiting free radical formation supporting antioxidant redox systems. By increasing available NO, they inhibit platelet aggregation primarily through a cGMP process potentially reducing the thrombotic state induced by COVID-19.^88,89

As the prevalence of ED is 78% in men with T2DM, some review articles advocate routine PDE5 inhibitor use in men with T2DM, especially with cheaper generic formulations.⁹⁰ Daily dosing is frequently used in conjunction with testosterone therapy in hypogonadal patients and PDE5 inhibitors are upregulated by restoration of testosterone levels.⁹⁰

Optimizing Diabetes Care

Realization that obese men with T2DM are particularly vulnerable to COVID-19 raises the question of modifying medications to improve outcomes. ACE inhibitors/ARBs are likely to be beneficial if not already prescribed, as are statins.⁹¹

DPP4 inhibitors and GLP1 receptor agonists may have a favorable impact on the modulation of viral entry and overproduction of inflammatory cytokines during COVID-19 infection, although current evidence is limited and not univocal. Given the sustained attenuation in appetite sensations and dietary energy intake, coupled with gastrointestinal intolerance, the use of GLP1 receptor agonists may further delay patient recovery, and a temporary suspension should be cautiously considered in the most fragile cases. Conversely, SGLT2 inhibitors may increase the likelihood of COVID-19–related ketoacidosis decompensation among patients with severe insulin deficiency. Hospitalized patients might be at higher risk for genitourinary infections and contraindications may appear if the estimated glomerular filtration rate falls <45 mL/min during acute illness.⁹¹ Interestingly, the summary of product characteristics for testosterone products state that they cause insulin sensitivity and may require a reduction in diabetes medication, including insulin.⁹²

U.K. Statistics for Type 2 Diabetes

The number of people diagnosed with T2DM has doubled in the past 20 years, currently standing at 3.8 million. There are estimated to be 1.2 million with T2DM who are undiagnosed. Official 2019 figures state that 12.3 million people are at risk of T2DM and two-thirds are men (8 million).⁶⁷ Statistics state that 68% of these are obese (5.3 million) and, based on the T4DM cutoff of 14 nmol/L, 40% of these men would be expected to be candidates for TRT (2.1 million), with a potential 40% reduction in progression to T2DM. These figures suggest that progression to T2DM could be prevented in 1 million at-risk men, by addressing low testosterone levels. Unfortunately, “testosterone” or “hypogonadism” is not mentioned in the current NHS strategy document.⁶⁷ Despite acknowledging that 78–90% of men suffer from ED, even in 2019, only 15–20% of men with T2DM have been asked about ED, making the diagnosis of hypogonadism unlikely.⁶⁷ This is despite NICE guidance recognizing that the presence of ED increases cardiovascular risk by 50% and recommending that All men with T2DM are asked annually about ED.⁶⁹

Close examination of the NHS strategy for dealing with the escalating costs of T2DM, currently £10 billion per year, reveals almost complete reliance on diet and exercise advice, which is unchanged from government documents of 15–20 years earlier. Despite the high burden of additional mortality associated with T2DM and the fact that 40% of COVID-19 deaths occur in patients with T2DM of whom 2 of 3 are men, there is still minimal interest in testosterone within U.K. diabetes practice, despite clear recommendation by multiple expert guidelines.^7,14–16

Conclusions

These studies suggest that men admitted with COVID-19 have significantly lower testosterone levels than with other acute hospital admissions. Furthermore, the virus is associated with a severe primary hypogonadism occurring in addition to the functional secondary hypogonadism associated with comorbid conditions in patients at high risk of infection. Unfortunately, bloods taken on acute admission do not reveal the previous baseline level for that patient. These recent studies raise the question as to whether men should be treated acutely with testosterone to boost resistance to the cytokine storm associated with COVID-19 infection. There seems little justification for using estrogens in the acute phase as victims of COVID-19 have raised estradiol levels. A possible role for ADT in the acute phase of the illness has been suggested, but RCTs would be required because of the adverse metabolic and quality–of-life effects of these drugs.

PDE5 inhibitors with their multiple anti-inflammatory, antioxidant, glycemic, endothelial, and pulmonary benefits represent promising preventive agents for future pandemics. These drugs have an excellent safety record, quality-of-life benefits, and are now available as generic products.

