- Email: [email protected]
Testosterone replacement therapy
SEX HORMONES
Testosterone replacement therapy
What’s new? C C
Leighton J Seal
C C C
Abstract
C
Testosterone replacement therapy is a well-tolerated and established treatment for hypogonadism, providing excellent clinical and biochemical relief from the effects of sex steroid deficiency. This review gives a practical clinical guide to managing testosterone replacement therapy. It outlines the indications for testosterone replacement, including the relevant testosterone threshold levels for treatment. There is also discussion of its use in non-gonadal illness such as HIV. Recent studies looking at the use of testosterone in cardiometabolic disease are discussed. The routes of administrating testosterone replacement therapy are summarized, with emphasis on the newer delivery systems that have become available recently. There is a discussion of the side effects of testosterone treatment including its effects on the prostate and haematological parameters. Finally, an outline of both safety and clinical testosterone level monitoring is presented.
C
result in hypoactive sexual desire disorder, which is characterized by low libido.5,6 Paediatrics In childhood, testosterone treatment causes growth of the genitalia. In boys with microphallus this has been utilized to assess the potential of penile growth and to improve penile size in infancy. Testosterone induces and maintains male secondary sexual characteristics and causes fusion of the epiphyses during growth. It can therefore be used to induce puberty when there is delay of this process and also to stop growth if a child is excessively tall.
Keywords ADAM; delayed puberty; hypogonadism; liver dysfunction; polycythaemia; prostate cancer; sarcopenia; testosterone; testosterone replacement therapy
Sarcopenia In HIV-related wasting, testosterone supplementation has been show to improve muscle strength7 and functional status.8 Therefore in HIV-related weight loss and sarcopenia it is recommended that a 3-month treatment with testosterone can be given but it should be no longer than this.9 In age-related sarcopenia, the evidence supporting the use of testosterone is contradictory and the risks of complications are higher, which means that the use of testosterone supplementation purely to improve functional status is questionable unless the patient has demonstrated hypogonadism.9
Indications There are many indications for testosterone replacement therapy but by far the most common is the treatment of male hypogonadism. Adult hypogonadism Testosterone therapy reverses the clinical features of hypogonadism. There is an increase in lean body mass and upper body strength1; there is a concurrent decrease in body fat, with increased muscle definition and a decrease in hip to waist ratio. In susceptible individuals, there is a loss of capital hair in a male pattern baldness distribution. There is an improvement in visio-spatial ability.2 General energy and drive increases and depression when present is reduced.3 Testosterone increases libido in both men and women.4,5 Testosterone can be very successful in treating libido disturbance in the context of hypogonadism, even in females where the testosterone deficiency seen post menopausally can
Female-to-male transsexualism Hormonal treatment is intrinsic to the management of gender dysphoria. Treatment should not be initiated without approval from a mental health practioner with a special interest in gender dysphoria.10 In female-to-male transsexuals, testosterone administered as an i.m. injection, once every 2e4 weeks, results in masculinization over 2e5 years. The aim of treatment is to get the testosterone levels into the normal male range.11 Sustanon has recently been licenced in the UK for this purpose. Osteoporosis Testosterone increases mineral deposition in the skeleton. It can increase bone mineral density in hypogonadism by 3.7%12 and there is a doseeresponse relationship between testosterone replacement therapy and the increase in bone mineral density.13
Leighton J Seal PhD FRCP is a consultant and Honorary Senior Lecturer in Endocrinology and Diabetes at St George’s Hospital, Tooting and also Consultant Endocrinologist at the Gender Identity Clinic at Charing Cross Hospital, London, UK. Competing interests: The author has been a speaker for Bayer Schering Pharmaceuticals and received fees for consulting for that company.
MEDICINE 37:9
New routes of administration Topical gel Long acting testosterone injection Use of testosterone in cardiometabolic disease Licensing of testosterone for transsexualism Use in HIV sarcopenia Testosterone appears not to increase the risk of prostate cancer
Cardiometabolic disorders Recent studies have shown that in heart failure, testosterone supplementation for men with borderline or low testosterone can
445
Ó 2009 Elsevier Ltd. All rights reserved.
