Testosterone Replacement Therapy in Hypogonadal Men

Christina Wang, Ronald S Swerdloff, Christina Wang, Ronald S Swerdloff

Abstract

All approved testosterone replacement methods, when used according to recommendations, can restore normal serum testosterone concentrations, and relieve symptoms in most hypogonadal men. Selection of the method depends on the patient's preference with advice from the physician. Dose adjustment is possible with most delivery methods but may not be necessary in all hypogonadal men. The use of hepatotoxic androgens must be avoided. Testosterone treatment induces reversible suppression of spermatogenesis; if fertility is desired in the near future, human chronic gonadotropin, selective estrogen receptor modulator, estrogen antagonist, or an aromatase inhibitor that stimulates endogenous testosterone production may be used.

Keywords: Endogenous testosterone stimulators; Implants; Intramuscular injections; Modified androgens; Oral capsules; Selective androgen receptor modulators; Transdermal gels.

Conflict of interest statement

Disclosure Drs. C. Wang and R.S. Swerdloff received research support from the Testosterone Replacement Therapy Manufacturers Consortium, Clarus Therapeutics, Chiasma, Crinetics Pharmaceuticals, and Corcept Therapeutics.

Copyright © 2021 Elsevier Inc. All rights reserved.

Figures

Figure 1.
Figure 1.
Chemical structure of testosterone and is conversion to 5α-dihydrotestosterone and estradiol. Addition of a methyl group at 17α position testosterone results in methyl-testosterone that is hepatotoxic. Removal of a methyl group at the 19-position from testosterone results in 19-nortestosterone. 19-nortestosterone and its derivatives are not hepatotoxic.