Little consideration has been given to the hypogonadal population with comorbidities, who may have survived the current pandemic but who may be at considerable risk from second- and third-wave infection, or future viral pandemics. It is well established from several longitudinal studies that low testosterone levels in men are associated with increased mortality, increased risk of T2DM, and that TRT reverses this increased risk of all-cause mortality. We now have firm evidence from a major RCT that TRT reverses progression to T2DM. As older men with T2DM are at greater risk of mortality from COVID-19, a therapy that potentially prevents progression to T2DM should also reduce the risk from COVID-19.^24,25 This approach is strongly endorsed by two recent review articles from Italy and the United States.^92,93 Current evidence-based guidelines from multiple medical disciplines already recommend screening, diagnosing, and treating men with hypogonadism in high-risk groups, such as type 2 diabetes, BMI >30 kg/m², and men with ED. Ultimately, if we do not follow the evidence, we are in danger of becoming preoccupied with COVID-19 mortality rather than all-cause mortality. Ultimately T2DM remains a major global health problem irrespective of the impact of COVID-19.

Footnotes

Author Disclosure Statement

Both G.H. and M.K. are occasional speakers for Besins and Bayer.

Funding Information

No funding was received for this article.

Cite this article as: Hackett G, Kirby M (2020) COVID-19, type 2 diabetes, and hypogonadism: lessons for acute management and long-term prevention. Androgens: Clinical Research and Therapeutics 1.1, 22–31, DOI: 10.1089/andro.2020.0004.

Abbreviations Used

References

NHS. COVID-19 daily deaths. 2020. https://www.england.nhs.uk/statistics/statistical-work-areas/covid-19-daily-deaths/ (last accessed July 9, 2020).

Worldometer. Coronavirus (COVID-19) mortality rate. https://www.worldometers.info/coronavirus/coronavirus-death-rate/ (last accessed September 15, 2020).

Haring

, John

, Volzke

, et al. Low testosterone concentrations in men contribute to the gender gap in cardiovascular morbidity and mortality. Gend Med. 2012; 9(6):557–568.

Ruige

, Mahmoud

, De Bacquer

, et al. Endogenous testosterone and cardiovascular disease in healthy men: A meta-analysis. Heart. 2011; 97(11):870–875.

Muraleedharan

, Marsh

, Kapoor

, et al. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol. 2013; 169(6):725–733.

Muraleedharan

, Jones

. Testosterone, and mortality. Clin Endocrinol. 2014; 81(4):477–487.

Mulhall

, Trost

, Brannigan

, et al. Evaluation and management of testosterone deficiency: AUA guideline. J Urol. 2018; 200(2):423–432.

Bakker

LEH

, Sleddering

, Schoones

, et al. Pathogenesis of type 2 diabetes in South Asians. Eur J Endocrinol. 2013; 169(5):R99–R114.

Heald

, Patel

. Anderson

S.G

. Vyas A. Rudenski A. Hughes E, et al. Migration is associated with lower total, but not free testosterone levels in South Asian men. Clin Endocrinol. (Oxf.). 2007; 67(5):651–655.

10.

Ackerman

, Lowe

, Lee

. Ethnic variation in allele distribution of the androgen receptor (AR) (CAG)n repeat. J Androl. 2012; 33(2):210–215.

11.

Spence

, Rayner

. Hypertension in blacks. Individualized therapy based on renin/aldosterone phenotyping. Hypertension. 2018; 72(2):263–269.

12.

Elshatarat

, Burgel

. Cardiovascular risk factors of taxi drivers. J Urban Health. 2016; 93(3):589–606.

13.

Yao

, Wang

, An

. Testosterone level and risk of type 2 diabetes in men: A systemic review and meta-analysis. Endocr Connect. 2018; 7(1):220–231.

14.

American Diabetes Association. Low testosterone in diabetes. https://www.diabetes.org/resources/men/low-testosterone (last accessed September 15, 2020).

15.

Goodman

, Guay

, Dandona

, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of testosterone and cardiovascular risk. Endocr Pract. 2015; 21(9):1066–1073.

16.

Hackett

, Kirby

, Edwards

, et al. British Society for Sexual Medicine guidelines on adult testosterone deficiency, with statements for UK practice. J Sex Med. 2017; 14(12):1504–1523.

17.

