Androgen replacement therapy
|Androgen replacement therapy|
Androgen replacement therapy (ART), often referred to as testosterone replacement therapy (TRT), is a form of hormone therapy in which androgens, often testosterone, are replaced. ART is often prescribed to counter the effects of male hypogonadism. It typically involves the administration of testosterone through injections, skin creams, patches, gels, or subcutaneous pellets.
ART is also prescribed to lessen the effects or delay the onset of normal male aging. However, this is controversial and is the subject of ongoing clinical trials. As men enter middle age they may notice changes caused by a relative decline in testosterone: fewer erections, fatigue, thinning skin, declining muscle mass and strength, and/or more body fat. Dissatisfaction with these changes causes some middle age men to seek ART.
The risks of diabetes and of testosterone deficiency in men over 45 (i.e., hypogonadism, specifically hypoandrogenism) are strongly correlated. Testosterone replacement therapies have been shown to improve blood glucose management. Still, "it is prudent not to start testosterone therapy in men with diabetes solely for the purpose of improving metabolic control if they show no signs and symptoms of hypogonadism."
Androgen replacement is used in postmenopausal women: the indications are to increase sexual desire; and to prevent or treat osteoporosis. The androgens used for androgen replacement in women include testosterone (and esters), prasterone (dehydroepiandrosterone; DHEA) (and the ester prasterone enanthate), methyltestosterone, nandrolone decanoate, and tibolone, among others.
|Route||Medication||Form(s)||Major brand name(s)||Dosage|
|Oral||Testosterone undecanoatea||Capsule||Andriol, Jatenzo||40–80 mg 1x/1–2 days|
|Methyltestosteroneb||Tablet||Metandren; Estratest||0.5–10 mg/day|
|Prasterone (DHEA)c||Tablet||N/A||25–100 mg/day|
|Testosterone||Cream; Gel||AndroGel||5–10 mg/day|
|Vaginal||Testosteroned||Cream; Gel||N/A||? mg 1x/1–3 days|
|Testosteroned||Suppository||N/A||1 mg 1x/2 days|
|Prasterone (DHEA)||Insert||Intrarosa||6.5 mg/day|
|Intramuscular||Testosterone enanthateb||Oil||Delatestryl; Primodian Depot||25–100 mg 1x/4–6 weeks|
|Testosterone cypionateb||Oil||Depo-Testost.; Depo-Testadiol||25–100 mg 1x/4–6 weeks|
|Testosterone isobutyratea,b||Water||Femandren M, Folivirin||25–50 mg 1x/4–6 weeks|
|Testosterone EBHb,e||Oil||Climacteron||150 mg 1x/4–8 weeks|
|Nandrolone decanoate||Oil||Deca-Durabolin||25–50 mg 1x/6–12 weeks|
|Prasterone enanthatea,b||Oil||Gynodian Depot||200 mg 1x/4–6 weeks|
|Subcutaneous||Testosterone||Implant||Testopel||50–100 mg 1x/3–6 months|
|Footnotes: a = Not available or no longer available in the United States. b = Alone and/or in combination with an estrogen. c = Over-the-counter. d = Compounded only. e = Discontinued. Sources: See template.|
The Food and Drug Administration (FDA) stated in 2015 that neither the benefits nor the safety of testosterone have been established for low testosterone levels due to aging. The FDA has required that testosterone labels include warning information about the possibility of an increased risk of heart attacks and stroke.
On January 31, 2014, reports of strokes, heart attacks, and deaths in men taking testosterone-replacement led the FDA to announce that it would be investigating this issue. The FDA's action followed three peer-reviewed studies of increased cardiovascular events and deaths. Due to an increased rate of adverse cardiovascular events compared to a placebo group, a randomized trial stopped early. Also, in November 2013, a study reported an increase in deaths and heart attacks in older men. Even after a correction was published, the "Androgen Study Group", a group with many members who have relationships with drug companies in the testosterone market, requested JAMA to retract the article as misleading due to substantial residual errors. Concerns have been raised that testosterone was being widely marketed without the benefit of data on efficacy and safety from large randomized controlled trials. As a result of the "potential for adverse cardiovascular outcomes", the FDA announced, in September 2014, a review of the appropriateness and safety of testosterone replacement therapy.
Methods of administration
There are several artificial androgens, many of which are manipulations of the testosterone molecule referred to as anabolic-androgenic steroids. Androgen replacement is administered by patch, tablet, pill, cream or gel; or depot injections given into fat or muscle.
