Morbidity and mortality in men: Role of androgens.

In this narrative review we provide an overview of the current literature on male hypogonadism and related comorbidities, also depicting the role of testosterone therapy (TTh) in the various settings. Male hypogonadism has been associated with major comorbidities such as type 2 diabetes mellitus, obesity and cardiovascular diseases, promoting a vicious cycle that may lead to further hypogonadism. The biological underpinnings of this association are currently under investigations, but clearly emerges the relevance of the hypothalamic-pituitary-gonadal axis. Hypogonadism has also been associated with increased risk of mortality. As such, TTh has the potential to oppose these patterns and improve cardiovascular and metabolic health in hypogonadal men. Clinical and observational data suggest that in males with hypogonadism, TTh, together with lifestyle changes and diabetes medications, may improve glycemia, reduce risk of progression to diabetes and provides positive effects on cardiovascular risk. Conversely, available data does not fully support any increased risk of prostate cancer in men under TTh. Of clinical relevance, a possible harmful role of hypogonadal status in men with COVID-19 eventually emerged.

Association of Male Hypogonadism With Risk of Hospitalization for COVID-19.

Importance: Male sex is associated with severe COVID-19. It is not known whether the risk of hospitalization differs between men with hypogonadism, men with eugonadism, and those receiving testosterone therapy (TTh). Objective: To compare COVID-19 hospitalization rates for men with hypogonadism who were not receiving TTh, men with eugonadism, and men receiving TTh. Design, Setting, and Participants: This cohort study was conducted in 2 large academic health systems in St Louis, Missouri, among 723 men with a history of COVID-19 who had testosterone concentrations measured between January 1, 2017, and December 31, 2021. Exposures: The primary exposure was gonadal status (hypogonadism, eugonadism, and TTh). Hypogonadism was defined as a total testosterone concentration below the limit of normal provided by the laboratory (which varied from 175 to 300 ng/dL [to convert to nanomoles per liter, multiply by 0.0347]). Main Outcomes and Measures: The primary outcome was rate of hospitalization for COVID-19. Statistical adjustments were made for group differences in age, body mass index, race and ethnicity, immunosuppression, and comorbid conditions. Results: Of the 723 study participants (mean [SD] age, 55 [14] years; mean [SD] body mass index, 33.5 [7.3]), 116 men had hypogonadism, 427 had eugonadism, and 180 were receiving TTh. Men with hypogonadism were more likely than men with eugonadism to be hospitalized with COVID-19 (52 of 116 [45%] vs 53 of 427 [12%]; P < .001). After multivariable adjustment, men with hypogonadism had higher odds than men with eugonadism of being hospitalized (odds ratio, 2.4; 95% CI, 1.4-4.4; P < .003). Men receiving TTh had a similar risk of hospitalization as men with eugonadism (odds ratio, 1.3; 95% CI, 0.7-2.3; P = .35). Men receiving inadequate TTh (defined as subnormal testosterone concentrations while receiving TTh) had higher odds of hospitalization compared with men who had normal testosterone concentrations while receiving TTh (multivariable adjusted odds ratio, 3.5; 95% CI, 1.5-8.6; P = .003). Conclusions and Relevance: This study suggests that men with hypogonadism were more likely to be hospitalized after COVID-19 infection compared with those with eugonadism, independent of other known risk factors. This increased risk was not observed among men receiving adequate TTh. Screening and appropriate therapy for hypogonadism need to be evaluated as a strategy to prevent severe COVID-19 outcomes among men.

Association of testosterone therapy with disease progression in older males with COVID-19.

