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Endocrine, Metabolic & Immune Disorders - Drug Targets

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ISSN (Online): 2212-3873

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Review Article

Is Testosterone the “Fountain of Youth” for Aging Men?

Author(s): Vito Angelo Giagulli*, Giuseppe Lisco, Francesco Mariano, Anna De Tullio and Vincenzo Triggiani

Volume 23, Issue 2, 2023

Published on: 05 September, 2022

Page: [169 - 178] Pages: 10

DOI: 10.2174/1871530322666220516160435

Price: $65

Abstract

Background: Late-Onset Hypogonadism (LOH) is defined as a clinical and biochemical syndrome associated with advancing age. It is characterized by specific symptoms and less specific manifestations due to deficiency of serum testosterone (T) levels.

Objective: This review aims to summarize the evidence related to LOH definition, diagnostic approach, and treatment to answer a clinical question: “Is Testosterone the fountain of youth for aging men?".

Methodology: MEDLINE/PubMed and institutional websites were searched for original papers, guidelines, and position statements published in the last ten years.

Results: Observational and randomized controlled studies on T replacement therapy in older men have been reported.

Discussion and Conclusion: Despite some heterogeneities regarding diagnostic definition, therapeutic target, and testosterone prescription, all guidelines agreed that male hypogonadism should be diagnosed and managed in aged men as in adulthood. However, trials assessing the efficacy of T therapy conducted for male rejuvenating are lacking; thus, T prescription for this purpose is not recommended.

Keywords: Testosterone deficiency, late-onset hypogonadism, testosterone replacement therapy, guidelines, older adults, antiaging.

