By Martin S. Lipsky, MD

Chancellor, South Jordan Campus, Roseman University of Health Sciences, South Jordan, UT

Dr. Lipsky reports no financial relationships relevant to this field of study.

SYNOPSIS: Cancer patients are at a higher risk of contracting SARS-CoV-2 vs. non-cancer patients. However, prostate cancer patients who received androgen deprivation therapy seem to be partially protected from such infections.

SOURCE: Montopoli M, Zumerle S, Vettor R, et al. Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: A population-based study (N = 4532). Ann Oncol 2020; May 6;S0923-7534(20)39797-0. doi: 10.1016/j.annonc.2020.04.479. [Online ahead of print].

The full spectrum of COVID-19 ranges from mild to severe disease. In the United States alone, the virus has caused more than 134,000 deaths.1 Research indicates SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) receptors on the cell surface to gain entry. In addition to ACE2 receptors, TMPRSS2, a serine protease found on the cell surface, can act as a cofactor to facilitate viral entry. Epidemiologic data indicate COVID-19 affects men more severely; one explanation is TMPRSS2, an androgen-regulated gene, is more prevalent in men. TMPRSS2 also is highly expressed in both localized and metastatic prostate cancers.2 First- or second-generation androgen deprivation therapies (ADTs) lower TMPRSS2 levels.

Based on this association, Montopoli et al hypothesized ADTs may protect patients afflicted with prostate cancer from SARS-CoV-2 infections. To test this hypothesis, the authors examined data from 9,280 patients (4,532 men) with laboratory-confirmed SARS-CoV-2 infections from 68 hospitals in an Italian region where the pandemic hit particularly hard. The parameters identified for each COVID-19-positive patient were gender, hospitalization, admission to intensive care unit (ICU), death, tumor diagnosis, prostate cancer diagnosis, and ADT. The authors found men developed more severe complications, were hospitalized more frequently, and experienced worse clinical outcomes than women. Among 4,532 men, 430 had cancer (118 with prostate cancer). Comparing the total number of SARS-CoV-2-positive cases, prostate cancer patients receiving ADT were at a significantly lower risk for contracting a SARS-CoV-2 infection vs. patients who did not receive ADT (odds ratio [OR], 4.05; 95% confidence interval [CI], 1.55-10.59). A greater difference was found comparing prostate cancer patients receiving ADT to patients with any other type of cancer (OR, 5.17; 95% CI, 2.02-13.40).

COMMENTARY

Current reports continue to emerge indicating COVID-19 affects older men with chronic illnesses more severely than women.3 While not all U.S. states report COVID-19 cases by sex, those that do reflect epidemiological data from other countries that indicate men are disproportionately affected. One proposed explanation for sex-related disparities and COVID-19 outcomes is differences in sex hormones.

Sex hormones play a role in modulating the immune system and contribute to variations in the immunologic responses of men and women. They help balance the immune response between helpful responses that combat infection and those that trigger harmful inflammation. In general, the male sex hormone testosterone is immunosuppressive, while the female sex hormone estrogen tends to enhance the immune response.4

Testosterone also stimulates TMPRSS2 gene expression, which is a cofactor for SARS-CoV-2 cell entry and may increase the susceptibility of men for severe SARS-CoV-2 infections. Montopoli et al found prostate patients receiving ADT demonstrated better COVID-19 outcomes and speculated ADT might block or decrease the severity of SARS-CoV-2 infections.

In contrast, some theoretical evidence suggests low testosterone may be harmful. Inflammatory cytokines play a central role in the progression of COVID-19 infection. While a robust immune system is needed to fight an infection, unchecked, the response may be detrimental. Since hypogonadism is associated with more pro-inflammatory cytokines, low testosterone might lead to immune system dysregulation and trigger the cytokine storm that often characterizes severe COVID-19 infection.5 Exactly how and if sex hormones positively or negatively affect outcomes in the milieu of COVID-19 remains uncertain.

The finding that ADT is associated with better outcomes provides a potential clue for developing effective treatments related to sex hormones. Trials evaluating therapies related to both testosterone and estrogen are in progress. Unraveling the exact role of the sex hormones offers the promise of developing beneficial therapeutic interventions using drugs that are already part of the primary care physician’s toolbox.

REFERENCES

  1. Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19). Cases in the U.S.
  2. Lucas JM, Heinlein C, Kim T, et al. The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. Cancer Discov 2014;4:1310-1325.
  3. Global Health 500. Sex, gender and COVID-19: Overview and resources.
  4. Klein SL, Marriott I, Fish EN. Sex-based differences in immune function and responses to vaccination. Trans R Soc Trop Med Hyg 2015;109:9-15.
  5. Mohamad NV, Wong SK, Wan Hasan WN, et al. The relationship between circulating testosterone and inflammatory cytokines in men. Aging Male 2019; 22:129-140.