Dhindsa

, Ghanim

, Batra

, Dandona

. Hypogonadotropic hypogonadism in men with diabesity. Diabetes Care. 2018; 41(7):1516–1525.

18.

Anderson

, May

, Lappé

, et al. Impact of testosterone replacement therapy on myocardial infarction, stroke, and death in men with low testosterone concentrations in an integrated healthcare system. Am J Cardiol. 2016; 117(5):794–799.

19.

Hackett

, Jones

, Strange. Ramachandran S. Statin, testosterone and phosphodiesterase 5-inhibitor treatments and age-related mortality in diabetes. World J Diabetes. 2017; 8(3):104–111.

20.

Dos Santos

, Sayegh

ALC

, Groehs

RVR

. Testosterone deficiency increases hospital readmission and mortality rates in male patients with heart failure. Arq Bras Cardiol. 2015; 105(3):256–264.

21.

Sharma

, Oni

, Wiegmann

, et al. Testosterone replacement therapy (TRT) is associated with delayed progression of chronic kidney disease: A retrospective analysis of testosterone normalization in US veterans. Ann Nephrol. 2020; 5(1):51–59.

22.

Baillargeon

, Urban

, Zhang

, et al. Testosterone replacement therapy and hospitalization rates in men with COPD. Chron Respir Dis. 2019; 16:1479972318793004.

23.

Jasuja

, Ameli

, Reisman

, et al. Health outcomes among long-term opioid users with testosterone prescription in the veterans health administration. JAMA Network Open. 2019; 2(12):e1917141.

24.

Haider

, Haider

, Saad

, et al. Remission of type 2 diabetes following long-term treatment with injectable testosterone undecanoate in patients with hypogonadism and type 2 diabetes: 11-year data from a real-world registry study. Diabetes Obes Metab. 2020. [Epub ahead of print]; DOI: 10.1111/dom.14122

25.

Quang

, Kalhan

. Cardiovascular benefits and risks of testosterone replacement therapy in hypogonadal men with type 2 diabetes mellitus and/or the metabolic syndrome: A systematic review. Br J Diabetes. 2018;18(4). DOI: https://doi.org/10.15277/bjd.2018.192

26.

Wittert

, Atlantis

, Bracken

, et al. Effect of testosterone treatment on type 2 diabetes incidence in high risk men enrolled in a lifestyle programme: 2-year randomised placebo-controlled study. Diabetes. 2020; 69(Supplement 1):274-OR.

27.

Hackett

, Cole

, Bhartia

, Wilkinson

, Raju

, Wilkinson

. Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: The BLAST study. J Sex Med. 2014; 11(3):840–856.

28.

Hackett

Metabolic effects of testosterone therapy in men with type 2 diabetes and metabolic syndrome. Sex Med Rev. 2019; 7(3):476–490.

29.

Corona

, Giagulli

, Maseroli

, et al. Therapy of endocrine disease: Testosterone supplementation and body composition: Results from a meta-analysis study. Eur J Endocrinol. 2016; 174(3):R99–R116.

30.

Kapoor

, Clarke

, Stanworth

, et al. The effect of testosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2007; 156(5):595–602.

31.

Kalinchenko

, Tishova

, Mskhalaya

, et al. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: The double-blinded placebo-controlled Moscow Study. Clin Endocrinol (Oxf). 2010; 73(5):602–612.

32.

Jones

, Arver

, Behre

, et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 Study). Diabetes Care. 2011; 34(4):828–837.

33.

Hackett

, Cole

, Bhartia

, et al. The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study). Int J Clin Pract. 2014; 68(2):203–215.

34.

Francomano

, Lenzi

, Aversa

. Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in ageing men with metabolic syndrome. Int J Endocrinol. 2014; 2014:527470.

35.

Gianatti

, Dupuis

, Hoermann

, et al. Effect of testosterone treatment on glucose metabolism in men with type 2 diabetes: A randomized controlled trial. Diabetes Care. 2014; 37(8):2098–2107.

36.

Dhindsa

, Ghanim

, Batra

, et al. Insulin resistance and inflammation in hypogonadotropic hypogonadism and their reduction after testosterone replacement in men with type 2 diabetes. Diabetes Care. 2016; 39(1):82–91.

37.