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[1]
Kaufman, J.M.; Vermeulen, A. The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr. Rev., 2005, 26(6), 833-876.
[http://dx.doi.org/10.1210/er.2004-0013] [PMID: 15901667]
[2]
Kaufman, J.M.; Lapauw, B.; Mahmoud, A. T’Sjoen, G.; Huhtaniemi, I.T. Lapauw. B.; Mahmoud, A.; T’Sjoen, G.; Huhtaniemi, I.T. Aging and the male reproductive system. Endocr. Rev., 2019, 40(4), 906-972.
[http://dx.doi.org/10.1210/er.2018-00178] [PMID: 30888401]
[3]
Wu, F.C.W.; Tajar, A.; Beynon, J.M.; Pye, S.R.; Silman, A.J.; Finn, J.D.; O’Neill, T.W.; Bartfai, G.; Casanueva, F.F.; Forti, G.; Giwercman, A.; Han, T.S.; Kula, K.; Lean, M.E.; Pendleton, N.; Punab, M.; Boonen, S.; Vanderschueren, D.; Labrie, F.; Huhtaniemi, I.T. EMAS Group. Identification of late-onset hypogonadism in middle-aged and elderly men. N. Engl. J. Med., 2010, 363(2), 123-135.
[http://dx.doi.org/10.1056/NEJMoa0911101] [PMID: 20554979]
[4]
Araujo, A.B.; Esche, G.R.; Kupelian, V.; O’Donnell, A.B.; Travison, T.G.; Williams, R.E.; Clark, R.V.; McKinlay, J.B. Prevalence of symptomatic androgen deficiency in men. J. Clin. Endocrinol. Metab., 2007, 92(11), 4241-4247.
[http://dx.doi.org/10.1210/jc.2007-1245] [PMID: 17698901]
[5]
Snyder, P.J.; Bhasin, S.; Cunningham, G.R.; Matsumoto, A.M.; Stephens-Shields, A.J.; Cauley, J.A.; Gill, T.M.; Barrett-Connor, E.; Swerdloff, R.S.; Wang, C.; Ensrud, K.E.; Lewis, C.E.; Farrar, J.T.; Cella, D.; Rosen, R.C.; Pahor, M.; Crandall, J.P.; Molitch, M.E.; Resnick, S.M.; Budoff, M.; Mohler, E.R., III; Wenger, N.K.; Cohen, H.J.; Schrier, S.; Keaveny, T.M.; Kopperdahl, D.; Lee, D.; Cifelli, D.; Ellenberg, S.S. Lesson from the testosterone trials. Endocr. Rev., 2018, 39(3), 369-386.
[http://dx.doi.org/10.1210/er.2017-00234] [PMID: 29522088]
[6]
Vigen, R.; O’Donnell, C.I.; Barón, A.E.; Grunwald, G.K.; Maddox, T.M.; Bradley, S.M.; Barqawi, A.; Woning, G.; Wierman, M.E.; Plomondon, M.E.; Rumsfeld, J.S.; Ho, P.M. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA, 2013, 310(17), 1829-1836.
[http://dx.doi.org/10.1001/jama.2013.280386] [PMID: 24193080]
[7]
Finkle, W.D.; Greenland, S.; Ridgeway, G.K.; Adams, J.L.; Frasco, M.A.; Cook, M.B.; Fraumeni, J.F., Jr; Hoover, R.N. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One, 2014, 9(1), e85805.
[http://dx.doi.org/10.1371/journal.pone.0085805] [PMID: 24489673]
[8]
Baillargeon, J.; Urban, R.J.; Ottenbacher, K.J.; Pierson, K.S.; Goodwin, J.S. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern. Med., 2013, 173(15), 1465-1466.
[http://dx.doi.org/10.1001/jamainternmed.2013.6895] [PMID: 23939517]
[9]
Lunenfeld, B.; Mskhalaya, G.; Zitzmann, M.; Arver, S.; Kalinchenko, S.; Tishova, Y.; Morgentaler, A. Recommendations on the diagnosis, treatment and monitoring of hypogonadism in men. Aging Male, 2015, 18(1), 5-15.
[http://dx.doi.org/10.3109/13685538.2015.1004049] [PMID: 25657080]
[10]
Dean, J.D.; McMahon, C.G.; Guay, A.T.; Morgentaler, A.; Althof, S.E.; Becher, E.F.; Bivalacqua, T.J.; Burnett, A.L.; Buvat, J.; El Meliegy, A.; Hellstrom, W.J.G.; Jannini, E.A.; Maggi, M.; McCullough, A.; Torres, L.O.; Zitzmann, M. The international society for sexual medicine’s process of care for the assessment and management of testosterone deficiency in adult men. J. Sex. Med., 2015, 12(8), 1660-1686.
[http://dx.doi.org/10.1111/jsm.12952] [PMID: 26081680]
[11]
Bhasin, S.; Brito, J.P.; Cunningham, G.R.; Hayes, F.J.; Hodis, H.N.; Matsumoto, A.M.; Snyder, P.J.; Swerdloff, R.S.; Wu, F.C.; Yialamas, M. A Testosterone therapy in men with hypogonadism: An endocrine society clinical practice guidelines. J. Clin. Endocrinol. Metab., 2018, 103(5), 1715-1744.
[http://dx.doi.org/10.1210/jc.2018-00229] [PMID: 29562364]
[12]
Mulhall, J.P.; Trost, L.W.; Brannigan, R.E.; Kurtz, E.G.; Redmon, J.B.; Chiles, K.A.; Lightner, D.J.; Miner, M.M.; Murad, M.H.; Nelson, C.J.; Platz, E.A.; Ramanathan, L.V.; Lewis, R.W. Evaluation and management of testosterone deficiency: AUA guideline. J. Urol., 2018, 200(2), 423-432.
[http://dx.doi.org/10.1016/j.juro.2018.03.115] [PMID: 29601923]
[13]
Dhole, G.R.; Arver, S.; Bettocchi, C.; Jones, T.H.; Kliesch, S. EAU guidelines on male hypogonadism; , 2019. Available at. https://uroweb.org/guideline/male-hypogonadism/
[14]
Hackett, G.; Kirby, M.; Edwards, D.; Jones, T.H.; Wylie, K.; Ossei-Gerning, N.; David, J.; Muneer, A. British Society for sexual medicine guidelines on adult testosterone deficiency, with statements for UK Practice. J. Sex. Med., 2017, 14(12), 1504-1523.
[http://dx.doi.org/10.1016/j.jsxm.2017.10.067] [PMID: 29198507]
[15]