IMPORTANCE: Low testosterone levels in males have been linked with increase in proinflammatory cytokines-a primary culprit in COVID-19 disease progression-and with adverse COVID-19 outcomes. To date, however, no published studies have assessed the effect of testosterone therapy on COVID-19 outcomes in older men. OBJECTIVE: To examine whether testosterone therapy reduced disease progression in older men diagnosed with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: Nested within a national cohort of older (aged ≥50 years) male patients diagnosed with COVID-19 between January 1, 2020 and July 1, 2021 from the Optum electronic health record COVID-19 database, two matched case-control studies of COVID-19 outcomes were conducted. Cases-defined, respectively, as persons who (a) were hospitalized ≤30 days after COVID-19 diagnosis (n = 33,380), and (b) were admitted to the intensive care unit or received mechanical ventilation during their COVID-19 hospitalization (n = 10,273)-were matched 1:1 with controls based on demographic and clinical factors. EXPOSURES: Testosterone therapy was defined based on receipt of prescription at ≤60, ≤90, or ≤120 days before COVID-19 diagnosis. MAIN OUTCOMES AND MEASURES: Adjusted odds ratios (ORs) for the risk of hospitalization within 30 days of COVID-19 diagnosis and intensive care unit admission/mechanical ventilation during COVID-19 hospitalization. RESULTS: The use of testosterone therapy was not associated with decreased odds of hospitalization (≤60 days: OR = 0.92, 95% confidence interval [CI] = 0.70-1.20; ≤90 days: OR = 0.87, 95% CI = 0.68-1.13; ≤120 days: OR = 0.97, 95% CI = 0.72-1.32) or intensive care unit admission/mechanical ventilation (≤60 days: OR = 0.67, 95% CI = 0.37-1.23; ≤90 days: OR = 0.63, 95% CI = 0.36-0.11; ≤120 days: OR = 0.58, 95% CI = 0.29-1.19). CONCLUSIONS AND RELEVANCE: This study showed that testosterone therapy was not associated with decreased risks of COVID-19 adverse outcomes. These findings may provide clinically relevant information regarding testosterone treatment in older men with COVID-19 and other respiratory viral infections with similar pathogenesis.

Late-Onset Hypogonadism in a Male Patient with Long COVID Diagnosed by Exclusion of ME/CFS.

After the acute phase of COVID-19, some patients have been reported to have persistent symptoms including general fatigue. We have established a COVID-19 aftercare clinic (CAC) to provide care for an increasing number of these patients. Here, we report the case of a 36-year-old man who developed post-COVID fatigue after acute infection with SARS-CoV-2. In the acute phase of COVID-19, the patient's fever resolved within four days; however, general fatigue persisted for three months, and he visited our CAC 99 days after the initial infection. Examination revealed a high Aging Male's Symptoms (AMS) score of 44 and low free testosterone (FT) level of 5.5 pg/mL, which meet the Japanese criteria of late-onset hypogonadism (LOH) syndrome. Imaging studies revealed an atrophic pituitary in addition to fatty liver and low bone mineral density. Anterior pituitary function tests showed a low follicle-stimulating hormonelevel and delayed reaction of luteinizing hormone (LH) after gonadotropin-releasing hormone (GnRH) stimulation, indicating the possibility of hypothalamic hypogonadism in addition to primary hypogonadism seen in patients with post-COVID-19 conditions. After the initiation of Japanese traditional medicine (Kampo medicine: hochuekkito followed by juzentaihoto), the patient's symptoms as well as his AMS score and serum FT level were noticeably improved. Furthermore, follow-up tests of GnRH stimulation revealed improvements in LH responsiveness. Although many patients have been reported to meet the criteria of ME/CFS such as our case, we emphasize the possibility of other underlying pathologies including LOH syndrome. In conclusion, LOH syndrome should be considered a cause of general fatigue in patients with post-COVID-19 conditions and herbal treatment might be effective for long COVID symptoms due to LOH (264 words).

TransCOVID: Does Gender-Affirming Hormone Therapy Play a Role in Contracting COVID-19?

