Testosterone Replacement Therapy: Indications, Application Protocols, and Side Effect Profile

Emine Demir; Erol Akpınar

doi:10.62425/rtpharma.1829150

Testosterone Replacement Therapy: Indications, Application Protocols, and Side Effect Profile

Abstract

Testosterone Replacement Therapy has evolved from speculative attempts in the 18th and 19th centuries to the isolation and synthesis of the hormone in the 1930s, followed by the development of different and safer methods of administration throughout the 20th century, leading to today's modern treatment protocols. Testosterone is the male sex hormone and is essential for maintaining male secondary sexual characteristics and fertility. Androgen deficiency seen in young men due to problems in brain regions such as the hypothalamus and pituitary gland, genetic problems, testicular disease, or damage caused by chemotherapy can be treated with testosterone replacement. Over the past decade, testosterone replacement therapy has been preferred for middle-aged or elderly men with age-related or obesity related declines in serum testosterone levels. However, these conditions are not approved indications for testosterone therapy. The benefits and safety of these drugs for treating age-related low testosterone levels have not yet been established. Some studies suggesting that testosterone replacement therapy increases the risk of cardiovascular disease led the FDA to issue a warning on January 31, 2014, which included explanations about the potential cardiovascular risks of testosterone replacement therapy. On February 28, 2025, the FDA issued a statement updating the risks of stroke, heart attack, and death after reviewing the results of a clinical study showing that approved testosterone products did not increase the risk of heart attack or stroke compared to a placebo, an inactive treatment. The FDA removed warnings about these risks from FDA-approved drugs. Only a warning regarding potential increases in blood pressure levels was added. The benefits of testosterone replacement therapy in treating the symptoms of hypogonadism have been proven by studies. This article contains a brief summary of studies conducted over the last 10 years regarding assessments of cardiovascular risks that may be associated with testosterone replacement therapy.

Keywords

References

Barbonetti, A., D’Andrea, S., & Francavilla, S. (2020). Testosterone replacement therapy. Andrology, 8(6), 1551-1566.
Behre, H., Wang, C., Handelsman, D., & Nieschlag, E. (2004). Pharmacology of testosterone preparations. Testosterone, action, deficiency, substitution, 405-444.
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. (2018). Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 103(5), 1715-1744. https://doi.org/10.1210/jc.2018-00229
Bogefors, K. (2018). Impact of androgen action on reproduction and cardiovascular disease in male cancer survivors.
Borst, S. E., & Mulligan, T. (2007). Testosterone replacement therapy for older men. Clin Interv Aging, 2(4), 561-566. https://doi.org/10.2147/cia.s1609
Brown-Séquard, C.-E. (1977). Des effets produits chez l'homme par des injections sous-cutanées d'un liquide retiré des testicules frais de cobaye et de chien. Comptes rendus des séances et mémoires de la Société de biologie et de ses filiales. Sér 9, t1 (1889), pages 68-72 ; 26 cm.
Cittadini, A., Isidori, A. M., & Salzano, A. (2022). Testosterone therapy and cardiovascular diseases. Cardiovascular research, 118(9), 2039-2057.
Corona, G., Monami, M., Rastrelli, G., Aversa, A., Tishova, Y., Saad, F., Lenzi, A., Forti, G., Mannucci, E., & Maggi, M. (2011). Testosterone and Metabolic Syndrome: A Meta‐Analysis Study. The Journal of Sexual Medicine, 8(1), 272-283. https://doi.org/10.1111/j.1743-6109.2010.01991.x