References

    1. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab 2018.
    1. Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA internal medicine. 2013;173(15):1465–1466.
    1. Layton JB, Li D, Meier CR, et al. Testosterone lab testing and initiation in the United Kingdom and the United States, 2000 to 2011. J. Clin. Endocrinol. Metab 2014;99(3):835–842.
    1. Handelsman DJ. Global trends in testosterone prescribing, 2000-2011: expanding the spectrum of prescription drug misuse. Med. J. Aust 2013;199(8):548–551.
    1. Bandari J, Ayyash OM, Emery SL, Wessel CB, Davies BJ. Marketing and Testosterone Treatment in the USA: A Systematic Review. European urology focus. 2017;3(4-5):395–402.
    1. Baillargeon J, Kuo YF, Westra JR, Urban RJ, Goodwin JS. Testosterone Prescribing in the United States, 2002-2016. JAMA. 2018;320(2):200–202.
    1. Ory J, White JT, Moore J, Grantmyre J. Canadian trends in testosterone therapy. Can Urol Assoc J. 2021;15(6):210–212.
    1. Nguyen CP, Hirsch MS, Moeny D, Kaul S, Mohamoud M, Joffe HV. Testosterone and "Age-Related Hypogonadism"--FDA Concerns. N. Engl. J. Med 2015;373(8):689–691.
    1. Vigen R, O'Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829–1836.
    1. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N. Engl. J. Med 2010;363(2):109–122.
    1. Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med. 2013;11:108.
    1. Corona G, Maseroli E, Rastrelli G, et al. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert Opin Drug Saf. 2014;13(10):1327–1351.
    1. Rosner W, Auchus RJ, Azziz R, Sluss PM, 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.
    1. Travison TG, Vesper HW, Orwoll E, et al. 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.
    1. Wilson JD. The role of 5alpha-reduction in steroid hormone physiology. Reprod. Fertil. Dev 2001;13(7-8):673–678.
    1. Peterson RE, Imperato-McGinley J, Gautier T, Sturla E. Male pseudohermaphroditism due to steroid 5-alpha-reductase deficiency. Am. J. Med 1977;62(2):170–191.
    1. Imperato-McGinley J, Zhu YS. Androgens and male physiology the syndrome of 5alpha-reductase-2 deficiency. Mol. Cell. Endocrinol 2002;198(1-2):51–59.
    1. Carani C, Qin K, Simoni M, et al. Effect of testosterone and estradiol in a man with aromatase deficiency. N. Engl. J. Med 1997;337(2):91–95.
    1. Bhasin S, Woodhouse L, Casaburi R, et al. Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab. 2001. ;281(6):E1172–E1181.
    1. Bhasin S, Woodhouse L, Casaburi R, et al. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle. Journal of Clinical Endocrinology Metabolism. 2005;90(2):678–688.
    1. Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N. Engl. J. Med 1996;335(1):1–7.
    1. Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal steroids and body composition, strength, and sexual function in men. N. Engl. J. Med 2013;369(11):1011–1022.
    1. Finkelstein JS, Lee H, Leder BZ, et al. Gonadal steroid-dependent effects on bone turnover and bone mineral density in men. J. Clin. Invest 2016;126(3):1114–1125.
    1. Cunningham GR, Stephens-Shields AJ, Rosen RC, et al. Testosterone Treatment and Sexual Function in Older Men With Low Testosterone Levels. J. Clin. Endocrinol. Metab 2016;101(8):3096–3104.
    1. Wang C, Swerdloff RS. Should the nonaromatizable androgen dihydrotestosterone be considered as an alternative to testosterone in the treatment of the andropause? J. Clin. Endocrinol. Metab 2002;87(4):1462–1466.
    1. Friedl KE, Hannan CJ Jr., Jones RE, Plymate SR. High-density lipoprotein cholesterol is not decreased if an aromatizable androgen is administered. Metabolism. 1990;39(1):69–74.
    1. Foss GL, Simpson SL. Oral methyltestosterone and jaundice. Br. Med. J 1959;1(5117):259–263.
    1. Welder AA, Robertson JW, Melchert RB. Toxic effects of anabolic-androgenic steroids in primary rat hepatic cell cultures. J Pharmacol Toxicol Methods. 1995;33(4):187–195.
    1. Boyer JL, Preisig R, Zbinden G, de Kretser DM, Wang C, Paulsen CA. Guidelines for assessment of potential hepatotoxic effects of synthetic androgens, anabolic agents and progestagens in their use in males as antifertility agents. Contraception. 1976;13(4):461.