Morales, A.; Bebb, R.A.; Manjoo, P.; Assimakopoulos, P.; Axler, J.; Collier, C.; Elliott, S.; Goldenberg, L.; Gottesman, I.; Grober, E.D.; Guyatt, G.H.; Holmes, D.T.; Lee, J.C. Diagnosis and management of testosterone deficiency syndrome in men: Clinical practice guideline. CMAJ, 2015, 187(18), 1369-1377.
[http://dx.doi.org/10.1503/cmaj.150033] [PMID: 26504097]
[16]
Yeap, B.B.; Grossmann, M.; McLachlan, R.I.; Handelsman, D.J.; Wittert, G.A.; Conway, A.J.; Stuckey, B.G.A.; Lording, D.W.; Allan, C.A.; Zajac, J.D.; Burger, H.G. Endocrine society of Australia position statement on male hypogonadism (part 1): Assessment and indications for testosterone therapy. Med. J. Aust., 2016, 205(4), 173-178.
[http://dx.doi.org/10.5694/mja16.00393] [PMID: 27510348]
[17]
Yeap, B.B.; Grossmann, M.; McLachlan, R.I.; Handelsman, D.J.; Wittert, G.A.; Conway, A.J.; Stuckey, B.G.A.; Lording, D.W.; Allan, C.A.; Zajac, J.D.; Burger, H.G. Endocrine society of Australia position statement on male hypogonadism (part 2): Treatment and therapeutic considerations. Med. J. Aust., 2016, 205(5), 228-231.
[http://dx.doi.org/10.5694/mja16.00448] [PMID: 27581270]
[18]
Corona, G.; Goulis, D.G.; Huhtaniemi, I.; Zitzmann, M.; Toppari, J.; Forti, G.; Vanderschueren, D.; Wu, F.C.; Corona, G.; Goulis, D.G.; Forti, G.; Behre, H.M.; Punab, M.; Toppari, J.; Krausz, C.; Krausz, C.; Rajpert-De Meyts, E.; Tüttelmann, F.; Isidori, A.M.; Ruiz-Castane, E.; Jezek, D.; Kopa, Z.; Toppari, J.; Simoni, M.; Simoni, M. 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(5), 970-987.
[http://dx.doi.org/10.1111/andr.12770] [PMID: 32026626]
[19]
Nieschlag, E.; Lammers, U.; Freischem, C.W.; Langer, K.; Wickings, E.J. Reproductive functions in young fathers and grandfathers. J. Clin. Endocrinol. Metab., 1982, 55(4), 676-681.
[http://dx.doi.org/10.1210/jcem-55-4-676] [PMID: 6809780]
[20]
Veldhuis, J.D.; Urban, R.J.; Lizarralde, G.; Johnson, M.L.; Iranmanesh, A. Attenuation of luteinizing hormone secretory burst amplitude as a proximate basis for the hypoandrogenism of healthy aging in men. J. Clin. Endocrinol. Metab., 1992, 75(3), 707-713.
[http://dx.doi.org/10.1210/jcem.75.3.1517359] [PMID: 1517359]
[21]
Harman, S.M.; Metter, E.J.; Tobin, J.D.; Pearson, J.; Blackman, M.R. Baltimore Longitudinal Study of Aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. J. Clin. Endocrinol. Metab., 2001, 86(2), 724-731.
[http://dx.doi.org/10.1210/jcem.86.2.7219] [PMID: 11158037]
[22]
Araujo, A.B.; O’Donnell, A.B.; Brambilla, D.J.; Simpson, W.B.; Longcope, C.; Matsumoto, A.M.; McKinlay, J.B. Prevalence and incidence of androgen deficiency in middle-aged and older men: Estimates from the Massachusetts Male Aging Study. J. Clin. Endocrinol. Metab., 2004, 89(12), 5920-5926.
[http://dx.doi.org/10.1210/jc.2003-031719] [PMID: 15579737]
[23]
Giagulli, V.A.; Castellana, M.; Lisco, G.; Triggiani, V. Critical evaluation of different available guidelines for late-onset hypogonadism. Andrology, 2020, 8(6), 1628-1641.
[http://dx.doi.org/10.1111/andr.12850] [PMID: 32593233]
[24]
Heinermann, L.A.; Zimmermann, T.; Vermeulen, A.; Thiel, C.; Hummel, W. A new ‘Aging Males’ Symptoms’ rating scale. Aging Male, 1999, 2(2), 105-114.
[http://dx.doi.org/10.3109/13685539909003173]
[25]
Morley, J.E.; Charlton, E.; Patrick, P.; Kaiser, F.E.; Cadeau, P.; McCready, D.; Perry, H.M., III Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism, 2000, 49(9), 1239-1242.
[http://dx.doi.org/10.1053/meta.2000.8625] [PMID: 11016912]
[26]
Smith, K.W.; Feldman, H.A.; McKinlay, J.B. Construction and field validation of a self-administered screener for testosterone deficiency (hypogonadism) in ageing men. Clin. Endocrinol. (Oxf.), 2000, 53(6), 703-711.
[http://dx.doi.org/10.1046/j.1365-2265.2000.01152.x] [PMID: 11155092]
[27]
Fiers, T.; Wu, F.; Moghetti, P.; Vanderschueren, D.; Lapauw, B.; Kaufman, J.M. Reassessing free-testosterone calculation by liquid chromatography-tandem mass spectrometry direct equilibrium dialysis. J. Clin. Endocrinol. Metab., 2018, 103(6), 2167-2174.
[http://dx.doi.org/10.1210/jc.2017-02360] [PMID: 29618085]
[28]
Corona, G.; Mannucci, E.; Petrone, L.; Balercia, G.; Fisher, A.D.; Chiarini, V.; Forti, G.; Maggi, M. ANDROTEST: A structured interview for the screening of hypogonadism in patients with sexual dysfunction. J. Sex. Med., 2006, 3(4), 706-715.
[http://dx.doi.org/10.1111/j.1743-6109.2006.00262.x] [PMID: 16839327]
[29]
Zitzmann, M.; Faber, S.; Nieschlag, E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J. Clin. Endocrinol. Metab., 2006, 91(11), 4335-4343.
[http://dx.doi.org/10.1210/jc.2006-0401] [PMID: 16926258]