Groti

, Zuran

, Antoni

, et al. The impact of testosterone replacement therapy on glycaemic control, vascular function, and components of the metabolic syndrome in obese hypogonadal men with type 2 diabetes. Aging Male. 2018; 21(3):158–169.

38.

Mohler

, Ellenberg

, Lewis

, et al. The effect of testosterone on cardiovascular biomarkers in the testosterone. J Clin Endocrinol Metab. 2018; 103(2):681–688.

39.

Yassin

, Haider

, et al. Testosterone therapy in men with hypogonadism prevents progression from prediabetes to type 2 diabetes: eight-year data from a registry study. Diabetes Care. 2019; 42(6):dc182388.

40.

Adesuyi

Ajayi L, Mathur R, Halushka PV. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Circulation. 1995; 91(11):2742–2747.

41.

Walker

, Zakai

, MacLehose

, et al. Association of testosterone therapy with risk of venous thromboembolism among men with and without hypogonadism. JAMA Intern Med. 2019; 180(2):190–197.

42.

Baillargeon

, Urban

, Morgentaler

, et al. Risk of venous thromboembolism in men receiving testosterone therapy. Mayo Clinic Proc. 2015; 90(8):P1038–P1045.

43.

Corona

, Dicuio

, Rastrelli

, et al. Testosterone treatment and cardiovascular and venous thromboembolism risk: What is ‘new’?. J Investig Med. 2017; 65(6):964–973.

44.

Houghton

, Alsawas

, Barrioneuvo

, et al. Testosterone therapy and venous thromboembolism: A systematic review and meta-analysis. Thromb Res. 2018; 172:94–103.

45.

Salter

, Mulhall

. Guideline of guidelines: Testosterone therapy for testosterone deficiency. BJUI. 2019; 124(5)722–729.

46.

Snyder

, Bhasin

, Cunningham

. Effects of testosterone treatment in older men. N Engl J Med. 2016; 374(7):611–624.

47.

Vlagopoulos

, Tighiouart

, Wiener

. Anemia as a risk factor for cardiovascular disease and all-cause mortality in diabetes: The impact of chronic kidney disease. JASN. 2005; 16(11):3403–3410.

48.

Barnes

PJ.

Sex differences in chronic obstructive pulmonary disease mechanisms. Am J Respir Crit Care Med. 2016; 193(8):813–824.

49.

Goren

, Vano-Galvan

, Wambier

. A preliminary observation: Male pattern hair loss among hospitalized COVID-19 patients in Spain—A potential clue to the role of androgens in COVID-19 severity. J Cosmet Dermatol. 2020; 19(7):1545–1547.

50.

Bang

, Yang

, Lho

, et al. Comparative studies on level of androgens in hair and plasma with premature male-pattern baldness. J Dermatol Sci. 2004; 34(1):11–16.

51.

Suba

Prevention and therapy of COVID-19 via exogenous oestrogen treatment for both male and female patients: An opinion paper. J Pharm Sci. 2020; 23(1):75–85.

52.

Pozzilli

, Lenzi

. Testosterone, a key hormone in the context of COVID-19 endemic. Metabolism. 2020; 108:154252.

53.

Storer

TW.

Bhasin S, Travison TG. Testosterone attenuates age-related fall in aerobic function in mobility limited older men with low testosterone. J Clin Endocrinol Metab. 2016; 101(6):2562–2569.

54.

Ruggieri

, Gagliardi

, Anticoli

. Sex-dependent outcome of hepatitis B and C viruses infections: Synergy of sex hormones and immune responses?. Front Immunol. 2018; 9:2302.

55.

Schroeder

, Tuku

, Jarczak

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. [Epub ahead of print]; DOI: 10.1101/2020.05.07.20073817

56.

Montopoli

, Zumerle

, Vettor

, et al. Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532). Ann Oncol. 31(8):1040-1045.

57.

Ling

, Wen

Xie

, Danyang

, et al. Effect of SARS-CoV-2 infection upon male gonadal function: A single center-based study. MedRxiv. [Epub ahead of print]; DOI: 10.1101/2020.03.21.20037267

58.

Shastri

, Wheat

, Agrawal

, et al. Delayed clearance of SARS-CoV2 in male compared to female patients: High ACE2 expression in testes suggests possible existence of gender-specific viral reservoirs. MedRxiv. [Epub ahead of print]; DOI: 10.1101/2020.04.16.20060566

59.