    1. Westaby D, Ogle SJ, Paradinas FJ, Randell JB, Murray-Lyon IM. Liver damage from long-term methyltestosterone. Lancet. 1977;2(8032):262.
    1. Joseph JF, Parr MK. Synthetic androgens as designer supplements. Curr Neuropharmacol. 2015;13(1):89–100.
    1. Rahnema CD, Crosnoe LE, Kim ED. Designer steroids - over-the-counter supplements and their androgenic component: review of an increasing problem. Andrology. 2015;3(2):150–155.
    1. Cunningham GR, Cordero E, Thornby JI. Testosterone replacement with transdermal therapeutic systems. Physiological serum testosterone and elevated dihydrotestosterone levels. JAMA. 1989;261(17):2525–2530.
    1. Findlay JC, Place V, Snyder PJ. Treatment of primary hypogonadism in men by the transdermal administration of testosterone. J. Clin. Endocrinol. Metab 1989;68(2):369–373.
    1. Meikle AW, Arver S, Dobs AS, Sanders SW, Rajaram L, Mazer NA. Pharmacokinetics and metabolism of a permeation-enhanced testosterone transdermal system in hypogonadal men: influence of application site- -a clinical research center study. J. Clin. Endocrinol. Metab 1996;81(5):1832–1840.
    1. Meikle AW, Mazer NA, Moellmer JF, et al. Enhanced transdermal delivery of testosterone across nonscrotal skin produces physiological concentrations of testosterone and its metabolites in hypogonadal men. J. Clin. Endocrinol. Metab 1992;74(3):623–628.
    1. Dobs AS, Meikle AW, Arver S, Sanders SW, Caramelli KE, Mazer NA. Pharmacokinetics, efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. J. Clin. Endocrinol. Metab 1999;84(10):3469–3478.
    1. Jordan WP Jr., Allergy and topical irritation associated with transdermal testosterone administration: a comparison of scrotal and nonscrotal transdermal systems. Am. J. Contact Dermat 1997;8(2):108–113.
    1. Jordan WP Jr., Atkinson LE, Lai C. Comparison of the skin irritation potential of two testosterone transdermal systems: an investigational system and a marketed product. Clin. Ther 1998;20(1):80–87.
    1. Swerdloff RS, Wang C, Cunningham G, et al. Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men. J. Clin. Endocrinol. Metab 2000;85(12):4500–4510.
    1. Wang C, Berman N, Longstreth JA, et al. Pharmacokinetics of transdermal testosterone gel in hypogonadal men: application of gel at one site versus four sites: a General Clinical Research Center Study. J. Clin. Endocrinol. Metab 2000;85(3):964–969.
    1. Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N. Engl. J. Med 2016;374(7):611–624.
    1. Swerdloff RS, Pak Y, Wang C, et al. Serum Testosterone (T) Level Variability in T Gel-Treated Older Hypogonadal Men: Treatment Monitoring Implications. J. Clin. Endocrinol. Metab 2015;100(9):3280–3287.
    1. Wang C, Swedloff RS, Iranmanesh A, et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. Testosterone Gel Study Group. J. Clin. Endocrinol. Metab 2000;85(8):2839–2853.
    1. Wang C, Cunningham G, Dobs A, et al. 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. J. Clin. Endocrinol. Metab 2004;89(5):2085–2098.
    1. Wang C, Swerdloff RS, Iranmanesh A, et al. Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men. Clin. Endocrinol. (Oxf) 2001;54(6):739–750.
    1. Kaufman JM, Miller MG, Fitzpatrick S, McWhirter C, Brennan JJ. One-year efficacy and safety study of a 1.62% testosterone gel in hypogonadal men: results of a 182-day open-label extension of a 6-month double-blind study. J Sex Med. 2012;9(4):1149–1161.
    1. Kaufman JM, Miller MG, Garwin JL, Fitzpatrick S, McWhirter C, Brennan JJ. Efficacy and safety study of 1.62% testosterone gel for the treatment of hypogonadal men. J Sex Med. 2011. ;8(7):2079–2089.
    1. Steidle C, Schwartz S, Jacoby K, Sebree T, Smith T, Bachand R. AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function. J. Clin. Endocrinol. Metab 2003;88(6):2673–2681.
    1. Dobs AS, McGettigan J, Norwood P, Howell J, Waldie E, Chen Y. A novel testosterone 2% gel for the treatment of hypogonadal males. J. Androl 2012;33(4):601–607.
    1. Wang C, Ilani N, Arver S, McLachlan RI, Soulis T, Watkinson A. Efficacy and safety of the 2% formulation of testosterone topical solution applied to the axillae in androgen-deficient men. Clin. Endocrinol. (Oxf) 2011;75(6):836–843.