SEX HORMONES
significantly improve their function capacity, improving by one or two New York Heart Association categories with treatment.14,15 In diabetes mellitus, testosterone supplementation for similar testosterone levels has resulted in improvement of HbA1C by 0.5e2.5%.16,17 It is too soon to recommend the general use of testosterone in these situations, but these areas are under active investigation.
testosterone levels, it can cause significant skin rashes due to an excipient that is included in the patch. This often limits its use. Testosterone in an alcohol-based gel gives good delivery of testosterone, with levels maintained in the physiological range throughout the day. With gels there is the risk of transfer of testosterone to other people for 6 hours after the gel is applied to the skin and so patients should be advised not to come into skinto-skin contact with another person during this time, especially with a female or prepubertal child. Testosterone tablets are rapidly absorbed from the gut but have a low bioavailablity. There is activation of the testosterone to dihydrotestosterone (DHT) by 5-alpha reductase, which is present in the gut lacteals, giving high DHT:testosterone levels. It can be effectively monitored only by measuring plasma DHT, not testosterone levels, and this assay is not widely available. It results in large testosterone swings on a daily basis which can have adverse effects on mood, energy and libido.
Initiation of testosterone therapy Because of the circadian rhythm of testosterone, levels must be measured in the morning at 9 a.m. to ensure they are reliable. It is also important to measure the testosterone on more than one occasion as up to 40% of abnormal testosterone values normalize on repeat testing. A total testosterone value of greater than 12 nmol/litre (providing there is normal sex hormone-binding globulin production) is normal and testosterone replacement is not indicated.18 Similarly a total testosterone level of less than 8 nmol/litre is considered hypogonadal and testosterone replacement is appropriate.18 This leaves a borderline plasma testosterone level between 8 and 12 nmol/litre, where testosterone replacement may be considered. In this situation the calculation of a free testosterone level can be useful. Using plasma total testosterone, albumin and SHBG levels it is possible to calculate both free and bioavailable testosterone levels. An easy-to-use calculator can be found at the website of the International Society for the Study of the Ageing Male.19 Free testosterone levels below 180 pmol/litre are hypogonadal and in those with levels of 180e250 pmol/litre a 12week trial of testosterone can be given, but it is important to review whether the patient has gained benefit from the treatment before continuing it on a more permanent basis.18
Monitoring The aim of monitoring is to maintain the plasma testosterone level within the physiological range for as long as possible with that particular preparation. Monitoring should be performed in the steady state, i.e. following at least four treatments. The monitoring requirements of each preparation are summarized in Table 1.
Safety monitoring The safety monitoring for this ongoing treatment is outlined in Table 2. This monitoring is designed to detect the major side effects of hormonal therapy.
Route
Side effects
There are many routes for the delivery of testosterone replacement. The active moiety is testosterone and so the pros and cons of each route are related to the differing pharmacokinetics of the preparations, which result in varying plasma testosterone levels with time (Table 1). The mainstays of testosterone replacement have been shortacting testosterone esters. They have many disadvantages, however, especially mood swings due to the constant waxing and waning of the testosterone levels they induce. They also have the highest incidence of polycythaemia, which is related to the amount of time that the plasma testosterone level is above the normal range. Recently a longer-acting preparation, testosterone undecanoate (NebidoÔ, Bayer Schering), has become available. This produces a much smoother testosterone profile and consequently a patient’s mood is generally more stable. There is a lower incidence of polycythaemia. Testosterone implants are small wax pellets that are inserted into a deep subcutaneous position, usually over the abdominal wall. The treatment involves a minor operative procedure using aseptic technique under local anaesthesia. There is a delay in the onset of action of 1e2 weeks post insertion but the procedure is very infrequent and plasma levels are kept within the physiological range for most of the 6-month period. There is only one patch preparation available in the UK: AndropatchÔ (Glaxo Smith Kline). Although it gives good
Polycythaemia Testosterone induces the production of erythropoietin and so red blood cells. The increase in blood viscosity can lead to an increased incidence of stroke in those who have a haematocrit above 50%.20 The development of polycythaemia appears to be proportional to the amount of supraphysiological testosterone that is administered. Polycythaemia usually responds to a decrease in the dose of testosterone, especially if this is changed to a non-injectable formulation. When this is inadequate, regular venesection to bring the haematocrit down into the normal range can be instituted.
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Liver dysfunction The incidence of hepatic dysfunction with alkylated steroid preparations such as methyl testosterone is high. There have been reported cases of fulminant hepatic failure.21 These anabolic steroids are no longer used in routine testosterone replacement. Abnormalities of liver function, with an incidence of up to 4.4%, has been reported in patients taking testosterone, so liver function test monitoring is required.22 Lipid profile In hypogonadism, reduced high-density lipoprotein, increased triglyceride and increased low-density lipoprotein cholesterol are present and these abnormalities are corrected when
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Ó 2009 Elsevier Ltd. All rights reserved.