Other significant adverse effects of testosterone supplementation include acceleration of pre-existing prostate cancer growth in individuals who have undergone androgen deprivation; increased hematocrit, which can require venipuncture in order to treat; and, exacerbation of sleep apnea. Adverse effects may also include minor side-effects such as acne and oily skin, as well as, significant hair loss and/or thinning of the hair, which may be prevented with 5-alpha reductase inhibitors ordinarily used for the treatment of benign prostatic hyperplasia, such as finasteride. Exogenous testosterone may also cause suppression of spermatogenesis, leading to, in some cases, infertility. It is recommended that physicians screen for prostate cancer with a digital rectal exam and prostate-specific antigen (PSA) level before starting therapy, and monitor PSA and hematocrit levels closely during therapy.
Some studies argue that ART increases the risk of prostate cancer, although the results are not conclusive.
Society and culture
As of September 2014, testosterone replacement therapy has been under review for appropriateness and safety by the Food and Drug Administration due to the "potential for adverse cardiovascular outcomes".
Frequency of use
In the United States usage increased from 0.5% in 2002 to 3.2% in 2013 and have since decreased to 1.7% in 2016.
Testosterone is being investigated as therapy for the following conditions:
- Erectile dysfunction
- Diabetes mellitus
- Chronic heart failure
- Dementia, but the evidence base is small and the balance of benefit needs to be clarified
- Transgender hormone therapy for transgender men
- "Testosterone therapy: Key to male vitality?". 2012.
- Kang, DY; Li, HJ (January 2015). "The effect of testosterone replacement therapy on prostate-specific antigen (PSA) levels in men being treated for hypogonadism: a systematic review and meta-analysis". Medicine. 94 (3): e410. doi:10.1097/MD.0000000000000410. PMC 4602637. PMID 25621688.
- Giwercman, A; Lundberg Giwercman, Y (2015). "Hypogonadism in young men treated for cancer". Hormones (Athens, Greece). 14 (4): 590–7. doi:10.14310/horm.2002.1650. PMID 26859600.
- Morales A, Bella AJ, Chun S, Lee J, Assimakopoulos P, Bebb R, Gottesman I, Alarie P, Dugré H, Elliott S (August 2010). "A practical guide to diagnosis, management and treatment of testosterone deficiency for Canadian physicians". Canadian Urological Association Journal. 4 (4): 269–75. PMC 2910774. PMID 20694106.
- Morimoto S, Jiménez-Trejo F, Cerbón M (2011). "Sex steroids effects in normal endocrine pancreatic function and diabetes". Current Topics in Medicinal Chemistry. 11 (13): 1728–35. doi:10.2174/156802611796117540. PMID 21463250.
- Basaria S (April 2014). "Male hypogonadism". Lancet. 383 (9924): 1250–63. doi:10.1016/S0140-6736(13)61126-5. PMID 24119423.
- Davis SR (1999). "The therapeutic use of androgens in women". J. Steroid Biochem. Mol. Biol. 69 (1–6): 177–84. doi:10.1016/S0960-0760(99)00054-0. PMID 10418991.
- Staff (March 3, 2015). "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". FDA. Retrieved March 5, 2015.
- Staff (January 31, 2014). "FDA evaluating risk of stroke, heart attack and death with FDA-approved testosterone products" (PDF). U.S. Food and Drug Administration. Retrieved September 17, 2014.
- Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, Cook MB, Fraumeni JF, Hoover RN (January 2014). "Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men" (PDF). PLOS ONE. 9 (1): e85805. doi:10.1371/journal.pone.0085805. PMC 3905977. PMID 24489673. Archived from the original (PDF) on March 4, 2016. Retrieved March 14, 2014.
- Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, Eder R, Tennstedt S, Ulloor J, Zhang A, Choong K, Lakshman KM, Mazer NA, Miciek R, Krasnoff J, Elmi A, Knapp PE, Brooks B, Appleman E, Aggarwal S, Bhasin G, Hede-Brierley L, Bhatia A, Collins L, LeBrasseur N, Fiore LD, Bhasin S (July 2010). "Adverse events associated with testosterone administration". The New England Journal of Medicine. 363 (2): 109–22. doi:10.1056/NEJMoa1000485. PMC 3440621. PMID 20592293.
- Vigen R, O'Donnell CI, Barón AE, Grunwald GK, Maddox TM, Bradley SM, Barqawi A, Woning G, Wierman ME, Plomondon ME, Rumsfeld JS, Ho PM (November 2013). "Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels". JAMA. 310 (17): 1829–36. doi:10.1001/jama.2013.280386. PMID 24193080.
- Staff (March 27, 2014). "JAMA attacked by Testosterone Money - re "Wall Street Journal" article". DM Law Firm. Retrieved March 18, 2015.
- Silverman, Ed (March 25, 2014). "A High Stakes Battle Over Testosterone". The Wall Street Journal. Retrieved August 24, 2015.