[30]
van den Beld, A.W.; de Jong, F.H.; Grobbee, D.E.; Pols, H.A.; Lamberts, S.W. Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. J. Clin. Endocrinol. Metab., 2000, 85(9), 3276-3282.
[PMID: 10999822]
[31]
Rastrelli, G.; Corona, G.; Maggi, M. Both comorbidity burden and low testosterone can explain symptoms and signs of testosterone deficiency in men consulting for sexual dysfunction. Asian J. Androl., 2020, 22(3), 265-273.
[http://dx.doi.org/10.4103/aja.aja_61_19] [PMID: 31249270]
[32]
Trost, L.W.; Mulhall, J.P. Challenges in testosterone measurement, data interpretation, and methodological appraisal of interventional trials. J. Sex. Med., 2016, 13(7), 1029-1046.
[http://dx.doi.org/10.1016/j.jsxm.2016.04.068] [PMID: 27209182]
[33]
Ruhayel, Y.; Malm, G.; Haugen, T.B.; Henrichsen, T.; Bjørsvik, C.; Grotmol, T.; Saether, T.; Malm, J.; Figenschau, Y.; Rylander, L.; Levine, R.J.; Giwercman, A. Seasonal variation in serum concentrations of reproductive hormones and urinary excretion of 6-sulfatoxymelatonin in men living north and south of the Arctic Circle: A longitudinal study. Clin. Endocrinol. (Oxf.), 2007, 67(1), 85-92.
[http://dx.doi.org/10.1111/j.1365-2265.2007.02843.x] [PMID: 17547693]
[34]
Plymate, S.R.; Tenover, J.S.; Bremner, W.J. Circadian variation in testosterone, sex hormone-binding globulin, and calculated non-sex hormone-binding globulin bound testosterone in healthy young and elderly men. J. Androl., 1989, 10(5), 366-371.
[http://dx.doi.org/10.1002/j.1939-4640.1989.tb00120.x] [PMID: 2592266]
[35]
Brambilla, D.J.; O’Donnell, A.B.; Matsumoto, A.M.; McKinlay, J.B. Intraindividual variation in levels of serum testosterone and other reproductive and adrenal hormones in men. Clin. Endocrinol. (Oxf.), 2007, 67(6), 853-862.
[http://dx.doi.org/10.1111/j.1365-2265.2007.02976.x] [PMID: 18052942]
[36]
Orwoll, E.S.; Nielson, C.M.; Labrie, F.; Barrett-Connor, E.; Cauley, J.A.; Cummings, S.R.; Ensrud, K.; Karlsson, M.; Lau, E.; Leung, P.C.; Lunggren, O.; Mellström, D.; Patrick, A.L.; Stefanick, M.L.; Nakamura, K.; Yoshimura, N.; Zmuda, J.; Vandenput, L.; Ohlsson, C. Osteoporotic fractures in men (MrOS) research group. Evidence for geographical and racial variation in serum sex steroid levels in older men. J. Clin. Endocrinol. Metab., 2010, 95(10), E151-E160.
[http://dx.doi.org/10.1210/jc.2009-2435] [PMID: 20668046]
[37]
Brambilla, D.J.; Matsumoto, A.M.; Araujo, A.B.; McKinlay, J.B. The effect of diurnal variation on clinical measurement of serum testosterone and other sex hormone levels in men. J. Clin. Endocrinol. Metab., 2009, 94(3), 907-913.
[http://dx.doi.org/10.1210/jc.2008-1902] [PMID: 19088162]
[38]
Crabbe, P.; Bogaert, V.; De Bacquer, D.; Goemaere, S.; Zmierczak, H.; Kaufman, J.M. Part of the interindividual variation in serum testosterone levels in healthy men reflects differences in androgen sensitivity and feedback set point: Contribution of the androgen receptor polyglutamine tract polymorphism. J. Clin. Endocrinol. Metab., 2007, 92(9), 3604-3610.
[http://dx.doi.org/10.1210/jc.2007-0117] [PMID: 17579205]
[39]
Ring, H.Z.; Lessov, C.N.; Reed, T.; Marcus, R.; Holloway, L.; Swan, G.E.; Carmelli, D. Heritability of plasma sex hormones and hormone binding globulin in adult male twins. J. Clin. Endocrinol. Metab., 2005, 90(6), 3653-3658.
[http://dx.doi.org/10.1210/jc.2004-1025] [PMID: 15755867]
[40]
Terrier, J.E.; Isidori, A.M. How food intakes modify testosterone level. J. Sex. Med., 2016, 13(9), 1292-1296.
[http://dx.doi.org/10.1016/j.jsxm.2016.07.001] [PMID: 27555502]
[41]
Wang, C.; Nieschlag, E.; Swerdloff, R.; Behre, H.M.; Hellstrom, W.J.; Gooren, L.J.; Kaufman, J.M.; Legros, J.J.; Lunenfeld, B.; Morales, A.; Morley, J.E.; Schulman, C.; Thompson, I.M.; Weidner, W.; Wu, F.C. Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations. Eur. J. Endocrinol., 2008, 159(5), 507-514.
[http://dx.doi.org/10.1530/EJE-08-0601] [PMID: 18955511]
[42]
Hammond, G.L.; Wu, T.S.; Simard, M. Evolving utility of sex hormone-binding globulin measurements in clinical medicine. Curr. Opin. Endocrinol. Diabetes Obes., 2012, 19(3), 183-189.
[http://dx.doi.org/10.1097/MED.0b013e328353732f] [PMID: 22531107]
[43]
Corona, G.; Torres, L.O.; Maggi, M. Testosterone therapy: What we have learned from trials. J. Sex. Med., 2020, 17(3), 447-460.
[http://dx.doi.org/10.1016/j.jsxm.2019.11.270] [PMID: 31928918]
[44]