Daggett, P., Wheeler, M., & Nabarro, J. (1978). Oral testosterone, a reappraisal. Hormone Research in Paediatrics, 9(3), 121-129.
David, K., Dingemanse, E., Freud, J., & Laqueur, E. (1935). Über krystallinisches männliches Hormon aus Hoden (Testosteron), wirksamer als aus Harn oder aus Cholesterin bereitetes Androsteron. Biological Chemistry, 233(5-6), 281-283. https://doi.org/doi:10.1515/bchm2.1935.233.5 6.281
Dimitropoulos, K., Verze, P., Van den Broeck, T., Salonia, A., Yuan, C. Y., Hatzimouratidis, K., & Dohle, G. (2019). What are the benefits and harms of testosterone therapy for male sexual dysfunction?—a systematic review. International Journal of Impotence Research, 31(6), 380 391.
Dinsmore, W. W., & Wyllie, M. G. (2012). The long‐term efficacy and safety of a testosterone mucoadhesive buccal tablet in testosterone‐deficient men. BJU international, 110(2), 162-169.
Dobs, A. S., Matsumoto, A., Wang, C., & Kipnes, M. (2004). Short-term pharmacokinetic comparison of a novel testosterone buccal system and a testosterone gel in testosterone deficient men. Current medical research and opinion, 20(5), 729-738.
FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use. (2/28/2025). https://www.fda.gov/drugs/drug-safety-and-availability/fda drug-safety-communication-fda-cautions-about-using-testosterone-products-low testosterone-due
Finkelstein, J. S., Whitcomb, R. W., O'Dea, L. S., Longcope, C., Schoenfeld, D. A., & Crowley, W. F., Jr. (1991). Sex steroid control of gonadotropin secretion in the human male. I. Effects of testosterone administration in normal and gonadotropin-releasing hormone-deficient men. J Clin Endocrinol Metab, 73(3), 609-620. https://doi.org/10.1210/jcem-73-3-609
Fischer J, G. C. (August 23, 2022.). Analogue-based Drug Discovery.
Fritz, L. S. M. A. (2005). Clinical Gynecologic Endocrinology And Infertility - 7th Edition. Lippincott Williams & Wilkins.
G.R. Dohle (Chair), S. A., C. Bettocchi,, & T.H. Jones, S. K. (2019). EAU Guidelines on Male Hypogonadism. In: European Association of Urology.
Gagliano-Jucá, T., & Basaria, S. (2019). Testosterone replacement therapy and cardiovascular risk. Nature Reviews Cardiology, 16(9), 555-574.
Gava, G., Mancini, I., Cerpolini, S., Baldassarre, M., Seracchioli, R., & Meriggiola, M. C. (2018). Testosterone undecanoate and testosterone enanthate injections are both effective and safe in transmen over 5 years of administration. Clin Endocrinol (Oxf), 89(6), 878-886.
Gerald, T., & Raj, G. (2022). Testosterone and the androgen receptor. Urologic Clinics, 49(4), 603-614.
Greenspan F. S., S. G. J. (1997). Basic & Clinical Endocrinology (S. G. J. Greenspan F. S., Ed. 5th. ed.). Group, C. C. W. (2020). The current status and future of andrology: a consensus report from the Cairo workshop group. Andrology, 8(1), 27-52.
Gruyter., W. D. (1895). Hoppe-Seyler's Zeitschrift für physiologische Chemie.
Huggins, C., & Hodges, C. V. (1972). Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J Clin, 22(4), 232-240. https://doi.org/10.3322/canjclin.22.4.232
Khera, M., Crawford, D., Morales, A., Salonia, A., & Morgentaler, A. (2014). A new era of testosterone and prostate cancer: from physiology to clinical implications. Eur Urol, 65(1), 115-123. https://doi.org/10.1016/j.eururo.2013.08.015
Khosla, S., Oursler, M. J., & Monroe, D. G. (2012). Estrogen and the skeleton. Trends Endocrinol Metab, 23(11), 576-581. https://doi.org/10.1016/j.tem.2012.03.008
Korbonits, M. r., Slawik, M., Cullen, D., Ross, R. J., Stalla, G. n., Schneider, H., Reincke, M., Bouloux, P. M., & Grossman, A. B. (2004). A comparison of a novel testosterone bioadhesive buccal system, striant, with a testosterone adhesive patch in hypogonadal males. The Journal of Clinical Endocrinology & Metabolism, 89(5), 2039-2043.
Laqueur, Ernst (12-11-2013). Huygens Institute, Hollanda Biyografik Sözlüğü 6.
Mackey, M.-A., Conway, A. J., & Handelsman, D. J. (1995). Andrology: Tolerability of intramuscular injections of testosterone ester in oil vehicle. Human Reproduction, 10(4), 862-865.
Mattern, C., Hoffmann, C., Morley, J. E., & Badiu, C. (2008). Testosterone supplementation for hypogonadal men by the nasal route. The Aging Male, 11(4), 171-178.
McMahon, C. G., Shusterman, N., & Cohen, B. (2017). Pharmacokinetics, clinical efficacy, safety profile, and patient-reported outcomes in patients receiving subcutaneous testosterone pellets 900 mg for treatment of symptoms associated with androgen deficiency. The Journal of Sexual Medicine, 14(7), 883-890.
Meikle, A. W., Arver, S., Dobs, A. S., Sanders, S. W., Rajaram, L., & Mazer, N. A. (1996). Pharmacokinetics and metabolism of a permeation-enhanced testosterone transdermal system in hypogonadal men: influence of application site--a clinical research center study. The Journal of Clinical Endocrinology & Metabolism, 81(5), 1832-1840.
Meikle, A. W., Mazer, N. A., Moellmer, J. F., Stringham, J. D., Tolman, K. G., Sanders, S. W., & Odell, W. D. (1992). Enhanced transdermal delivery of testosterone across nonscrotal skin produces physiological concentrations of testosterone and its metabolites in hypogonadal men. The Journal of Clinical Endocrinology & Metabolism, 74(3), 623-628.
