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Exp Clin Endocrinol Diabetes 2024; 132(01): 23-32
DOI: 10.1055/a-2201-8816
Article

Male Hypogonadism After Recovery from Acute COVID-19 Infection: A Prospective Observational Study

Aravind Prasad
1   Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India.
,
K. G Rashmi
1   Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India.
,
Jayaprakash Sahoo
1   Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India.
,
Sadishkumar Kamalanathan
1   Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India.
,
Mukta Wyawahare
2   Department of Internal Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India.
,
R Anusuya
3   Department of Biostatistics, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India.
,
Dukhabandhu Naik
1   Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India.
› Author Affiliations Funding This study was entirely supported by intramural funding from the Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry.
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Abstract

Background The severe acute respiratory syndrome coronavirus 2 can affect the hypothalamic-pituitary-gonadal axis (HPG) due to the expression of the angiotensin-converting enzyme 2 receptor.

Objectives To assess the prevalence of hypogonadism and Sertoli cell dysfunction in coronavirus disease 2019 (COVID-19) male survivors.

Method Male subjects recovered from acute COVID-19 infection were prospectively observed. The primary outcomes included the proportion of hypogonadism, defined biochemically as serum testosterone<230 ng/dL or CFT of<6.4 ng/mL if the total testosterone is between 230–320 ng/m. Sertoli cell dysfunction was defined as inhibin-B level<54.5 pg/mL. Subjects with hypogonadism were followed up at 12 months to assess the recovery of the HPG axis.

Results Eighty-three subjects aged≥18 years were evaluated at a median of 120 (±35) days post-recovery. Their mean age was 49.50±12.73 years, and the mean BMI was 26.84±5.62 kg/m2. Low testosterone was detected in 21 (24.71%) and low inhibin-B was detected in 14 (19.71%) out of 71 subjects at 3 months. Subjects with low testosterone were younger, with a mean age of 43.29±12.03 years (P-0.08) and higher BMI (P-0.012). The severity of COVID-19 infection, duration of hospitalization, and other factors were not significantly associated with low testosterone. At 12 months, 18 out of 21 subjects came for follow-up, of which 9 (50%) showed persistently low testosterone, suggestive of hypogonadism.

Conclusion Following COVID-19 infection, testosterone levels recovered over time; however, a significant proportion of subjects had low levels at 12-month follow-up. These findings have long-term implications for the management of COVID-19 subjects.

