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.[1] 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, more body fat. Dissatisfaction with these changes causes some middle age men to seek ART.

Medical uses

Men

Androgen replacement is the classic treatment of hypogonadism.[2] It is also used in men who have lost the ability to produce androgens due to disease or its treatment.[3]

Diabetes

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.[4][5] 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."[6]

Women

Androgen replacement is also used in postmenopausal women, for instance to increase sexual desire and to prevent or treat osteoporosis.[7] 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.[7]

Androgen replacement therapy formulations and dosages used in women
RouteMedicationForm(s)Major brand name(s)Dose rangeFrequency
OralTestosterone undecanoateaCapsuleAndriol40–80 mgEvery 1–2 days
OralMethyltestosteronebTabletMetandren; Estratest0.5–10 mgDaily
OralNormethandronea,bTabletGinecoside5 mgDaily
OralTiboloneaTabletLivial1.25–2.5 mgDaily
OralPrasterone (dehydroepiandrosterone)cTabletN/A25–100 mgDaily
SublingualTestosteronedTabletN/A0.25–0.5 mgDaily
SublingualMethyltestosteroneTabletMetandren0.25 mgDaily
TransdermalTestosteroneaPatchIntrinsa150–300 μg/dayEvery 3–4 days
TransdermalTestosteroneCream; GelAndroGel5–10 mgDaily
VaginalTestosteronedCream; GelN/AUnspecifiedEvery 1–3 days
VaginalPrasterone (dehydroepiandrosterone)InsertIntrarosa6.5 mgDaily
IntramuscularTestosterone enanthatebOilDelatestryl; Ditate-DS25–100 mgEvery 4–6 weeks
IntramuscularTestosterone cypionatebOilDepo-Testosterone; Depo-Testadiol25–100 mgEvery 4–6 weeks
IntramuscularTestosterone enanthate benzilic acid hydrazoneb,eOilClimacteron150 mgEvery 4–8 weeks
IntramuscularNandrolone decanoateOilDeca-Durabolin25–50 mgEvery 6–12 weeks
IntramuscularPrasterone enanthatea,bOilGynodian Depot200 mgEvery 4–6 weeks
SubcutaneousTestosteroneImplantTestopel50–100 mgEvery 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. Miscellaneous: Direct link to table. Sources: General: [8][9][10][11][12][13][14][15][16][7] Specific: [17][18][19][20][21]

Adverse effects

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.[22] The FDA has required that testosterone labels include warning information about the possibility of an increased risk of heart attacks and stroke.[22]

Heart disease

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.[23] The FDA's action followed three peer-reviewed studies of increased cardiovascular events and deaths.[24] Due to an increased rate of adverse cardiovascular events compared to a placebo group, a randomized trial stopped early.[25] Also, in November 2013, a study reported an increase in deaths and heart attacks in older men.[26] 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,[27][28] requested JAMA to retract the article as misleading due to substantial residual errors.[29] Concerns have been raised that testosterone was being widely marketed ahead of large randomized controlled trials.[30] 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.[31][32][33]

Other

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.[34] 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.[35] Exogenous testosterone may also cause suppression of spermatogenesis, leading to, in some cases, infertility.[36] 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.[37]

Some studies argue that ART increases the risk of prostate cancer, although the results are not conclusive.[38]

Society and culture

Regulation

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".[31][32][33]

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.[39]

A UK study in 2013 showed that prescriptions for testosterone replacement, particularly transdermal products, almost doubled between 2000 and 2010.[40]

Forms

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.[23]

Research

In addition, a number of other effects of testosterone have led to research into possible therapeutic roles in:

See also

References

  1. ↑ "Testosterone therapy: Key to male vitality?". 2012.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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 = Journal De l'Association Des Urologues Du Canada. 4 (4): 269–75. PMC 2910774. PMID 20694106.
  5. ↑ 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.
  6. ↑ Basaria S (April 2014). "Male hypogonadism". Lancet. 383 (9924): 1250–63. doi:10.1016/S0140-6736(13)61126-5. PMID 24119423.
  7. 1 2 3 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.
  8. ↑ Morley JE, Perry HM (May 2003). "Androgens and women at the menopause and beyond". J. Gerontol. A Biol. Sci. Med. Sci. 58 (5): M409–16. doi:10.1093/gerona/58.5.M409. PMID 12730248.
  9. ↑ Rogerio A. Lobo; Jennifer Kelsey; Robert Marcus (22 May 2000). Menopause: Biology and Pathobiology. Academic Press. pp. 454–. ISBN 978-0-08-053620-0.
  10. ↑ Carrie Bagatell; William J. Bremner (27 May 2003). Androgens in Health and Disease. Springer Science & Business Media. pp. 374–. ISBN 978-1-59259-388-0.
  11. ↑ Jacques Lorrain (1994). Comprehensive Management of Menopause. Springer Science & Business Media. pp. 301–. ISBN 978-0-387-97972-4.
  12. ↑ Khorram O (December 2001). "Potential therapeutic effects of prescribed and over-the-counter androgens in women". Clin Obstet Gynecol. 44 (4): 880–92. doi:10.1097/00003081-200112000-00025. PMID 11600868.
  13. ↑ Barbara G. Wells; Joseph T. DiPiro; Terry L. Schwinghammer; Cecily V. DiPiro (22 August 2014). Pharmacotherapy Handbook, 9/E. McGraw-Hill Education. p. 288. ISBN 978-0-07-182129-2.
  14. ↑ David B. Seifer (27 July 1999). Menopause: Endocrinology and Management. Springer Science & Business Media. pp. 359–. ISBN 978-1-59259-246-3.
  15. ↑ Alexandre Hohl (30 March 2017). Testosterone: From Basic to Clinical Aspects. Springer. pp. 341–343. ISBN 978-3-319-46086-4.
  16. ↑ Margaret Nusbaum; Jo Ann Rosenfeld (2 December 2004). Sexual Health Across the Lifecycle: A Practical Guide for Clinicians. Cambridge University Press. pp. 77–. ISBN 978-0-521-53421-5.
  17. ↑ Laura Marie Borgelt (2010). Women's Health Across the Lifespan: A Pharmacotherapeutic Approach. ASHP. pp. 558–. ISBN 978-1-58528-194-7. Despite the lack of clinical trials and quality-control standards, custom-compounded testosterone creams, ointments, and gel forms are popular formulations for improving women's sexual desire.68-70 For women, an appropriate dosage of compounded 1% testosterone gel, cream, or ointment is 0.5 g/day, which should deliver 5 mg of testosterone daily, one tenth the generally prescribed dosage for men.39 The product can be applied directly to any skin surface (but commonly the clitoris, labia, thigh, arm, or abdomen) several times weekly.
  18. ↑ Patrick J. Culligan; Roger P. Goldberg (6 March 2007). Urogynecology in Primary Care. Springer Science & Business Media. pp. 116–. ISBN 978-1-84628-167-9. Topical vaginal testosterone is often used in premenopausal women as a first step in the treatment of sexual dysfunction and vaginal lichen planus. Topical testosteorne preparations can be compounded in 1% to 2% formulations and should be applied up to 3 times per week.
  19. ↑ Maxine A. Papadakis; Stephen J. McPhee; Michael W. Rabow (11 September 2017). Current Medical Diagnosis and Treatment 2018, 57th Edition. McGraw-Hill Education. p. 1217–1218. ISBN 978-1-259-86149-9. Testosterone can also be compounded as a cream containing 1 mg/mL, with 1 mL applied to the abdomen daily. Vaginal testosterone is an option for postmenopausal women who cannot use systemic or vaginal estrogen due to breast cancer. Testosterone 150–300 mcg/day vaginally appears to reduce vaginal dryness and dyspareunia without increasing systemic estrogen levels.
  20. ↑ Joseph E. Pizzorno (2013). Textbook of Natural Medicine. Elsevier Health Sciences. pp. 1602–. ISBN 1-4377-2333-0. At present, bioidentical testosterone can be obtained only froma compounding pharmacy, where 4 to 6 mg of bioidentical testosterone is generally formulated alone or together with the biestrogen or triestrogen formulation. Testosterone cream applied to the genital region can be used as an alternative delivery method. Common prescriptions are anywhere from 1 to 10 mg/g of cream.
  21. ↑ https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208470s000lbl.pdf
  22. 1 2 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.
  23. 1 2 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ Staff (March 27, 2014). "JAMA attacked by Testosterone Money - re "Wall Street Journal" article". DM Law Firm. Retrieved March 18, 2015.
  28. ↑ Silverman, Ed (March 25, 2014). "A High Stakes Battle Over Testosterone". The Wall Street Journal. Retrieved August 24, 2015.
  29. ↑ Abraham Morgentaler; the Androgen Study Group et al. "Letter to JAMA Asking for Retraction of Misleading Article on Testosterone Therapy". Androgen Study Group.
  30. ↑ McCullough, Marie (April 4, 2014). "As testosterone use grows, questions on risks await answers". Philly.com. Retrieved March 19, 2015.
  31. 1 2 Tavernise, Sabrina (September 17, 2014). "F.D.A. Panel Backs Limits on Testosterone Drugs". The New York Times. Retrieved September 18, 2014.
  32. 1 2 Staff (September 5, 2014). "FDA Panel To Review Testosterone Therapy Appropriateness and Safety". CNN News. Retrieved September 14, 2014.
  33. 1 2 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.
  34. ↑ 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.
  35. ↑ 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.
  36. ↑ "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.
  37. ↑ "Introduction - Testosterone and Aging - NCBI Bookshelf".
  38. ↑ "Medscape: Medscape Access". medscape.com.
  39. ↑ Baillargeon, Jacques; Kuo, Yong-Fang; Westra, Jordan R.; Urban, Randall J.; Goodwin, James S. (10 July 2018). "Testosterone Prescribing in the United States, 2002-2016". JAMA. 320 (2): 200. doi:10.1001/jama.2018.7999.
  40. ↑ 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.
  41. ↑ Walther, Andreas; Mahler, Fiona; Debelak, Rudolf; Ehlert, Ulrike (13 February 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.
  42. ↑ 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. (22 February 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.
  43. ↑ 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.
  44. ↑ 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.
  45. ↑ 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.6.1.1.7. PMID 12809074.
  46. ↑ 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.
  47. ↑ Cherrier MM (2009). "Testosterone effects on cognition in health and disease". Frontiers of Hormone Research. 37: 150–62. doi:10.1159/000176051. PMID 19011295.
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