Snyder, P.J.; Ellenberg, S.S.; Cunningham, G.R.; Matsumoto, A.M.; Bhasin, S.; Barrett-Connor, E.; Gill, T.M.; Cella, D.; Rosen, R.C.; Resnick, S.M.; Swerdloff, R.S.; Cauley, J.A.; Cifelli, D.; Fluharty, L.; Pahor, M.; Ensrud, K.E.; Lewis, C.E.; Molitch, M.E.; Crandall, J.P.; Wang, C.; Budoff, M.J.; Wenger, N.K.; Mohler, E.R. Rd.; Bild, D.E.; Cook, N.L.; Keaveny, T.M.; Kopperdahl, D.L.; Lee, D.; Schwartz, A.V.; Storer, T.W.; Ershler, W.B.; Roy, C.N.; Raffel, L.J.; Romashkan, S.; Hadley, E. The Testosterone Trials: Seven coordinated trials of testosterone treatment in elderly men. Clin. Trials, 2014, 11(3), 362-375.
[http://dx.doi.org/10.1177/1740774514524032] [PMID: 24686158]
[45]
Giagulli, V.A.; Vermeulen, A. Leydig cell function in infertile men with idiopathic oligospermic infertility. J. Clin. Endocrinol. Metab., 1988, 66(1), 62-67.
[http://dx.doi.org/10.1210/jcem-66-1-62] [PMID: 2891722]
[46]
Taylor, A.E.; Keevil, B.; Huhtaniemi, I.T. Mass spectrometry and immunoassay: How to measure steroid hormones today and tomorrow. Eur. J. Endocrinol., 2015, 173(2), D1-D12.
[http://dx.doi.org/10.1530/EJE-15-0338] [PMID: 25877990]
[47]
Vesper, H.W.; Bhasin, S.; Wang, C.; Tai, S.S.; Dodge, L.A.; Singh, R.J.; Nelson, J.; Ohorodnik, S.; Clarke, N.J.; Salameh, W.A.; Parker, C.R., Jr; Razdan, R.; Monsell, E.A.; Myers, G.L. Interlaboratory comparison study of serum total testosterone [corrected] measurements performed by mass spectrometry methods. Steroids, 2009, 74(6), 498-503.
[http://dx.doi.org/10.1016/j.steroids.2009.01.004] [PMID: 19428438]
[48]
Huhtaniemi, I.T.; Tajar, A.; Lee, D.M.; O’Neill, T.W.; Finn, J.D.; Bartfai, G.; Boonen, S.; Casanueva, F.F.; Giwercman, A.; Han, T.S.; Kula, K.; Labrie, F.; Lean, M.E.; Pendleton, N.; Punab, M.; Silman, A.J.; Vanderschueren, D.; Forti, G.; Wu, F.C. EMAS Group Comparison of Serum. Testosterone and estradiol measurements in 3174 European men using platform immunoassay and mass spectrometry; relevance for the diagnostics in aging men. Eur. J. Endocrinol., 2012, 166(6), 983-991.
[http://dx.doi.org/10.1530/EJE-11-1051] [PMID: 22423144]
[49]
Travison, T.G.; Vesper, H.W.; Orwoll, E.; Wu, F.; Kaufman, J.M.; Wang, Y.; Lapauw, B.; Fiers, T.; Matsumoto, A.M.; Bhasin, S. Harmonized reference ranges for circulating testosterone levels in men of four cohort studies in the United States and Europe. J. Clin. Endocrinol. Metab., 2017, 102(4), 1161-1173.
[http://dx.doi.org/10.1210/jc.2016-2935] [PMID: 28324103]
[50]
Giagulli, V.A.; Triggiani, V.; Carbone, M.D.; Corona, G.; Tafaro, E.; Licchelli, B.; Guastamacchia, E. The role of long-acting parenteral testosterone undecanoate compound in the induction of secondary sexual characteristics in males with hypogonadotropic hypogonadism. J. Sex. Med., 2011, 8(12), 3471-3478.
[http://dx.doi.org/10.1111/j.1743-6109.2011.02497.x] [PMID: 21995803]
[51]
Rosner, W.; Auchus, R.J.; Azziz, R.; Sluss, P.M.; Raff, H. Position statement: Utility, limitations, and pitfalls in measuring testosterone: An Endocrine Society position statement. J. Clin. Endocrinol. Metab., 2007, 92(2), 405-413.
[http://dx.doi.org/10.1210/jc.2006-1864] [PMID: 17090633]
[52]
Yeap, B.B.; Alfonso, H.; Chubb, S.A.P.; Handelsman, D.J.; Hankey, G.J.; Norman, P.E.; Flicker, L. Reference ranges and determinants of testosterone, dihydrotestosterone, and estradiol levels measured using liquid chromatography-tandem mass spectrometry in a population-based cohort of older men. J. Clin. Endocrinol. Metab., 2012, 97(11), 4030-4039.
[http://dx.doi.org/10.1210/jc.2012-2265] [PMID: 22977273]
[53]
Bhasin, S.; Pencina, M.; Jasuja, G.K.; Travison, T.G.; Coviello, A.; Orwoll, E.; Wang, P.Y.; Nielson, C.; Wu, F.; Tajar, A.; Labrie, F.; Vesper, H.; Zhang, A.; Ulloor, J.; Singh, R.; D’Agostino, R.; Vasan, R.S. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J. Clin. Endocrinol. Metab., 2011, 96(8), 2430-2439.
[http://dx.doi.org/10.1210/jc.2010-3012] [PMID: 21697255]
[54]
Morris, P.D.; Malkin, C.J.; Channer, K.S.; Jones, T.H. A mathematical comparison of techniques to predict biologically available testosterone in a cohort of 1072 men. Eur. J. Endocrinol., 2004, 151(2), 241-249.
[http://dx.doi.org/10.1530/eje.0.1510241] [PMID: 15296480]
[55]
Antonio, L.; Wu, F.C.W.; O’Neill, T.W.; Pye, S.R.; Ahern, T.B.; Laurent, M.R.; Huhtaniemi, I.T.; Lean, M.E.J.; Keevil, B.G.; Rastrelli, G.; Forti, G.; Bartfai, G.; Casanueva, F.F.; Kula, K.; Punab, M.; Giwercman, A.; Claessens, F.; Decallonne, B.; Vanderschueren, D. European Male Ageing Study Study Group.Low free testosterone is associated with hypogonadal signs and symptoms in men with normal total testosterone. J. Clin. Endocrinol. Metab., 2016, 101(7), 2647-2657.
[http://dx.doi.org/10.1210/jc.2015-4106] [PMID: 26909800]
[56]