    1. Stahlman J, Britto M, Fitzpatrick S, et al. Serum testosterone levels in non-dosed females after secondary exposure to 1.62% testosterone gel: effects of clothing barrier on testosterone absorption. Curr. Med. Res. Opin 2012a;28(2):291–301.
    1. Stahlman J, Britto M, Fitzpatrick S, et al. Effect of application site, clothing barrier, and application site washing on testosterone transfer with a 1.62% testosterone gel. Curr. Med. Res. Opin 2012b;28(2):281–290.
    1. Stahlman J, Britto M, Fitzpatrick S, et al. Effects of skin washing on systemic absorption of testosterone in hypogonadal males after administration of 1.62% testosterone gel. Curr. Med. Res. Opin 2012c;28(2):271–279.
    1. Wang C, Swerdloff R, Kipnes M, et al. New testosterone buccal system (Striant) delivers physiological testosterone levels: pharmacokinetics study in hypogonadal men. J. Clin. Endocrinol. Metab 2004;89(8):3821–3829.
    1. Rogol AD, Tkachenko N, Bryson N. Natesto™ , a novel testosterone nasal gel, normalizes androgen levels in hypogonadal men. Andrology. 2016;4(1):46–54.
    1. Gronski MA, Grober ED, Gottesman IS, Ormsby RW, Bryson N. Efficacy of Nasal Testosterone Gel (Natesto(®)) Stratified by Baseline Endogenous Testosterone Levels. J Endocr Soc. 2019;3(9): 1652–1662.
    1. Lee J, Brock G, Barkin J, Bryson N, Gronski MA, Ormsby R. MY-T study: Symptom-based titration decisions when using testosterone nasal gel, Natesto(®). Can Urol Assoc J. 2019;13(10):301–306.
    1. Ramasamy R, Masterson TA, Best JC, et al. Effect of Natesto on Reproductive Hormones, Semen Parameters and Hypogonadal Symptoms: A Single Center, Open Label, Single Arm Trial. J. Urol 2020;204(3):557–563.
    1. Skakkebaek NE, Bancroft J, Davidson DW, Warner P. Androgen replacement with oral testosterone undecanoate in hypogonadal men: a double blind controlled study. Clin. Endocrinol. (Oxf) 1981;14(1):49–61.
    1. Nieschlag E, Mauss J, Coert A, Kicovic P. Plasma androgen levels in men after oral administration of testosterone or testosterone undecanoate. Acta Endocrinol. (Copenh) 1975;79(2):366–374.
    1. Horst HJ, Holtje WJ, Dennis M, Coert A, Geelen J, Voigt KD. Lymphatic absorption and metabolism of orally administered testosterone undecanoate in man. Klin. Wochenschr 1976;54(18):875–879.
    1. Schnabel PG, Bagchus W, Lass H, Thomsen T, Geurts TB. The effect of food composition on serum testosterone levels after oral administration of Andriol Testocaps. Clin. Endocrinol. (Oxf) 2007;66(4):579–585.
    1. Gooren LJ. A ten-year safety study of the oral androgen testosterone undecanoate. J Androl 1994;15(3):212–215.
    1. Legros JJ, Meuleman EJ, Elbers JM, Geurts TB, Kaspers MJ, Bouloux PM. Oral testosterone replacement in symptomatic late-onset hypogonadism: effects on rating scales and general safety in a randomized, placebo-controlled study. Eur. J. Endocrinol 2009;160(5):821–831.
    1. Yin A, Alfadhli E, Htun M, et al. Dietary fat modulates the testosterone pharmacokinetics of a new self-emulsifying formulation of oral testosterone undecanoate in hypogonadal men. J. Androl 2012;33(6):1282–1290.
    1. Yin AY, Htun M, Swerdloff RS, et al. Reexamination of pharmacokinetics of oral testosterone undecanoate in hypogonadal men with a new self-emulsifying formulation. J. Androl 2012;33(2):190–201.
    1. Swerdloff RS, Wang C, White WB, et al. A New Oral Testosterone Undecanoate Formulation Restores Testosterone to Normal Concentrations in Hypogonadal Men. J. Clin. Endocrinol. Metab 2020.
    1. Swerdloff RS, Dudley RE, Page ST, Wang C, Salameh WA. Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels. Endocr. Rev 2017;38(3):220–254.
    1. DelConte A, Patel MV, Papangkorn K, et al. SAT-052 A Novel Oral Testosterone Therapy (TLANDO) Safely Restores Testosterone to Eugonadal Levels with Fixed Dose Treatment. Journal of the Endocrine Society. 2020;4(Supplement_1).
    1. Nieschlag E, Nieschlag S. Testosterone deficiency: a historical perspective. Asian J Androl. 2014;16(2):161–168.
    1. Snyder PJ, Lawrence DA. Treatment of male hypogonadism with testosterone enanthate. J. Clin. Endocrinol. Metab 1980;51(6):1335–1339.