- Abraham Morgentaler; the Androgen Study Group et al. "Letter to JAMA Asking for Retraction of Misleading Article on Testosterone Therapy". Androgen Study Group.CS1 maint: uses authors parameter (link)
- McCullough, Marie (April 4, 2014). "As testosterone use grows, questions on risks await answers". Philly.com. Retrieved March 19, 2015.
- Tavernise, Sabrina (September 17, 2014). "F.D.A. Panel Backs Limits on Testosterone Drugs". The New York Times. Retrieved September 18, 2014.
- Staff (September 5, 2014). "FDA Panel To Review Testosterone Therapy Appropriateness and Safety". CNN News. Retrieved September 14, 2014.
- Staff (September 17, 2014). "Joint Meeting for Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety And Risk Management Advisory Committee (DSARM AC) - FDA background documents for the discussion of two major issues in testosterone replacement therapy (TRT): 1. The appropriate indicated population for TRT, and 2. The potential for adverse cardiovascular outcomes associated with use of TRT" (PDF). Food and Drug Administration. Retrieved September 14, 2014.
- Pastuszak AW, Pearlman AM, Lai WS, Godoy G, Sathyamoorthy K, Liu JS, Miles BJ, Lipshultz LI, Khera M (August 2013). "Testosterone replacement therapy in patients with prostate cancer after radical prostatectomy". The Journal of Urology. 190 (2): 639–44. doi:10.1016/j.juro.2013.02.002. PMC 4544840. PMID 23395803.
- Grech A, Breck J, Heidelbaugh J (2014). "Adverse effects of testosterone replacement therapy: an update on the evidence and controversy". Ther Adv Drug Saf. 5: 190–200. doi:10.1177/2042098614548680. PMC 4212439. PMID 25360240.
- "Contraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on methods for the regulation of male fertility". Lancet. 336 (8721): 955–9. October 1990. doi:10.1016/0140-6736(90)92416-F. PMID 1977002.
- "Introduction - Testosterone and Aging - NCBI Bookshelf".
- "Medscape: Medscape Access". medscape.com.
- Baillargeon, Jacques; Kuo, Yong-Fang; Westra, Jordan R.; Urban, Randall J.; Goodwin, James S. (July 10, 2018). "Testosterone Prescribing in the United States, 2002-2016". JAMA. 320 (2): 200. doi:10.1001/jama.2018.7999. PMC 6396809.
- Gan EH, Pattman S, Pearce S, Quinton R (October 2013). "A UK epidemic of testosterone prescribing, 2001-2010". Clinical Endocrinology. 79 (4): 564–70. doi:10.1111/cen.12178. PMID 23480258.
- Walther, Andreas; Mahler, Fiona; Debelak, Rudolf; Ehlert, Ulrike (February 13, 2017). "Psychobiological Protective Factors Modifying the Association Between Age and Sexual Health in Men: Findings From the Men's Health 40+ Study". American Journal of Men's Health. 11 (3): 737–747. doi:10.1177/1557988316689238. PMC 5675228.
- Finkelstein, Joel S.; Lee, Hang; Leder, Benjamin Z.; Burnett-Bowie, Sherri-Ann M.; Goldstein, David W.; Hahn, Christopher W.; Hirsch, Sarah C.; Linker, Alex; Perros, Nicholas; Servais, Andrew B.; Taylor, Alexander P.; Webb, Matthew L.; Youngner, Jonathan M.; Yu, Elaine W. (February 22, 2016). "Gonadal steroid–dependent effects on bone turnover and bone mineral density in men". Journal of Clinical Investigation. 126 (3): 1114–1125. doi:10.1172/JCI84137. PMC 4767351.
- Farley JF, Blalock SJ (July 2009). "Trends and determinants of prescription medication use for treatment of osteoporosis". American Journal of Health-System Pharmacy. 66 (13): 1191–201. doi:10.2146/ajhp080248. PMID 19535658.
- Traish AM, Saad F, Guay A (2009). "The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance". Journal of Andrology. 30 (1): 23–32. doi:10.2164/jandrol.108.005751. PMID 18772488.
- Boyanov MA, Boneva Z, Christov VG (March 2003). "Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency". The Aging Male. 6 (1): 1–7. doi:10.1080/tam.126.96.36.199. PMID 12809074.
- Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, Miceli M, Mammi C, Piepoli M, Fini M, Rosano GM (September 2009). "Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study". Journal of the American College of Cardiology. 54 (10): 919–27. doi:10.1016/j.jacc.2009.04.078. PMID 19712802.
- Cherrier MM (2009). "Testosterone effects on cognition in health and disease". Frontiers of Hormone Research. 37: 150–62. doi:10.1159/000176051. PMID 19011295.