Lisco, G.; Giagulli, V.A.; De Tullio, A.; De Pergola, G.; Guastamacchia, E.; Triggiani, V. Age-related male hypogonadism and cognitive impairment in the elderly: Focus on the effects of testosterone replacement therapy on cognition. Geriatrics (Basel), 2020, 5(4), 76.
[http://dx.doi.org/10.3390/geriatrics5040076] [PMID: 33081371]
[57]
Swerdloff, R.; Wang, C. Reflections on the T trials. Andrology, 2020, 8(6), 1512-1518.
[http://dx.doi.org/10.1111/andr.12901] [PMID: 32902162]
[58]
Paduch, D.A.; Polzer, P.K.; Ni, X.; Basaria, S. Testosterone replacement in androgen-deficient men with ejaculatory dysfunction: A randomized controlled trial. J. Clin. Endocrinol. Metab., 2015, 100(8), 2956-2962.
[http://dx.doi.org/10.1210/jc.2014-4434] [PMID: 26158605]
[59]
Giagulli, V.A.; Guastamacchia, E.; Licchelli, B.; Triggiani, V. Serum testosterone and cognitive function in ageing male: Updating the evidence. Recent Pat. Endocr. Metab. Immune Drug Discov., 2016, 10(1), 22-30.
[http://dx.doi.org/10.2174/1872214810999160603213743] [PMID: 27981914]
[60]
Walther, A.; Breidenstein, J.; Miller, R. Association of testosterone treatment with alleviation of depressive symptoms in men: A systematic review and meta-analysis. JAMA Psychiatry, 2019, 76(1), 31-40.
[http://dx.doi.org/10.1001/jamapsychiatry.2018.2734] [PMID: 30427999]
[61]
Hua, J.T.; Hildreth, K.L.; Pelak, V.S. Effects of testosterone therapy on cognitive function in aging: A systematic review. Cogn. Behav. Neurol., 2016, 29(3), 122-138.
[http://dx.doi.org/10.1097/WNN.0000000000000104] [PMID: 27662450]
[62]
Snyder, P.J.; Bhasin, S.; Cunningham, G.R.; Matsumoto, A.M.; Stephens-Shields, A.J.; Cauley, J.A.; Gill, T.M.; Barrett-Connor, E.; Swerdloff, R.S.; Wang, C.; Ensrud, K.E.; Lewis, C.E.; Farrar, J.T.; Cella, D.; Rosen, R.C.; Pahor, M.; Crandall, J.P.; Molitch, M.E.; Cifelli, D.; Dougar, D.; Fluharty, L.; Resnick, S.M.; Storer, T.W.; Anton, S.; Basaria, S.; Diem, S.J.; Hou, X.; Mohler, E.R., III; Parsons, J.K.; Wenger, N.K.; Zeldow, B.; Landis, J.R.; Ellenberg, S.S. Testosterone Trials Investigators. Effects of testosterone treatment in older men. N. Engl. J. Med., 2016, 374(7), 611-624.
[http://dx.doi.org/10.1056/NEJMoa1506119] [PMID: 26886521]
[63]
Rochira, V.; Antonio, L.; Vanderschueren, D. EAA clinical guideline on management of bone health in the andrological outpatient clinic. Andrology, 2018, 6(2), 272-285.
[http://dx.doi.org/10.1111/andr.12470] [PMID: 29499097]
[64]
Giagulli, V.A.; Castellana, M.; Pelusi, C.; Triggiani, V. Androgens, body composition, and their metabolism based on sex. Front. Horm. Res., 2019, 53, 18-32.
[http://dx.doi.org/10.1159/000494900] [PMID: 31499499]
[65]
Corona, G.; Giagulli, V.A.; Maseroli, E.; Vignozzi, L.; Aversa, A.; Zitzmann, M.; Saad, F.; Mannucci, E.; Maggi, M. Therapy of endocrine disease: Testosterone supplementation and body composition: Results from a meta-analysis study. Eur. J. Endocrinol., 2016, 174(3), R99-R116.
[http://dx.doi.org/10.1530/EJE-15-0262] [PMID: 26537862]
[66]
Basaria, S.; Coviello, A.D.; Travison, T.G.; Storer, T.W.; Farwell, W.R.; Jette, A.M.; Eder, R.; Tennstedt, S.; Ulloor, J.; Zhang, A.; Choong, K.; Lakshman, K.M.; Mazer, N.A.; Miciek, R.; Krasnoff, J.; Elmi, A.; Knapp, P.E.; Brooks, B.; Appleman, E.; Aggarwal, S.; Bhasin, G.; Hede-Brierley, L.; Bhatia, A.; Collins, L.; LeBrasseur, N.; Fiore, L.D.; Bhasin, S. Adverse events associated with testosterone administration. N. Engl. J. Med., 2010, 363(2), 109-122.
[http://dx.doi.org/10.1056/NEJMoa1000485] [PMID: 20592293]
[67]
Xu, L.; Freeman, G.; Cowling, B.J.; Schooling, C.M. Testosterone therapy and cardiovascular events among men: A systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med., 2013, 11(1), 108.
[http://dx.doi.org/10.1186/1741-7015-11-108] [PMID: 23597181]
[68]
FDA drug safety communication FDA cautions about using T products for low T due to aging requires labeling change to inform of possible increased risk of heart attack and stroke with use. US Food and Drug Administration website, 2015. Available from: http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm Published March 3, 2015
[69]
Information Update-Possible cardiovascular problems associated with testosterone products. Available from: 2014. https://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2014/40587a-eng.php Published July, 15, 2014
[70]
Corona, G.; Dicuio, M.; Rastrelli, G.; Maseroli, E.; Lotti, F.; Sforza, A.; Maggi, M. Testosterone treatment and cardiovascular and venous thromboembolism risk: What is ‘new’? J. Investig. Med., 2017, 65(6), 964-973.
[http://dx.doi.org/10.1136/jim-2017-000411] [PMID: 28495861]
[71]