    1. Sokol RZ, Palacios A, Campfield LA, Saul C, Swerdloff RS. Comparison of the kinetics of injectable testosterone in eugonadal and hypogonadal men. Ferti Steril. 1982;37(3):425–430.
    1. McFarland J, Craig W, Clarke NJ, Spratt DI. Serum Testosterone Concentrations Remain Stable Between Injections in Patients Receiving Subcutaneous Testosterone. Journal of the Endocrine Society. 2017;1(8):1095–1103.
    1. Kaminetsky J, Jaffe JS, Swerdloff RS. Pharmacokinetic Profile of Subcutaneous Testosterone Enanthate Delivered via a Novel, Prefilled Single-Use Autoinjector: A Phase II Study. Sexual medicine. 2015;3(4):269–279.
    1. Kaminetsky JC, McCullough A, Hwang K, Jaffe JS, Wang C, Swerdloff RS. A 52-Week Study of Dose-Adjusted Subcutaneous Testosterone Enanthate in Oil Self-Administered via Disposable Auto-injector. J. Urol 2018.
    1. Morgentaler A, Dobs AS, Kaufman JM, et al. Long acting testosterone undecanoate therapy in men with hypogonadism: results of a pharmacokinetic clinical study. J. Urol 2008;180(6):2307–2313.
    1. Wang C, Harnett M, Dobs AS, Swerdloff RS. Pharmacokinetics and safety of long-acting testosterone undecanoate injections in hypogonadal men: an 84-week phase III clinical trial. J. Androl 2010;31(5):457–465.
    1. von Eckardstein S, Nieschlag E. Treatment of male hypogonadism with testosterone undecanoate injected at extended intervals of 12 weeks: a phase II study. J. Androl 2002;23(3):419–425.
    1. Nieschlag E, Buchter D, von Eckardstein S, Abshagen K, Simoni M, Behre HM. Repeated intramuscular injections of testosterone undecanoate for substitution therapy in hypogonadal men. Clin. Endocrinol. (Oxf) 1999;51(6):757–763.
    1. Behre HM, Abshagen K, Oettel M, Hubler D, Nieschlag E. Intramuscular injection of testosterone undecanoate for the treatment of male hypogonadism: phase I studies. Eur. J. Endocrinol 1999;140(5):414–419.
    1. Pastuszak AW, Hu Y, Freid JD. Occurrence of Pulmonary Oil Microembolism After Testosterone Undecanoate Injection: A Postmarketing Safety Analysis. Sexual medicine. 2020;8(2):237–242.
    1. Handelsman DJ, Conway AJ, Boylan LM. Pharmacokinetics and pharmacodynamics of testosterone pellets in man. J. Clin. Endocrinol. Metab 1990;71(1):216–222.
    1. Handelsman DJ, Mackey MA, Howe C, Turner L, Conway AJ. An analysis of testosterone implants for androgen replacement therapy. Clin. Endocrinol. (Oxf) 1997;47(3):311–316.
    1. McCullough AR, Khera M, Goldstein I, Hellstrom WJ, Morgentaler A, Levine LA. A multi-institutional observational study of testosterone levels after testosterone pellet (Testopel((R))) insertion. J Sex Med. 2012;9(2):594–601.
    1. McMahon CG, Shusterman N, Cohen B. 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. J Sex Med. 2017;14(7):883–890.
    1. Hayden RP, Bennett NE, Tanrikut C. Hematocrit Response and Risk Factors for Significant Hematocrit Elevation with Implantable Testosterone Pellets. J. Urol 2016;196(6):1715–1720.
    1. Ip FF, di Pierro I, Brown R, Cunningham I, Handelsman DJ, Liu PY. Trough serum testosterone predicts the development of polycythemia in hypogonadal men treated for up to 21 years with subcutaneous testosterone pellets. Eur. J. Endocrinol 2010;162(2):385–390.
    1. Krzastek SC, Smith RP. Non-testosterone management of male hypogonadism: an examination of the existing literature. Translational andrology and urology. 2020;9(Suppl 2):S160–s170.
    1. Aydogdu A, Swerdloff RS. Emerging medication for the treatment of male hypogonadism. Expert Opin Emerg Drugs. 2016;21(3):255–266.
    1. Wang C, Iranmanesh A, Berman N, et al. Comparative pharmacokinetics of three doses of percutaneous dihydrotestosterone gel in healthy elderly men--a clinical research center study. J. Clin. Endocrinol. Metab 1998;83(8):2749–2757.
    1. de Lignieres B. Transdermal dihydrotestosterone treatment of 'andropause'. Ann. Med 1993;25(3):235–241.
    1. Ly LP, Jimenez M, Zhuang TN, Celermajer DS, Conway AJ, Handelsman DJ. A double-blind, placebo-controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility, and quality of life in older men with partial androgen deficiency. J. Clin. Endocrinol. Metab 2001;86(9):4078–4088.