Based on the possible effects of androgens on the course of COVID-19, it can be posited that Gender-Affirming Hormone Therapy (GAHT) may affect the course of the disease in people with GD. We aimed to investigate the relationship between GAHT and contracting COVID-19, as well as the severity of the disease in individuals with Gender Dysphoria (GD). The single center, cross-sectional, web-based survey was completed by people with GD who received GAHT. The questionnaire contained three parts: a sociodemographic data form; a GAHT data form; a COVID-19-related data form. Of the 238 participants, 179 were individuals with female-to-male (FtM) and 59 male-to-female (MtF) GD. We detected that the risk of contracting COVID-19 increased 3.46 times in people with FtM GD, who had received testosterone therapy, in comparison to people with MtF GD, who received estrogen and anti-androgen therapy. Additionally, people with FtM GD who contracted COVID-19 had received longer testosterone therapy when compared to those who did not contract COVID-19. Our findings indicate that individuals with FtM GD who receive testosterone treatment within the scope of GAHT are at higher risk of contracting COVID-19 and that the clinicians who follow-up on GAHT should be more careful about this issue.

The Double Edge Sword of Testosterone's Role in the COVID-19 Pandemic.

COVID-19 is a complex disease with a multifaceted set of disturbances involving several mechanisms of health and disease in the human body. Sex hormones, estrogen, and testosterone, seem to play a major role in its pathogenesis, development, spread, severity, and mortalities. Examination of factors such as age, gender, ethnic background, genetic prevalence, and existing co-morbidities, may disclose the mechanisms underlying SARS-CoV-2 infection, morbidity, and mortality, paving the way for COVID-19 amelioration and substantial flattening of the infection curve. In this mini-review, we focus on the role of testosterone through a discussion of the intricate mechanisms of disease development and deterioration. Accumulated evidence suggests that there are links between high level (normal male level) as well as low level (age-related hypogonadism) testosterone in disease progression and expansion, supporting its role as a double-edged sword. Unresolved questions point to the essential need for further targeted studies to substantiate these contrasting mechanisms.

COVID-19 Infection in Men on Testosterone Replacement Therapy.

BACKGROUND: Men who contract coronavirus disease 2019 (COVID-19) appear to have worse clinical outcomes compared with women which raises the possibility of androgen-dependent effects. AIM: We sought to determine if testosterone replacement therapy (TRT) is associated with worse clinical outcomes. METHODS: Through a retrospective chart review, we identified 32 men diagnosed with COVID-19 and on TRT. They were propensity score matched to 63 men diagnosed with COVID-19 and not on TRT. Data regarding comorbidities and endpoints such as hospital admission, intensive care unit admission, ventilator utilization, thromboembolic events, and death were extracted. Chi-square and Kruskal-Wallis tests examined differences in categorical and continuous variables, respectively. Logistic regression analysis tested the relationship between TRT status and the study endpoints. RESULTS: There were no statistically significant differences between the 2 groups, and TRT was not a predictor of any of the endpoints on multivariate analysis. CONCLUSION: These results suggest that TRT is not associated with a worse clinical outcome in men diagnosed with COVID-19. Rambhatla A, Bronkema CJ, Corsi N, et al. COVID-19 Infection in Men on Testosterone Replacement Therapy. J Sex Med 2021;18:215-218.

Sex Hormones and Novel Corona Virus Infectious Disease (COVID-19).

Given the rapid spread of the coronavirus disease 2019 (COVID-19) pandemic and its overwhelming effect on health care systems and the global economy, innovative therapeutic strategies are urgently needed. The proposed primary culprit of COVID-19 is the intense inflammatory response-an augmented immune response and cytokine storm-severely damaging the lung tissue and rendering some patients' conditions severe enough to require assisted ventilation. Sex differences in the response to inflammation have been documented and can be attributed, at least in part, to sex steroid hormones. Moreover, age-associated decreases in sex steroid hormones, namely, estrogen and testosterone, may mediate proinflammatory increases in older adults that could increase their risk of COVID-19 adverse outcomes. Sex hormones can mitigate the inflammation response and might provide promising therapeutic potential for patients with COVID-19. In this article, we explore the possible anti-inflammatory effects of estrogen and testosterone and the anabolic effect of testosterone, with particular attention to the potential therapeutic role of hormone replacement therapy in older men and women with COVID-19.