Key words

testosterone - inhibin-B - HPG axis - sertoli cell


Publication History

Received: 03 July 2023
Received: 29 August 2023

Accepted: 20 October 2023

Article published online:
04 December 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 WHO Coronavirus (COVID-19) Dashboard. 2023; https://covid19.who.int
    PubMed
  • 2 Walls AC, Park YJ, Tortorici MA. et al. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020; 181: 281-292.e6
    CrossrefPubMedSearch in Google Scholar
  • 3 Heurich A, Hofmann-Winkler H, Gierer S. et al. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol 2014; 88: 1293-1307
    CrossrefPubMedSearch in Google Scholar
  • 4 Lamers MM, Haagmans BL. SARS-CoV-2 pathogenesis. Nat Rev Microbiol 2022; 20: 270-284
    CrossrefPubMedSearch in Google Scholar
  • 5 Espinosa OA, Zanetti ADS, Antunes EF. et al. Prevalence of comorbidities in patients and mortality cases affected by SARS-CoV2: A systematic review and meta-analysis. Rev Inst Med Trop Sao Paulo 2020; 62: e43
    CrossrefPubMedSearch in Google Scholar
  • 6 Islam N, Shkolnikov VM, Acosta RJ. et al. Excess deaths associated with covid-19 pandemic in 2020: Age and sex disaggregated time series analysis in 29 high income countries. BMJ 2021; 373: n1137
    CrossrefPubMedSearch in Google Scholar
  • 7 Wang Z, Xu X. scRNA-seq profiling of human testes reveals the presence of the ACE2 receptor, a target for SARS-CoV-2 infection in spermatogonia, Leydig and Sertoli cells. Cells 2020; 9: 920
    CrossrefPubMedSearch in Google Scholar
  • 8 Giagulli VA, Guastamacchia E, Magrone T. et al. Worse progression of COVID-19 in men: Is testosterone a key factor?. Andrology 2021; 9: 53-64
    CrossrefPubMedSearch in Google Scholar
  • 9 Scully EP, Haverfield J, Ursin RL. et al. Considering how biological sex impacts immune responses and COVID-19 outcomes. Nat Rev Immunol 2020; 20: 442-447
    CrossrefPubMedSearch in Google Scholar
  • 10 Li F, Boon ACM, Michelson AP. et al. Estrogen hormone is an essential sex factor inhibiting inflammation and immune response in COVID-19. Sci Rep 2022; 12: 9462
    CrossrefPubMedSearch in Google Scholar
  • 11 Enikeev D, Taratkin M, Morozov A. et al. Prospective two-arm study of the testicular function in patients with COVID-19. Andrology 2022; 10: 1047-1056
    CrossrefPubMedSearch in Google Scholar
  • 12 Apaydin T, Sahin B, Dashdamirova S. et al. The association of free testosterone levels with coronavirus disease 2019. Andrology 2022; 10: 1038-1046
    CrossrefPubMedSearch in Google Scholar
  • 13 Koç E, Keseroğlu BB. Does COVID-19 worsen the semen parameters? Early results of a tertiary healthcare center. Urol Int 2021; 105: 743-748
    CrossrefPubMedSearch in Google Scholar
  • 14 Dhindsa S, Zhang N, McPhaul MJ. et al. Association of circulating sex hormones with inflammation and disease severity in patients with COVID-19. JAMA Netw Open 2021; 4: e2111398
    CrossrefPubMedSearch in Google Scholar
  • 15 Ma L, Xie W, Li D. et al. Evaluation of sex-related hormones and semen characteristics in reproductive-aged male COVID-19 patients. J Med Virol 2021; 93: 456-462
    CrossrefPubMedSearch in Google Scholar
  • 16 Rastrelli G, Di Stasi V, Inglese F. et al. Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients. Andrology 2021; 9: 88-98
    CrossrefPubMedSearch in Google Scholar
  • 17 Çayan S, Uğuz M, Saylam B. et al. Effect of serum total testosterone and its relationship with other laboratory parameters on the prognosis of coronavirus disease 2019 (COVID-19) in SARS-CoV-2 infected male patients: A cohort study. Aging Male 2020; 23: 1493-1503
    CrossrefPubMedSearch in Google Scholar
  • 18 Afshari P, Zakerkish M, Abedi P. et al. Effect of COVID-19 infection on sex hormone levels in hospitalized patients: A prospective longitudinal study in Iran. Health Sci Rep 2022; 24: e1011
    CrossrefPubMedSearch in Google Scholar
  • 19 Clausen CL, Holm JT, Erik SN. et al. Pituitary-gonadal hormones associated with respiratory failure in men and women hospitalized with COVID-19: An observational cohort study. Endocr Connect 2022; 12: e220444
    CrossrefPubMedSearch in Google Scholar
  • 20 Salonia A, Pontillo M, Capogrosso P. et al. Severely low testosterone in males with COVID-19: A case-control study. Andrology 2021; 9: 1043-1052
    CrossrefPubMedSearch in Google Scholar
  • 21 Chen L, Huang X, Yi Z. et al. Ultrasound imaging findings of acute testicular infection in patients with coronavirus disease 2019: A single-center-based study in Wuhan, China. J Ultrasound Med 2021; 40: 1787-1794
    CrossrefPubMedSearch in Google Scholar