ClinicalTrials.gov. Estrogen patch for COVID-19 symptoms. https://clinicaltrials.gov/ct2/show/NCT04359329 (last accessed July 9, 2020).

60.

Correspondence. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020; 395(10234):1417–1418.

61.

Montopoli

, Zumerle

, Vettor

Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: A population-based study of 4532 men. Andrology. [Epub ahead of print]; DOI: 10.1111/andr.12821.

62.

Patel

, Zhong

, Liaw

, et al. Does androgen deprivation therapy protect against severe complications from COVID-19?. Ann Oncol. 2020; S0923-7534(20)39933-6.

63.

Keeting

, O’ Malley

, Freedman

, et al. Diabetes and cardiovascular disease during androgen deprivation therapy: Observational study of veterans with prostate cancer. JCNI. 2010; 102(1):39–46.

64.

Patasius

, Kincius

, Kazlauskas

, et al. The role of androgen-deprivation therapy on suicide among patients with advanced prostate cancer: A nationwide population-based cohort study. Psychooncology. 2019; 28(10):2098–2100.

65.

Wei

Lei EC-C, Kao-Yang YH. Incidence of type 2 diabetes mellitus in men receiving steroid 5α-reductase inhibitors: Population-based cohort study. BMJ. 2019; 365:l1204.

66.

Adamowicz

, Juszczak

, Drewa

. May patients receiving 5-alpha-reductase inhibitors be in higher risk of COVID-19 complications?. Med Hypotheses. 2020; 140:109751.

67.

Diabetes

. Facts and figures. https://www.diabetes.org.uk/professionals/position-statements-reports/statistics (last accessed September 15, 2020).

68.

Nordström

, Hadrévi

, Ol sson

, Franks

, Nordström

. Higher prevalence of type 2 diabetes in men than in women is associated with differences in visceral fat mass. J Clin Endocrinol Metab. 2016; 101(10):3740–3746.

69.

NICE. Type 2 diabetes in adults: management. https://www.nice.org.uk/guidance/ng28 (last accessed September 15, 2020).

70.

Santi

, Giannetta

, Isidori

, et al. Effects of chronic use of phosphodiesterase inhibitors on endothelial markers in type 2 diabetes mellitus: A meta-analysis. Eur J Endocrinol. 2015; 172(3):R103–R114.

71.

Huang

, Sundquist

, Ji

. Use of phosphodiesterase 5 inhibitors is associated with lower risk of colorectal cancer in men with benign colorectal neoplasms. Gastroenterology. 2019; 157(3):672–681.e4.

72.

Sutton

, Magagnoli

, Cummings

, Hardin

. The association between phosphodiesterase-5 inhibitors and colorectal cancer in a national cohort of patients. Clin Transl Gastroenterol. 2020; 11(6):e00173.

73.

Busse

, Chow

, McCurdy

, Khanna

. COVID-19 and the RAAS-a potential role for angiotensin II?. Crit Care. 2020; 24(1):136.

74.

Isidori

, Giannetta

, Pofi

, et al. Targeting the NO-cGMP-PDE5 pathway in COVID-19 infection. Andrology (In Press). DOI: 10.1111/andr.12837

75.

Corbin

, Beasley

, Blount

, Francis

. High lung PDE5: A strong basis for treating pulmonary hypertension with PDE5 inhibitors. Biochem Biophys Res Commun. 2005; 334(3):930–938.

76.

Beltrán-Gámez

, Sandoval-Zárate

, Pulido

. Phosphodiesterase-5 inhibitors for the treatment of pulmonary arterial hypertension. Arch Cardiol Mex. 2015; 85(3):215–224.

77.

Karasu-Minareci

, Ozbudak

, Ozbilim

, Sadan

. Acute effects of vardenafil on pulmonary artery responsiveness in pulmonary hypertension. Sci World J. 2012; 2012:718279.

78.

Kiss

, Kovacs

, Komocsi

, et al. Novel mechanisms of sildenafil in pulmonary hypertension involving cytokines/chemokines, MAP kinases and Akt. PLoS One. 2014; 9(8):e104890.

79.

Barnes

, Brown

, Burns

, Williams

. Phosphodiesterase 5 inhibitors for pulmonary hypertension. Cochrane Database Syst Rev. 2019; 1(1):CD026721.