Giagulli, V.A.; Triggiani, V.; Corona, G.; Carbone, D.; Licchelli, B.; Tafaro, E.; Resta, F.; Sabbà, C.; Maggi, M.; Guastamacchia, E. Evidence-based medicine update on Testosterone Replacement Therapy (TRT) in male hypogonadism: Focus on new formulations. Curr. Pharm. Des., 2011, 17(15), 1500-1511.
[http://dx.doi.org/10.2174/138161211796197160] [PMID: 21521164]
[72]
Cunningham, G.R.; Ellenberg, S.S.; Bhasin, S.; Matsumoto, A.M.; Parsons, J.K.; Preston, P.; Cauley, J.A.; Gill, T.M.; Swerdloff, R.S.; Wang, C.; Ensrud, K.E.; Lewis, C.E.; Pahor, M.; Crandall, J.P.; Molitch, M.E.; Cifelli, D.; Basaria, S.; Diem, S.J.; Stephens-Shields, A.J.; Hou, X.; Snyder, P.J. Prostate-specific antigen levels during testosterone treatment of hyogonadal older men: Data from a controlled trial. J. Clin. Endocrinol. Metab., 2019, 104(12), 6238-6246.
[http://dx.doi.org/10.1210/jc.2019-00806] [PMID: 31504596]
[73]
Platz, E.A.; Barber, J.R.; Chadid, S.; Lu, J.; Dobs, A.S.; Kanarek, N.F.; Nelson, W.G.; Bradwin, G.; McGlynn, K.A.; Rohrmann, S. Nationally representative estimates of serum testosterone concentration in never-smoking, lean men without aging-associated comorbidities. J. Endocr. Soc., 2019, 3(10), 1759-1770.
[http://dx.doi.org/10.1210/js.2019-00151] [PMID: 31528824]
[74]
Arcopinto, M.; Salzano, A.; Bossone, E.; Ferrara, F.; Bobbio, E.; Sirico, D.; Vriz, O.; De Vincentiis, C.; Matarazzo, M.; Saldamarco, L.; Saccà, F.; Napoli, R.; Iacoviello, M.; Triggiani, V.; Isidori, A.M.; Vigorito, C.; Isgaard, J.; Cittadini, A. Multiple hormone deficiencies in chronic heart failure. Int. J. Cardiol., 2015, 184, 421-423.
[http://dx.doi.org/10.1016/j.ijcard.2015.02.055] [PMID: 25755056]
[75]
Giagulli, V.A.; Guastamacchia, E.; De Pergola, G.; Iacoviello, M.; Triggiani, V. Testosterone deficiency in male: A risk factor for heart failure. Endocr. Metab. Immune Disord. Drug Targets, 2013, 13(1), 92-99.
[http://dx.doi.org/10.2174/1871530311313010011] [PMID: 23369141]
[76]
Bossone, E.; Arcopinto, M.; Iacoviello, M.; Triggiani, V.; Cacciatore, F.; Maiello, C.; Limongelli, G.; Masarone, D.; Perticone, F.; Sciacqua, A.; Perrone-Filardi, P.; Mancini, A.; Volterrani, M.; Vriz, O.; Castello, R.; Passantino, A.; Campo, M.; Modesti, P.A.; De Giorgi, A.; Monte, I.; Puzzo, A.; Ballotta, A.; Caliendo, L.; D’Assante, R.; Marra, A.M.; Salzano, A.; Suzuki, T.; Cittadini, A. TOSCA Investigators. Multiple hormonal and metabolic deficiency syndrome in chronic heart failure: Rationale, design, and demographic characteristics of the T.O.S.CA. Registry. Intern. Emerg. Med., 2018, 13(5), 661-671.
[http://dx.doi.org/10.1007/s11739-018-1844-8] [PMID: 29619769]
[77]
Salzano, A.; Marra, A.M.; Arcopinto, M.; D’Assante, R.; Triggiani, V.; Coscioni, E.; Pasquali, D.; Rengo, G.; Suzuki, T.; Bossone, E.; Cittadini, A. Combined effects of growth hormone and testosterone replacement treatment in heart failure. ESC Heart Fail., 2019, 6(6), 1216-1221.
[http://dx.doi.org/10.1002/ehf2.12520] [PMID: 31696666]
[78]
Giagulli, V.A.; Moghetti, P.; Kaufman, J.M.; Guastamacchia, E.; Iacoviello, M.; Triggiani, V. Managing erectile dysfunction in heart failure. Endocr. Metab. Immune Disord. Drug Targets, 2013, 13(1), 125-134.
[http://dx.doi.org/10.2174/1871530311313010015] [PMID: 23369145]
[79]
Calogero, A.E.; Giagulli, V.A.; Mongioì, L.M.; Triggiani, V.; Radicioni, A.F.; Jannini, E.A.; Pasquali, D.; Klinefelter Italia, N. Klinefelter ItaliaN Group (KING). Klinefelter syndrome: Cardiovascular abnormalities and metabolic disorders. J. Endocrinol. Invest., 2017, 40(7), 705-712.
[http://dx.doi.org/10.1007/s40618-017-0619-9] [PMID: 28258556]
[80]
Giagulli, V.A.; Campone, B.; Castellana, M.; Salzano, C.; Fisher, A.D.; de Angelis, C.; Pivonello, R.; Colao, A.; Pasquali, D.; Maggi, M.; Triggiani, V. Neuropsychiatric aspects in men with Klinefelter syndrome. Endocr. Metab. Immune Disord. Drug Targets, 2019, 19(2), 109-115.
[http://dx.doi.org/10.2174/1871530318666180703160250] [PMID: 29972105]
[81]
Grossmann, M.; Matsumoto, A.M. A perspective on middle-aged andolder men with functional hypogonadism: Focus on holistic management. J. Clin. Endocrinol. Metab., 2017, 102(3), 1067-1075.
[http://dx.doi.org/10.1210/jc.2016-3580] [PMID: 28359097]
[82]
Giagulli, V.A.; Castellana, M.; Carbone, M.D.; Pelusi, C.; Ramunni, M.I.; De Pergola, G.; Guastamacchia, E.; Triggiani, V. Weight loss more than glycemic control may improve testosterone in obese type 2 diabetes mellitus men with hypogonadism. Andrology, 2020, 8(3), 654-662.
[http://dx.doi.org/10.1111/andr.12754] [PMID: 31919991]
[83]