Melmed, S., Polonsky, K. S., Larsen, P. R., & Kronenberg, H. M. (2015). Williams textbook of endocrinology. Elsevier Health Sciences.
Miner, M., Canty, D. J., & Shabsigh, R. (2008). Testosterone replacement therapy in hypogonadal men: assessing benefits, risks, and best practices. Postgrad Med, 120(3), 130-153. https://doi.org/10.3810/pgm.2008.09.1914
Morgentaler, A., Miner, M. M., Caliber, M., Guay, A. T., Khera, M., & Traish, A. M. (2015). Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc, 90(2), 224-251. https://doi.org/10.1016/j.mayocp.2014.10.011
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. (2018). Evaluation and Management of Testosterone Deficiency: AUA Guideline. J Urol, 200(2), 423 432. https://doi.org/10.1016/j.juro.2018.03.115
Nieschlag, E. (2015). Current topics in testosterone replacement of hypogonadal men. Best Pract Res Clin Endocrinol Metab, 29(1), 77-90. https://doi.org/10.1016/j.beem.2014.09.008
Oskui, P. M., French, W. J., Herring, M. J., Mayeda, G. S., Burstein, S., & Kloner, R. A. (2013). Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. J Am Heart Assoc, 2(6), e000272. https://doi.org/10.1161/jaha.113.000272
Ponce, O. J., Spencer-Bonilla, G., Alvarez-Villalobos, N., Serrano, V., Singh-Ospina, N., Rodriguez Gutierrez, R., Salcido-Montenegro, A., Benkhadra, R., Prokop, L. J., & Bhasin, S. (2018). The efficacy and adverse events of testosterone replacement therapy in hypogonadal men: a systematic review and meta-analysis of randomized, placebo-controlled trials. The Journal of Clinical Endocrinology & Metabolism, 103(5), 1745-1754.
Rogol, A. D., Tkachenko, N., & Bryson, N. (2016). Natesto™, a novel testosterone nasal gel, normalizes androgen levels in hypogonadal men. Andrology, 4(1), 46-54.
Seftel, A. D. (2015). Re: Testosterone Products: Drug Safety Communication - FDA Cautions about Using Testosterone Products for Low Testosterone due to Aging; Requires Labeling Change to Inform of Possible Increased Risk of Heart Attack and Stroke. J Urol, 194(3), 759-760. https://doi.org/10.1016/j.juro.2015.06.058
Shoskes, J. J., Wilson, M. K., & Spinner, M. L. (2016). Pharmacology of testosterone replacement therapy preparations. Translational andrology and urology, 5(6), 834.
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. (2016). Effects of testosterone treatment in older men. New England Journal of Medicine, 374(7), 611-624.
Testosterone-containing medicines - referral No consistent evidence of an increased risk of heart problems with testosterone medicines. (08.01.2015). European Medicines Agency (EMA). https://www.ema.europa.eu/en/medicines/human/referrals/testosterone-containing medicines
Traish, A. M. (2016). Testosterone therapy in men with testosterone deficiency: are the benefits and cardiovascular risks real or imagined? American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 311(3), R566-R573.
Traish, A. M. (2025). Impact of Testosterone Deficiency and Testosterone Therapy on Men’s Health. Principles of Precision Hormone Therapy: Healthy Aging and Prevention of Chronic Disease, 249.
van Roijen, J. H., Ooms, M. P., Weber, R. F., Brinkmann, A. O., Grootegoed, J. A., & Vreeburg, J. T. (1997). Comparison of the response of rat testis and accessory sex organs to treatment with testosterone and the synthetic androgen methyltrienolone (R1881). J Androl, 18(1), 51-61. https://www.ncbi.nlm.nih.gov/pubmed/9089068
Vigen, R., O'Donnell, C. I., Baron, 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. (2013). Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA, 310(17), 1829-1836. https://doi.org/10.1001/jama.2013.280386
Walker, W. H. (2009). Molecular mechanisms of testosterone action in spermatogenesis. Steroids, 74(7), 602-607. https://doi.org/10.1016/j.steroids.2008.11.017
Wang, C., Cunningham, G., Dobs, A., Iranmanesh, A., Matsumoto, A. M., Snyder, P. J., Weber, T., Berman, N., Hull, L., & Swerdloff, R. S. (2004). Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. The Journal of Clinical Endocrinology & Metabolism, 89(5), 2085-2098.
Wang, C., Swerdloff, R., Kipnes, M., Matsumoto, A. M., Dobs, A. S., Cunningham, G., Katznelson, L., Weber, T. J., Friedman, T. C., & Snyder, P. (2004). New testosterone buccal system (Striant) delivers physiological testosterone levels: pharmacokinetics study in hypogonadal men. The Journal of Clinical Endocrinology & Metabolism, 89(8), 3821-3829.
Xu, L., Freeman, G., Cowling, B. J., & Schooling, C. M. (2013). Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC medicine, 11(1), 108.
Zarrouf, F. A., Artz, S., Griffith, J., Sirbu, C., & Kommor, M. (2009). Testosterone and depression: systematic review and meta-analysis. J Psychiatr Pract, 15(4), 289-305. https://doi.org/10.1097/01.pra.0000358315.88931.fc
Zitzmann, M. (2020). Testosterone, mood, behaviour and quality of life. Andrology, 8(6), 1598-1605. https://doi.org/10.1111/andr.12867
Zitzmann, M. (2024). Testosterone deficiency and chronic kidney disease. Journal of Clinical and Translational Endocrinology, 37. https://doi.org/ARTN 100365 10.1016/j.jcte.2024.100365