80.

Kosutova

, Mikolka

, Balentova

, et al. Effects of phosphodiesterase 5 inhibitor sildenafil on the respiratory parameters, inflammation, and apoptosis in a saline lavage-induced model of acute lung injury. J Physiol Pharmacol. 2018;69(5).

81.

Blanco

, Gimeno

, Munoz

, et al. Hemodynamic and gas exchange effects of sildenafil in patients with chronic obstructive pulmonary disease and pulmonary hypertension. Am J Respir Crit Care Med. 2010; 181(3):270–278.

82.

Vitulo

, Stanziola

, Confalonieri

, et al. Sildenafil in severe pulmonary hypertension associated with chronic obstructive pulmonary disease: A randomized controlled multicenter clinical trial. J Heart Lung Transplant. 2017; 36(2):166–174.

83.

Faoro

, Lamotte

, Deboeck

, et al. Effects of sildenafil on exercise capacity in hypoxic normal subjects. High Alt Med Biol. 2007; 8(2):155–163.

84.

de Visser

, Walther

, Laghmani

, et al. Sildenafil attenuates pulmonary inflammation and fibrin deposition, mortality, and right ventricular hypertrophy in neonatal hyperoxic lung injury. Respir Res. 2009; 10(1):30.

85.

Rapôso

, Luna

, Nunes

, Thomé

, Peixoto

. Role of iNOS-NO-cGMP signaling in modulation of inflammatory and myelination processes. Brain Res Bull. 2014; 104:60–73.

86.

Cadirci

, Halici

, Odabasoglu

, et al. Sildenafil treatment attenuates lung and kidney injury due to overproduction of oxidant activity in a rat model of sepsis: A biochemical and histopathological study. Clin Exp Immunol. 2011; 166(3):374–384.

87.

Vlachopoulos

, Ioakeimidis

, Rokkas

, et al. Acute effect of sildenafil on inflammatory markers/mediators in patients with vasculogenic erectile dysfunction. Int J Cardiol. 2015; 182:98–101.

88.

Yang

, Jin

, Jang

, et al. Sildenafil reduces neointimal hyperplasia after angioplasty and inhibits platelet aggregation via activation of cGMP-dependent protein kinase. Sci Rep. 2019; 9(1):7769.

89.

Gudmundsdóttir

, McRobbie

, Robinson

, et al. Sildenafil potentiates nitric oxide mediated inhibition of human platelet aggregation. Biochem Biophys Res Commun. 2005; 337(1):382–385.

90.

Hackett

Should all men with type 2 diabetes be routinely prescribed a phosphodiesterase type 5 inhibitor?. World J Mens Health. 2020; 38(3):271–284. https://doi.org/10.5534/wjmh.200027

91.

Mirabelli

, Chiefari

, Puccio

, Foti

, Brunetti

. Potential benefits and harms of novel antidiabetic drugs during COVID-19 crisis. Int J Environ Res Public Health. 2020; 17(10):3664.

92.

Giagulli

, Guastamacchia

, Magrone

. Worse progression of COVID-19 in men: Is testosterone a key factor?

Andrology

. 2020. https://doi.org/10.1111/andr.12836

93.

Al-Lami

, Urban

, Volpi

, Algburi

, Baillargeon

Sex Hormones and Novel Corona Virus Infectious Disease (COVID-19). May Clinic Proc. DOI: https://doi.org/10.1016/j.mayocp.2020.05.013

COVID-19,Type 2 Diabetes,and Hypogonadism: Lessons for Acute Management and Long-Term Prevention

Abstract

Introduction

What Is Currently Known About Testosterone and Cardiovascular and All-Cause Mortality?

Venous thrombotic embolism and testosterone

The Role of Sex Hormones in the COVID-19 Pandemic

Lessons from Recent COVID-19 Studies?

Is High Testosterone a Promoter of COVID-19 Infection?

Long-Term Prevention Strategy for Men at High Risk in the United Kingdom

Role of Daily Phosphodiesterase Type 5 Inhibitors in Prevention?

Optimizing Diabetes Care

U.K. Statistics for Type 2 Diabetes

Conclusions

Footnotes

Author Disclosure Statement

Funding Information

Abbreviations Used

References