  • 22 Carneiro F, Teixeira TA, Bernardes FS. et al. Radiological patterns of incidental epididymitis in mild-to-moderate COVID-19 patients revealed by colour Doppler ultrasound. Andrologia 2021; 53: e13973
    CrossrefPubMedSearch in Google Scholar
  • 23 Dai P, Qiao F, Chen Y. et al. SARS-CoV-2 and male infertility: From short- to long-term impacts. J Endocrinol Invest 2023; 46: 1491-1507
    CrossrefPubMedSearch in Google Scholar
  • 24 Mukherjee AG, Wanjari UR, Gopalakrishnan AV. et al. Insights into the scenario of SARS-CoV-2 infection in male reproductive toxicity. Vaccines (Basel) 2023; 11: 510
    CrossrefPubMedSearch in Google Scholar
  • 25 Guo J, Sheng K, Wu S. et al. An Update on the relationship of SARS-CoV-2 and male reproduction. Front Endocrinol (Lausanne) 2021; 12: 788321
    CrossrefPubMedSearch in Google Scholar
  • 26 Duarte-Neto AN, Teixeira TA, Caldini EG. et al. Testicular pathology in fatal COVID-19: A descriptive autopsy study. Andrology 2022; 10: 13-23
    CrossrefPubMedSearch in Google Scholar
  • 27 Yang M, Chen S, Huang B. et al. Pathological findings in the testes of COVID-19 patients: Clinical implications. Eur Urol Focus 2020; 6: 1124-1129
    CrossrefPubMedSearch in Google Scholar
  • 28 Tariq J, Chatterjee T, Andreoli L. et al. COVID-19 and fertility-at the crossroads of autoimmunity and thrombosis. Rheumatol Int 2021; 41: 1885-1894
    CrossrefPubMedSearch in Google Scholar
  • 29 Stein SR, Ramelli SC, Grazioli A. et al. SARS-CoV-2 infection and persistence in the human body and brain at autopsy. Nature 2022; 612: 758-763
    CrossrefPubMedSearch in Google Scholar
  • 30 Kazakou P, Paschou SA, Psaltopoulou T. et al. Early and late endocrine complications of COVID-19. Endocr Connect 2021; 10: R229-R239
    CrossrefPubMedSearch in Google Scholar
  • 31 Bornstein SR, Cozma D, Kamel M. et al. Long-COVID, metabolic and endocrine disease. Horm Metab Res 2022; 54: 562-566
    Thieme ConnectPubMedSearch in Google Scholar
  • 32 Rashmi KG, Perumal N, Cherian A. et al. Hypothalamic-pituitary adrenal axis status 3 months after recovery from COVID-19 infection. Endocr Res 2023; 1-9
    CrossrefPubMedSearch in Google Scholar
  • 33 Salonia A, Pontillo M, Capogrosso P. et al. Testosterone in males with COVID-19: A 7-month cohort study. Andrology 2022; 10: 34-41
    CrossrefPubMedSearch in Google Scholar
  • 34 Salonia A, Pontillo M, Capogrosso P. et al. Testosterone in males with COVID-19: a 12-month cohort study. Andrology 2023; 11: 17-23
    CrossrefPubMedSearch in Google Scholar
  • 35 Karkin K, Gürlen G. Does COVID-19 cause testicular damage? A cross-sectional study comparing hormonal parameters. Eur Rev Med Pharmacol Sci 2022; 26: 3745-3750
    CrossrefPubMedSearch in Google Scholar
  • 36 Paoli D, Pallotti F, Anzuini A. et al. Male reproductive health after 3 months from SARS-CoV-2 infection: A multicentric study. J Endocrinol Invest 2023; 46: 89-101
    CrossrefPubMedSearch in Google Scholar
  • 37 Ministry of Home and Family Welfare. Home. 2023; https://www.mohfw.gov.in
    PubMed
  • 38 Charlson ME, Pompei P, Ales KL. et al. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis 1987; 40: 373-383
    CrossrefPubMedSearch in Google Scholar
  • 39 Morley JE, Charlton E, Patrick P. et al. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism 2000; 49: 1239-1242
    CrossrefPubMedSearch in Google Scholar
  • 40 Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999; 84: 3666-3672
    CrossrefPubMedSearch in Google Scholar
  • 41 Corona G, Goulis DG, Huhtaniemi I. et al. European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males: Endorsing organization: European Society of Endocrinology. Andrology 2020; 8: 970-987
    CrossrefPubMedSearch in Google Scholar
  • 42 Jayasena CN, Anderson RA, Llahana S. et al. Society for Endocrinology guidelines for testosterone replacement therapy in male hypogonadism. Clin Endocrinol (Oxf) 2022; 96: 200-219
    CrossrefPubMedSearch in Google Scholar
  • 43 Wu FC, Tajar A, Beynon JM. et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 2010; 363: 123-135
    CrossrefPubMedSearch in Google Scholar
  • 44 Tajar A, Forti G, O'Neill TW. et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: Evidence from the European Male Ageing Study. J Clin Endocrinol Metab 2010; 95: 1810-1818
    CrossrefPubMedSearch in Google Scholar
  • 45 Grunewald S, Glander HJ, Paasch U. et al. Age-dependent inhibin B concentration in relation to FSH and semen sample qualities: A study in 2448 men. Reproduction 2013; 145: 237-244
    CrossrefPubMedSearch in Google Scholar