Details

Primary Language

English

Subjects

Medical Pharmacology

Journal Section

Review

Authors

Emine Demir ^*
0009-0004-4639-6626
Türkiye

Erol Akpınar
0000-0003-1428-6807
Türkiye

Early Pub Date

January 18, 2026

Publication Date

January 18, 2026

Submission Date

November 24, 2025

Acceptance Date

December 24, 2025

Published in Issue

Year 2026 Volume: 4 Number: 1

DOI

https://doi.org/10.62425/rtpharma.1829150

IZ

https://izlik.org/JA96EB93GC

Cite

RIS / Bibtex

APA

Demir, E., & Akpınar, E. (2026). Testosterone Replacement Therapy: Indications, Application Protocols, and Side Effect Profile. Recent Trends in Pharmacology, 4(1), 29-38. https://doi.org/10.62425/rtpharma.1829150

AMA

1.Demir E, Akpınar E. Testosterone Replacement Therapy: Indications, Application Protocols, and Side Effect Profile. Recent Trends in Pharmacology. 2026;4(1):29-38. doi:10.62425/rtpharma.1829150

Chicago

Demir, Emine, and Erol Akpınar. 2026. “Testosterone Replacement Therapy: Indications, Application Protocols, and Side Effect Profile”. Recent Trends in Pharmacology 4 (1): 29-38. https://doi.org/10.62425/rtpharma.1829150.

EndNote

Demir E, Akpınar E (April 1, 2026) Testosterone Replacement Therapy: Indications, Application Protocols, and Side Effect Profile. Recent Trends in Pharmacology 4 1 29–38.

IEEE

[1]E. Demir and E. Akpınar, “Testosterone Replacement Therapy: Indications, Application Protocols, and Side Effect Profile”, Recent Trends in Pharmacology, vol. 4, no. 1, pp. 29–38, Apr. 2026, doi: 10.62425/rtpharma.1829150.

ISNAD

Demir, Emine - Akpınar, Erol. “Testosterone Replacement Therapy: Indications, Application Protocols, and Side Effect Profile”. Recent Trends in Pharmacology 4/1 (April 1, 2026): 29-38. https://doi.org/10.62425/rtpharma.1829150.

JAMA

1.Demir E, Akpınar E. Testosterone Replacement Therapy: Indications, Application Protocols, and Side Effect Profile. Recent Trends in Pharmacology. 2026;4:29–38.

MLA

Demir, Emine, and Erol Akpınar. “Testosterone Replacement Therapy: Indications, Application Protocols, and Side Effect Profile”. Recent Trends in Pharmacology, vol. 4, no. 1, Apr. 2026, pp. 29-38, doi:10.62425/rtpharma.1829150.

Vancouver

1.Emine Demir, Erol Akpınar. Testosterone Replacement Therapy: Indications, Application Protocols, and Side Effect Profile. Recent Trends in Pharmacology. 2026 Apr. 1;4(1):29-38. doi:10.62425/rtpharma.1829150