Androgen replacement therapy

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Androgen replacement therapy (ART), often referred to as testosterone replacement therapy (TRT), is a hormone treatment often prescribed to counter the effects of male hypogonadism. ART typically involves the administration of testosterone, either by injection or by use of testosterone skin creams or gels. ART may also be 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, assessing the benefits and harms of its use in otherwise healthy older men.[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. This dissatisfaction with the changes of aging has led to the development of the idea of androgen replacement therapy. Androgen replacement therapy is also used for men who have lost testicular function to disease, cancer, or other causes. For men who have had prostate cancer or at elevated risk, androgen replacement therapy remains controversial because some studies have shown that it increases the risk for prostate cancer; others refute that risk.[2]

History[edit]

Male hormones are called androgens from Greek words andro meaning man, and gen meaning giving birth to. Primary among them is the natural hormone testosterone, which is produced in the testes, ovaries and adrenals. Females also produce testosterone in the adrenals and as a precursor to estrogen, but the amount of circulating testosterone is generally far less than in males. Both sexes also produce an androgen precursor called dihydroepiandrostene (DHEAS) from which the body can make androgens. Androgens cause the secondary sex characteristics of males: facial hair, thicker skin, low body fat, deeper voice, muscularity, penis and scrotal growth and darkening, broad shoulders, body hair, erection of the penis, etc. With increasing age, testosterone production declines, and many of these changes start to reverse.

The decline with age in the physical characteristics of men has given rise to a term, andropause, derived from the term menopause. Menopause is literally defined as the permanent pausing of menstruation, but "menopause" as a medical rather than a physiological condition marks the decline of estrogen and, as with andropause, has given rise to medical treatments to avert such a lowering of the female hormone. Another term used is Progressive Androgen Deficiency of the Aging Male (PADAM).

There are several artificial androgens, including nandrolone and various other manipulations of the testosterone molecule. Androgen replacement is administered by patch, tablet, pill, cream or gel; or depot injections given into fat or muscle.[3]

Adverse effects[edit]

Users report an increased alertness and well-being, heightened libido and erection ability, increase in lean muscle mass and concomitant decrease in body fat.[citation needed]

The Testosterone in Older Men with Mobility Limitations (TOM) trial, a National Institute of Aging randomized trial, was halted early by the Data Safety and Monitoring Committee because the incidence of adverse cardiovascular events was higher in the testosterone group than the placebo group.[4]

On January 31, 2014, reports of strokes, heart attacks, and deaths in men taking FDA-approved testosterone-replacement led the Food and Drug Administration (FDA) to announce that it would be investigating this issue.[3] FDA's action followed three peer-reviewed studies of increased cardiovascular events and deaths.[5] Also in November 2013, a study in the Journal of the American Medical Association reported an increase of 30% in deaths and heart attacks in older men.[6] Even after a correction was published, the "Androgen Study Group" requested JAMA to retract the article as misleading due to substantial residual errors.[7] Many members of the Androgen Study Group have relationships with drug companies in the testosterone market.[8] Concerns that testosterone is being widely marketed ahead of large randomized controlled trials have been made.[9] 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 (TRT).[10][11][12]

Other adverse effects of testosterone supplementation include minor side effects such as acne and oily skin, and more significant complications such as increased hematocrit which can require venipuncture in order to treat, exacerbation of sleep apnea and acceleration of pre-existing prostate cancer growth in individuals who have undergone androgen deprivation.[citation needed] Another adverse effect may be significant hair loss and/or thinning of the hair.[citation needed] Exogenous testosterone also causes suppression of spermatogenesis and can lead to infertility.[citation needed] 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 hematocrit and PSA levels closely during therapy.[citation needed]

There is the possibility of abuse: some athletes may demand far higher levels of androgen than normal in order to out-perform others, other people may feel they require greater doses in order to achieve what they perceive as a feeling of greater well-being.[citation needed] A UK study in 2013 showed that prescriptions for testosterone replacement, particularly transdermal, almost doubled between 2000 and 2010.[13]

Therapeutic indications[edit]

Androgen replacement has a direct role in the treatment of hypogonadism, and may improve associated features such as anemia,[14] and fatigue.[15]

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

Androgen therapy use in women[edit]

Androgen therapy is one method of pharmacological treatments that have been used for hypoactive sexual desire disorder. This is generally more common among women who have had an oophorectomy or who are in a postmenopausal state. However, like most hormonal treatments, this is also controversial and opponents argue that the clinical significance is marginal.[21] Especially among women with surgically induced menopause, the addition of androgens appears to improve libido, enjoyment, ability to reach orgasm, and initiation of sex.[22] One study found that after a 24-week trial, those women taking androgens had significantly higher scores of sexual desire compared to a placebo group.[21] As with all pharmacological drugs, there are side effects in using androgens, which include hirsutism, acne, polycythaemia, increased high-density lipoproteins, cardiovascular risks, and endometrial hyperplasia is a possibility in women without hysterectomy.[21] This is another area in which long-term use has not been demonstrated. In Europe, a patch has been approved for surgically menopausal and postmenopausal women; however, this has not been approved by the FDA in the United States yet.[21]

Diabetes and testosterone[edit]

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.[23][24] 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."[25]

Management guidelines for diabetes developed by expert groups in Europe and the United States are to some extent at odds with more recent Canadian consensus guidelines.[26][27]