    1. von Eckardstein S, Noe G, Brache V, et al. A clinical trial of 7 alpha-methyl-19-nortestosterone implants for possible use as a long-acting contraceptive for men. Journal of Clinical Endocrinology Metabolism. 2003;88(11):5232–5239.
    1. Anderson RA, Wallace AM, Sattar N, Kumar N, Sundaram K. Evidence for Tissue Selectivity of the Synthetic Androgen 7{alpha}-Methyl-19-Nortestosterone in Hypogonadal Men. Journal of Clinical Endocrinology Metabolism. 2003;88(6):2784–2793.
    1. Surampudi P, Page ST, Swerdloff RS, et al. Single, escalating dose pharmacokinetics, safety and food effects of a new oral androgen dimethandrolone undecanoate in man: a prototype oral male hormonal contraceptive. Andrology. 2014;2(4):579–587.
    1. Ayoub R, Page ST, Swerdloff RS, et al. Comparison of the single dose pharmacokinetics, pharmacodynamics, and safety of two novel oral formulations of dimethandrolone undecanoate (DMAU): a potential oral, male contraceptive. Andrology. 2017;5(2):278–285.
    1. Wu S, Yuen F, Swerdloff RS, et al. Safety and Pharmacokinetics of Single-Dose Novel Oral Androgen 11beta-Methyl-19-Nortestosterone-17beta-Dodecylcarbonate in Men. J. Clin. Endocrinol. Metab 2019;104(3):629–638.
    1. Yuen F, Thirumalai A, Pham C, et al. Daily Oral Administration of the Novel Androgen 11β-MNTDC Markedly Suppresses Serum Gonadotropins in Healthy Men. J. Clin. Endocrinol. Metab 2020;105(3):e835–847.
    1. Thirumalai A, Yuen F, Amory JK, et al. Dimethandrolone Undecanoate, a Novel, Nonaromatizable Androgen, Increases P1NP in Healthy Men Over 28 Days. J. Clin. Endocrinol. Metab 2021;106(1):e171–e181.
    1. Basaria S, Collins L, Dillon EL, et al. The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men. J. Gerontol. A. Biol. Sci. Med. Sci 2013;68(1):87–95.
    1. Bhasin S, Jasuja R. Selective androgen receptor modulators as function promoting therapies. Curr Opin Clin Nutr Metab Care. 2009;12(3):232–240.
    1. Narayanan R, Coss CC, Dalton JT. Development of selective androgen receptor modulators (SARMs). Mol. Cell. Endocrinol 2018;465:134–142.
    1. Solomon ZJ, Mirabal JR, Mazur DJ, Kohn TP, Lipshultz LI, Pastuszak AW. Selective Androgen Receptor Modulators: Current Knowledge and Clinical Applications. Sexual medicine reviews. 2019;7(1):84–94.
    1. Dalton JT, Barnette KG, Bohl CE, et al. The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial. Journal of cachexia, sarcopenia and muscle. 2011;2(3):153–161.
    1. Dalton JT, Taylor RP, Mohler ML, Steiner MS. Selective androgen receptor modulators for the prevention and treatment of muscle wasting associated with cancer. Current opinion in supportive and palliative care. 2013;7(4):345–351.
    1. Dobs AS, Boccia RV, Croot CC, et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. The lancet oncology. 2013;14(4):335–345.
    1. Crawford J, Prado CM, Johnston MA, et al. Study Design and Rationale for the Phase 3 Clinical Development Program of Enobosarm, a Selective Androgen Receptor Modulator, for the Prevention and Treatment of Muscle Wasting in Cancer Patients (POWER Trials). Current oncology reports. 2016;18(6):37.
    1. Srinath R, Dobs A. Enobosarm (GTx-024, S-22): a potential treatment for cachexia. Future oncology (London, England). 2014;10(2):187–194.
    1. Machek SB, Cardaci TD, Wilburn DT, Willoughby DS. Considerations, possible contraindications, and potential mechanisms for deleterious effect in recreational and athletic use of selective androgen receptor modulators (SARMs) in lieu of anabolic androgenic steroids: A narrative review. Steroids. 2020;164:108753.
    1. Coviello AD, Matsumoto AM, Bremner WJ, et al. Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression. J. Clin. Endocrinol. Metab 2005;90(5):2595–2602.
    1. Rohayem J, Hauffa BP, Zacharin M, Kliesch S, Zitzmann M. Testicular growth and spermatogenesis: new goals for pubertal hormone replacement in boys with hypogonadotropic hypogonadism? -a multicentre prospective study of hCG/rFSH treatment outcomes during adolescence. Clin. Endocrinol. (Oxf) 2017;86(1):75–87.