  • 46 Patel D, Naik D, Kamalanathan S. et al. Thyroid function abnormalities and outcomes in hospitalized patients with COVID-19 infection: A cross-sectional study. Horm Metab Res 2023; 55: 169-175
    Thieme ConnectPubMedSearch in Google Scholar
  • 47 Nachtigall I, Lenga P, Jóźwiak K. et al. Clinical course and factors associated with outcomes among 1904 patients hospitalized with COVID-19 in Germany: An observational study. Clin Microbiol Infect 2020; 26: 1663-1669
    CrossrefPubMedSearch in Google Scholar
  • 48 Bennett TD, Moffitt RA, Hajagos JG. et al. Clinical characterization and prediction of clinical severity of SARS-CoV-2 infection among US adults using data from the US National COVID Cohort Collaborative. JAMA Netw Open 2021; 4: e2116901
    CrossrefPubMedSearch in Google Scholar
  • 49 Kojima N, Adams K, Self WH. et al. Changing severity and epidemiology of adults hospitalized with coronavirus disease 2019 (COVID-19) in the United States after introduction of COVID-19 vaccines, March 2021-August 2022. Clin Infect Dis 2023; 77: 547-557
    CrossrefPubMedSearch in Google Scholar
  • 50 Victor PJ, Mathews KP, Paul H. et al. Protective effect of COVID-19 vaccine among health care workers during the second wave of the pandemic in India. Mayo Clin Proc 2021; 96: 2493-2494
    CrossrefPubMedSearch in Google Scholar
  • 51 Moreno-Perez O, Merino E, Alfayate R. et al. Male pituitary-gonadal axis dysfunction in post-acute COVID-19 syndrome-prevalence and associated factors: A Mediterranean case series. Clin Endocrinol (Oxf) 2022; 96: 353-362
    CrossrefPubMedSearch in Google Scholar
  • 52 Urhan E, Karaca Z, Unuvar GK. et al. Investigation of pituitary functions after acute coronavirus disease 2019. Endocr J 2022; 69: 649-658
    CrossrefPubMedSearch in Google Scholar
  • 53 Yamamoto Y, Otsuka Y, Sunada N. et al. Detection of male hypogonadism in patients with post COVID-19 condition. J Clin Med 2022; 11: 1955
    CrossrefPubMedSearch in Google Scholar
  • 54 Karkin K, Gürlen G. Does COVID-19 cause testicular damage? A cross-sectional study comparing hormonal parameters. Eur Rev Med Pharmacol Sci 2022; 26: 3745-3750
    CrossrefPubMedSearch in Google Scholar
  • 55 Paoli D, Pallotti F, Anzuini A. et al. Male reproductive health after 3 months from SARS-CoV-2 infection: A multicentric study. J Endocrinol Invest 2023; 46: 89-101
    CrossrefPubMedSearch in Google Scholar
  • 56 Gul A, Zengin S, Dundar G. et al. Do SARS-CoV-2 Infection (COVID-19) and the medications administered for its treatment impair testicular functions?. Urol Int 2021; 105: 944-948
    CrossrefPubMedSearch in Google Scholar
  • 57 Guo TH, Sang MY, Bai S. et al. Semen parameters in men recovered from COVID-19. Asian J Androl 2021; 23: 479-483
    CrossrefPubMedSearch in Google Scholar
  • 58 Xu H, Wang Z, Feng C. et al. Effects of SARS-CoV-2 infection on male sex-related hormones in recovering patients. Andrology 2021; 9: 107-114
    CrossrefPubMedSearch in Google Scholar
  • 59 Costa GMJ, Lacerda SMSN, Figueiredo AFA. et al. High SARS-CoV-2 tropism and activation of immune cells in the testes of non-vaccinated deceased COVID-19 patients. BMC Biol 2023; 21: 36
    CrossrefPubMedSearch in Google Scholar
  • 60 Fernandez CJ, Chacko EC, Pappachan JM. Male obesity-related secondary hypogonadism – pathophysiology, clinical implications and management. Eur Endocrinol 2019; 15: 83-90
    CrossrefPubMedSearch in Google Scholar
  • 61 Carto CA, Gurayah AA, Arbelaez MCS. et al. Association between comorbidities and longitudinal changes in total testosterone among men from the Baltimore Longitudinal Study of Aging. J Sex Med 2023; 20: 605-611
    CrossrefPubMedSearch in Google Scholar
  • 62 Cinislioglu AE, Cinislioglu N, Demirdogen SO. et al. The relationship of serum testosterone levels with the clinical course and prognosis of COVID-19 disease in male patients: A prospective study. Andrology 2022; 10: 24-33
    CrossrefPubMedSearch in Google Scholar
  • 63 Al-Bashiti AI, Ahmed KA, Alqaisi KM. Relationship of inflammatory mediators and sex-related parameters in Jordanian adult men patients with Covid-19. J Med Biochem 2022; 41: 474-482
    CrossrefPubMedSearch in Google Scholar
  • 64 Al-Kuraishy HM, Al-Gareeb AI, Alarfaj SJ. et al. Long COVID and risk of erectile dysfunction in recovered patients from mild to moderate COVID-19. Sci Rep 2023; 13: 5977
    CrossrefPubMedSearch in Google Scholar
  • 65 Heinemann L, Zimmermann T, Vermeulen A. et al. A new “Aging Male's Symptoms” (AMS) rating scale. Aging Male 1999; 2: 105-114
    CrossrefPubMedSearch in Google Scholar