SEX HORMONES
A summary of the routes of administration of testosterone and required monitoring Preparation Short-acting testosterone injection C Testosterone enthanate (Proviron Ô) C Mixed testosterone esters (SustenonÔ) C Testosterone proprionate (VirormoneÔ) Long-acting testosterone
Dose Intramuscular injection 100e250 mg 2e4 weeks
Advantages Rapid onset Adequate plasma levels Avoids daily dosing
1000mg/12 weeks Loading: C Short-acting testosterone and Nebido 1000 mg C 6 weeks later Nebido 1000 mg C 6 weeks after that Nebido 1000 mg C Then 1000 mg/12 weeks Testosterone 600e 1200 mg/4e8 months Deep subcutaneous wax pellets inserted via a minor operation
Reduced frequency of injection Smoother testosterone profile Mood more stable Less polycythaemia
Testosterone patch AndropatchÔ.
Patch 5e10 mg per day
Testosterone gel TestogelÔ, TestimÔ, ProstrakenÔ
5e10 mg (1e2 packs)
Testosterone undecanoate C RestandolÔ
40e120 mg tds orally
No needles Testosterone level in physiological range Mimics circadian rhythm No needles Testosterone level in physiological range Mimics circadian rhythm Orally active
C
Testosterone undecanoate (NebidoÔ)
Testosterone implant
C
C
Very infrequent Smooth testosterone profile Low polycythaemia risk Good mood stability
Disadvantages Supra-physiological levels for 3e5 days Aggression Hypersexuality Polycythaemia Rapid decline in testosterone Variable mood Loading phase Oil embolism if injection is administered too quickly
Monitoring Peak levels (1 week after the injection) 25e30 nmol/litre Trough level (day the injection due, before the injection given) 8e12 nmol/litre
Delayed onset Minor operation 1 cm scar Bleeding Infection Extrudation of pellets Lack of energy and reduced libido prior to next pellet insertion Daily dosing Skin allergies Large patch
Testosterone levels 4, 5 and 6 months after pellet insertion Aim: 10e15 nmol/litre by next insertion
Testosterone level 4e6 hours after application Aim: 15e20 nmol/litre
Daily Time needed for gel to dry Transfer of testosterone
Testosterone level 4e6 hours after application Aim: 15e20 nmol/litre
Monitoring by DHT (assay not widely available) Large testosterone swings Variable:
DHT 4 hours after a dose Aim: 1e3 nmol/litre
C C C
Testosterone levels week 10, 11 and 12 before the 1st 12-week injection 10e15 nmol/litre
mood energy levels libido.
DHT, Dihydrotestosterone. Drug manufacturers: Proviron, Cambridge Laboratories; Sustenon, Organon; Virormone, Nordic; Nebido, Bayer Schering; Testosterone implant, Organon; Andropatch, Glaxo Smith Kline; Testogel, Bayer Schering; Testim, Ipsen; Tostran, ProStraken; Restandol, Organon.
Table 1
MEDICINE 37:9
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Ó 2009 Elsevier Ltd. All rights reserved.
SEX HORMONES
Summary
Investigations and safety monitoring for testosterone replacement therapy
Testosterone replacement therapy is a well tolerated and established treatment for hypogonadism, which provides excellent clinical and biochemical relief from the effects of sex steroid deficiency. Recent advances in the delivery systems have made its use much more comfortable, convenient and capable of delivering more physiological levels of testosterone. A
Test Initial visit Diagnostic
Safety
LH FSH Testosterone SHBG Prolactin LFTs FBC (polycythaemia) PSA Lipid profile
REFERENCES 1 Wang C, Swerdloff RS, Iranmanesh A, et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab 2000; 85: 2839e53. 2 Slabbekoorn D, Van Goozen SH, Megens J, Gooren LJ, CohenKettenis PT. Activating effects of cross-sex hormones on cognitive functioning: a study of short-term and long-term hormone effects in transsexuals. Psychoneuroendocrinology 1999; 24: 423e47. 3 Pope Jr HG, Cohane GH, Kanayama G, Siegel AJ, Hudson JI. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry 2003; 160: 105e11. 4 Anastasiadis AG, Davis AR, Salomon L, Burchardt M, Shabsigh R. Hormonal factors in female sexual dysfunction. Curr Opin Urol 2002; 12: 503e7. 5 Buster JE, Kingsberg SA, Aguirre O, et al. Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Obstet Gynecol 2005; 105: 944e52. 6 Simon J, Braunstein G, Nachtigall L, et al. Testosterone patch increases sexual activity and desire in surgically menopausal women with hypoactive sexual desire disorder. J Clin Endocrinol Metab 2005; 90: 5226e33. 7 Bhasin S, Storer TW, Asbel-Sethi N, et al. Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels. J Clin Endocrinol Metab 1998; 83: 3155e62. 8 Kong A, Edmonds P. Testosterone therapy in HIV wasting syndrome: systematic review and meta-analysis. Lancet Infect Dis 2002; 2: 692e9. 9 Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2006; 91: 1995e2010. 10 Seal LJ. The practical management of adults with gender dysphoria. In: Barrett J, ed. Transsexual and other disorders of gender identity: a practical guide to management. Oxford: Radcliffe, 2007. 11 Mahmoud A, Comhaire FH. Mechanisms of disease: late-onset hypogonadism. Nat Clin Pract Urol 2006; 3: 430e8. 12 Isidori AM, Giannetta E, Greco EA, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol (Oxf) 2005; 63: 280e93. 13 Aminorroaya A, Kelleher S, Conway AJ, Ly LP, Handelsman DJ. Adequacy of androgen replacement influences bone density response to testosterone in androgen-deficient men. Eur J Endocrinol 2005; 152: 881e6. 14 Malkin CJ, Pugh PJ, West JN, et al. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur Heart J 2006; 27: 57e64.