Corona, G.; Rastrelli, G.; Morelli, A.; Sarchielli, E.; Cipriani, S.; Vignozzi, L.; Maggi, M. Treatment of functional hypogonadism besides pharmacological substitution. World J. Mens Health, 2020, 38(3), 256-270.
[http://dx.doi.org/10.5534/wjmh.190061] [PMID: 31496147]
[84]
Giagulli, V.A.; Castellana, M.; Murro, I.; Pelusi, C.; Guastamacchia, E.; Triggiani, V.; De Pergola, G. The role of diet and weight loss in improving secondary hypogonadism in men with obesity with or without type 2 diabetes mellitus. Nutrients, 2019, 11(12), 2975.
[http://dx.doi.org/10.3390/nu11122975] [PMID: 31817436]
[85]
Pelusi, C.; Giagulli, V.A.; Baccini, M.; Fanelli, F.; Mezzullo, M.; Fazzini, A.; Bianchi, N.; Carbone, M.D.; De Pergola, G.; Mastroroberto, M.; Morselli Labate, A.M.; Pasquali, R. Clomiphene citrate effect in obese men with low serum testosterone treated with metformin due to dysmetabolic disorders: A randomized, double-blind, placebo-controlled study. PLoS One, 2017, 12(9), e0183369.
[http://dx.doi.org/10.1371/journal.pone.0183369] [PMID: 28886024]
[86]
Giagulli, V.A.; Silvestrini, A.; Bruno, C.; Triggiani, V.; Mordente, A.; Mancini, A. Is there room for SERMs or SARMs as alternative therapies for adult male hypogonadism? Int. J. Endocrinol., 2020, 2020, 9649838.
[http://dx.doi.org/10.1155/2020/9649838] [PMID: 32411230]
[87]
Pelusi, C.; Fanelli, F.; Baccini, M.; Triggiani, V.; Bartolomeo, N.; Carbone, M.D.; De Pergola, G.; Di Dalmazi, G.; Pagotto, U.; Pasquali, R.; Giagulli, V.A. Effect of clomiphene citrate treatment on the Sertoli cells of dysmetabolic obese men with low testosterone levels. Clin. Endocrinol. (Oxf.), 2020, 92(1), 38-45.
[http://dx.doi.org/10.1111/cen.14122] [PMID: 31677181]
[88]
Giagulli, V.A.; Carbone, M.D.; Ramunni, M.I.; Licchelli, B.; De Pergola, G.; Sabbà, C.; Guastamacchia, E.; Triggiani, V. Adding liraglutide to lifestyle changes, metformin and testosterone therapy boosts erectile function in diabetic obese men with overt hypogonadism. Andrology, 2015, 3(6), 1094-1103.
[http://dx.doi.org/10.1111/andr.12099] [PMID: 26447645]
[89]
Sciannimanico, S.; Grimaldi, F.; Vescini, F.; De Pergola, G.; Iacoviello, M.; Licchelli, B.; Guastamacchia, E.; Giagulli, V.A.; Triggiani, V. Metformin: Up to date. Endocr. Metab. Immune Disord. Drug Targets, 2020, 20(2), 172-181.
[http://dx.doi.org/10.2174/1871530319666190507125847] [PMID: 31670618]
[90]
Giagulli, V.A.; Guastamacchia, E.; Magrone, T.; Jirillo, E.; Lisco, G.; De Pergola, G.; Triggiani, V. Worse progression of COVID-19 in men: Is testosterone a key factor? Andrology, 2021, 9(1), 53-64.
[http://dx.doi.org/10.1111/andr.12836] [PMID: 32524732]
[91]
Lisco, G.; Giagulli, V.A.; De Pergola, G.; De Tullio, A.; Guastamacchia, E.; Triggiani, V. Covid-19 in man: A very dangerous affair. Endocr. Metab. Immune Disord. Drug Targets, 2021, 21(9), 1544-1554.
[http://dx.doi.org/10.2174/1871530321666210101123801] [PMID: 33388025]
[92]
Lisco, G.; De Tullio, A.; Giagulli, V.A.; Guastamacchia, E.; De Pergola, G.; Triggiani, V. Hypothesized mechanisms explaining poor prognosis in type 2 diabetes patients with COVID-19: A review. Endocrine, 2020, 70(3), 441-453.
[http://dx.doi.org/10.1007/s12020-020-02444-9] [PMID: 32779091]
[93]
Matzkin, M.E.; Calandra, R.S.; Rossi, S.P.; Bartke, A.; Frungieri, M.B. Hallmarks of testicular aging: The challenge of anti-inflammatory and antioxidant therapies using natural and/or pharmacological compounds to improve the physiopathological status of the aged male gonad. Cells, 2021, 10(11), 3114.
[http://dx.doi.org/10.3390/cells10113114] [PMID: 34831334]
[94]
Santiago, J.; Silva, J.V.; Alves, M.G.; Oliveira, P.F.; Fardilha, M. Testicular aging: An overview of ultrastructural, cellular, and molecular alterations. J. Gerontol. A Biol. Sci. Med. Sci., 2019, 74(6), 860-871.
[http://dx.doi.org/10.1093/gerona/gly082] [PMID: 29688289]
[95]
Frungieri, M.B.; Calandra, R.S.; Bartke, A.; Matzkin, M.E. Male and female gonadal ageing: Its impact on health span and life span. Mech. Ageing Dev., 2021, 197, 111519.
[http://dx.doi.org/10.1016/j.mad.2021.111519] [PMID: 34139215]
[96]
Frungieri, M.B.; Calandra, R.S.; Bartke, A.; Matzkin, M.E. Ageing and inflammation in the male reproductive tract. Andrologia, 2018, 50(11), e13034.
[http://dx.doi.org/10.1111/and.13034] [PMID: 29740839]
[97]
Mills, K.F.; Yoshida, S.; Stein, L.R.; Grozio, A.; Kubota, S.; Sasaki, Y.; Redpath, P.; Migaud, M.E.; Apte, R.S.; Uchida, K.; Yoshino, J.; Imai, S.I. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab., 2016, 24(6), 795-806.
[http://dx.doi.org/10.1016/j.cmet.2016.09.013] [PMID: 28068222]

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