Notes[edit]

  1. ^ "Testosterone therapy: Key to male vitality?". 2012. 
  2. ^ Medscape http://www.medscape.com/viewarticle/540617_2 |url= missing title (help). 
  3. ^ a b 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. 
  4. ^ Basaria S, et al. (Jul 2010). "Adverse Events Associated with Testosterone Administration". New England Journal of Medicine 363 (2): 109–22. doi:10.1056/NEJMoa1000485. PMC 3440621. PMID 20592293. 
  5. ^ William D. Finkle; Sander Greenland; Gregory K. Ridgeway; John L. Adarns; Melissa A. Frasco; Michael B. Cook; Joseph F. Fraumeni, Jr., ;Robert N. Hoover (January 2014). "Increased Risk of Non-fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men". PLoS ONE 9 (1): e85805. doi:10.1371/journal.pone.0085805. PMC 3905977. PMID 24489673. 
  6. ^ "Association of Testosterone Therapy With Mortality, Myocardial Infarction, and Stroke in Men With Low Testosterone Levels". JAMA. Nov 6, 2013. 
  7. ^ Abraham Morgentaler; the Androgen Study Group; et al. "Letter to JAMA Asking for Retraction of Misleading Article on Testosterone Therapy". Androgen Study Group. 
  8. ^ |url=http://www.medpagetoday.com/Endocrinology/GeneralEndocrinology/4495%7C
  9. ^ |url=http://articles.philly.com/2014-04-04/news/48838961_1_testosterone-low-t-male-hormone-replacement%7C
  10. ^ Tavernise, Sabrina (September 17, 2014). "F.D.A. Panel Backs Limits on Testosterone Drugs". New York Times. Retrieved September 18, 2014. 
  11. ^ Staff (September 5, 2014). "FDA Panel To Review Testosterone Therapy Appropriateness and Safety". CNN News. Retrieved September 14, 2014. 
  12. ^ 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. 
  13. ^ Gan, EH; Pattman, S; H 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. 
  14. ^ Makipour S, Kanapuru B, Ershler WB (October 2008). "Unexplained anemia in the elderly". Semin. Hematol. 45 (4): 250–4. doi:10.1053/j.seminhematol.2008.06.003. PMC 2586804. PMID 18809095. 
  15. ^ Miner M, Canty DJ, Shabsigh R (September 2008). "Testosterone replacement therapy in hypogonadal men: assessing benefits, risks, and best practices". Postgrad Med 120 (3): 130–53. doi:10.3810/pgm.2008.09.1914. PMID 18824832. 
  16. ^ Farley JF, Blalock SJ (July 2009). "Trends and determinants of prescription medication use for treatment of osteoporosis". Am J Health Syst Pharm 66 (13): 1191–201. doi:10.2146/ajhp080248. PMID 19535658. 
  17. ^ Traish AM, Saad F, Guay A (2009). "The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance". J. Androl. 30 (1): 23–32. doi:10.2164/jandrol.108.005751. PMID 18772488. 
  18. ^ PMID12809074
  19. ^ Caminiti G, Volterrani M, Iellamo F, et al. (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". J. Am. Coll. Cardiol. 54 (10): 919–27. doi:10.1016/j.jacc.2009.04.078. PMID 19712802. 
  20. ^ Cherrier MM (2009). "Testosterone effects on cognition in health and disease". Front Horm Res 37: 150–62. doi:10.1159/000176051. PMID 19011295. 
  21. ^ a b c d Eden, K.J., & Wylie, K.R. (2009). "Quality of sexual life and menopause". Women’s Health 5 (4): 385–396. doi:10.2217/whe.09.24. 
  22. ^ Nappi, R.E. et al. (2006). "Clitoral stimulation in postmenopausal women with sexual dysfunction: A pilot randomized study with hormone therapy". European Menopause Journal 55: 288–295. doi:10.1016/j.maturitas.2006.04.014. 
  23. ^ Morales (August 2010). "A practical guide to diagnosis, management and treatment of testosterone deficiency for Canadian physicians". Can Urol Assoc J 4 (4): 269–75. PMC 2910774. PMID 20694106. 
  24. ^ Francisco Jimenez-Trejo, Marco Cerbon, Sumiko Morimoto (2011). "Sex steroids effects in normal endocrine pancreatic function and diabetes". Current Topics in Medicinal Chemistry 11 (13): 1728–1735. doi:10.2174/156802611796117540. PMID 21463250. 
  25. ^ Basaria S (Apr 5, 2014). "Male hypogonadism". Lancet 383 (9924): 1250–63. doi:10.1016/S0140-6736(13)61126-5. PMID 24119423. 
  26. ^ Woo, V (2009). "Important differences: Canadian Diabetes Association 2008 clinical practice guidelines and the consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes". Diabetologia 52 (3): 552–3; author reply 554–5. doi:10.1007/s00125-008-1236-0. PMID 19107458. 
  27. ^ Nathan, DM; Buse, JB; Davidson, MB; Ferrannini, E; Holman, RR; Sherwin, R; Zinman, B; American Diabetes, Association; European Association for the Study of Diabetes (2009). "Medical management of hyperglycaemia in type 2 diabetes mellitus: A consensus algorithm for the initiation and adjustment of therapy: A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes". Diabetologia 52 (1): 17–30. doi:10.1007/s00125-008-1157-y. PMID 18941734.