    1. Matsumoto AM, Paulsen CA, Bremner WJ. Stimulation of sperm production by human luteinizing hormone in gonadotropin-suppressed normal men. J. Clin. Endocrinol. Metab 1984;59(5):882–887.
    1. Finkel DM, Phillips JL, Snyder PJ. Stimulation of spermatogenesis by gonadotropins in men with hypogonadotropic hypogonadism. N. Engl. J. Med 1985;313(11):651–655.
    1. Liu PY, Wishart SM, Handelsman DJ. A double-blind, placebo-controlled, randomized clinical trial of recombinant human chorionic gonadotropin on muscle strength and physical function and activity in older men with partial age-related androgen deficiency. J. Clin. Endocrinol. Metab 2002;87(7):3125–3135.
    1. Liu PY, Turner L, Rushford D, et al. Efficacy and safety of recombinant human follicle stimulating hormone (Gonal-F) with urinary human chorionic gonadotrophin for induction of spermatogenesis and fertility in gonadotrophin-deficient men. Hum Reprod 1999;14(6):1540–1545.
    1. Liu PY, Gebski VJ, Turner L, Conway AJ, Wishart SM, Handelsman DJ. Predicting pregnancy and spermatogenesis by survival analysis during gonadotrophin treatment of gonadotrophin-deficient infertile men. Hum. Reprod 2002;17(3):625–633.
    1. Liu PY, Baker HW, Jayadev V, Zacharin M, Conway AJ, Handelsman DJ. Induction of spermatogenesis and fertility during gonadotropin treatment of gonadotropin-deficient infertile men: predictors of fertility outcome. J. Clin. Endocrinol. Metab 2009;94(3):801–808.
    1. Burger HG, de Kretser DM, Hudson B, Wilson JD. Effects of preceding androgen therapy on testicular response to human pituitary gonadotropin in hypogonadotropic hypogonadism: a study of three patients. Ferti Steril. 1981;35(1):64–68.
    1. Ley SB, Leonard JM. Male hypogonadotropic hypogonadism: factors influencing response to human chorionic gonadotropin and human menopausal gonadotropin, including prior exogenous androgens. Journal of Clinical Endocrinology Metabolism. 1985;61(4):746–752.
    1. Ohlander SJ, Lindgren MC, Lipshultz LI. Testosterone and male infertility. Urol. Clin. North Am 2016;43(2):195–202.
    1. Liu PY, Swerdloff RS, Christenson PD, Handelsman DJ, Wang C. Rate, extent, and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis. Lancet. 2006;367(9520):1412–1420.
    1. McBride JA, Coward RM. Recovery of spermatogenesis following testosterone replacement therapy or anabolic-androgenic steroid use. Asian J Androl. 2016;18(3):373–380.
    1. Handelsman D, Shankara-Narayana N, Yu C, et al. Rate and extent of recovery from reproductive and cardiac dysfunction due to androgen abuse in men. J. Clin. Endocrinol. Metab 2020.
    1. Wenker EP, Dupree JM, Langille GM, et al. The Use of HCG-Based Combination Therapy for Recovery of Spermatogenesis after Testosterone Use. J Sex Med. 2015;12(6):1334–1337.
    1. Hsieh TC, Pastuszak AW, Hwang K, Lipshultz LI. Concomitant intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapy. J. Urol 2013;189(2):647–650.
    1. Guay AT, Jacobson J, Perez JB, Hodge MB, Velasquez E. Clomiphene increases free testosterone levels in men with both secondary hypogonadism and erectile dysfunction: who does and does not benefit? Int. J. Impot. Res 2003;15(3):156–165.
    1. Moskovic DJ, Katz DJ, Akhavan A, Park K, Mulhall JP. Clomiphene citrate is safe and effective for long-term management of hypogonadism. BJU Int. 2012;110(10):1524–1528.
    1. Leder BZ, Rohrer JL, Rubin SD, Gallo J, Longcope C. Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels. J. Clin. Endocrinol. Metab 2004;89(3):1174–1180.
    1. Dias JP, Shardell MD, Carlson OD, et al. Testosterone vs. aromatase inhibitor in older men with low testosterone: effects on cardiometabolic parameters. Andrology. 2017;5(1):31–40.
    1. Mehta A, Bolyakov A, Roosma J, Schlegel PN, Paduch DA. Successful testicular sperm retrieval in adolescents with Klinefelter syndrome treated with at least 1 year of topical testosterone and aromatase inhibitor. Fertil. Steril 2013;100(4):970–974.
    1. Punjani N, Bernie H, Salter C, Flores J, Benfante N, Mulhall JP. The Utilization and Impact of Aromatase Inhibitor Therapy in Men With Elevated Estradiol Levels on Testosterone Therapy. Sexual medicine. 2021;9(4):100378.

Source: PubMed

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