Glucose Weight Blood pressure DRE (over 45 years) Follow-up visit Every 3 months titration Every 12 months stable Testosterone levels LFTs FBC (polycythaemia) PSA Lipids Weight Blood pressure DRE (over 45 years) DRE, digital rectal examination; LH, luteinizing hormone; FSH, folliclestimulating hormone; SHBG, sex hormone binding globulin; LFT, liver function test; FBC, full blood count; PSA, prostrate specific antigen.
Table 2
appropriate testosterone replacement is given.12,23 When supraphysiological treatment is used, as is seen in athletes who abuse testosterone, there is a reversal of the lipid parameters back to the adverse profile.24,25 Obstructive sleep apnoea Testosterone therapy exacerbates the symptoms of obstructive sleep apnoea and, more worryingly, increases the occurrence of cardiac arrhythmia in this condition.25,26 It is relatively contraindicated in this condition. Prostate neoplasia Prostate cancer is often considered the most worrying side effect of testosterone treatment but reassuringly, there is very little evidence that testosterone replacement to appropriate values in the physiological range is causative in prostate cancer development.27e29 Testosterone is contraindicated in active hormonal cancer, including breast and prostate cancer. In men who are taking testosterone replacement therapy, the development of prostate cancer must be routinely screened for by PSA and DRE monitoring.9
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Ó 2009 Elsevier Ltd. All rights reserved.
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15 Pugh PJ, Jones RD, West JN, Jones TH, Channer KS. Testosterone treatment for men with chronic heart failure. Heart 2004; 90: 446e7. 16 Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006; 154: 899e906. 17 Boyanov MA, Boneva Z, Christov VG. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male 2003; 6: 1e7. 18 Nieschlag E, Swerdloff R, Behre HM, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males. ISA, ISSAM, and EAU recommendations. Eur Urol 2005; 48: 1e4. 19 Free & bioavailable testosterone calculator. International Society for the Study of the Ageing Male. Also available at: http://www.issam.ch/ freetesto.htm (accessed 28 Apr 2009). 20 Krauss DJ, Taub HA, Lantinga LJ, Dunsky MH, Kelly CM. Risks of blood volume changes in hypogonadal men treated with testosterone enanthate for erectile impotence. J Urol 1991; 146: 1566e70. 21 Wilder EM. Death due to liver failure following the use of methandrostenolone. Can Med Assoc J 1962; 87: 768e9. 22 van Kesteren PJ, Asscheman H, Megens JA, Gooren LJ. Mortality and morbidity in transsexual subjects treated with cross-sex hormones. Clin Endocrinol (Oxf) 1997; 47: 337e42. 23 Whitsel EA, Boyko EJ, Matsumoto AM, Anawalt BD, Siscovick DS. Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis. Am J Med 2001; 111: 261e9. 24 Hurley BF, Seals DR, Hagberg JM, et al. High-density-lipoprotein cholesterol in bodybuilders v powerlifters. Negative effects of androgen use. JAMA 1984; 252: 507e13. 25 Bhasin S. Effects of testosterone administration on fat distribution, insulin sensitivity, and atherosclerosis progression. Clin Infect Dis 2003; 37(Suppl 2): S142e9.
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26 Matsumoto AM, Sandblom RE, Schoene RB, et al. Testosterone replacement in hypogonadal men: effects on obstructive sleep apnoea, respiratory drives, and sleep. Clin Endocrinol (Oxf) 1985; 22: 713e21. 27 Barqawi A, Crawford ED. Testosterone replacement therapy and the risk of prostate cancer. Is there a link? Int J Impot Res 2006; 18: 323e8. 28 Rhoden EL, Morgentaler A. Testosterone replacement therapy in hypogonadal men at high risk for prostate cancer: results of 1 year of treatment in men with prostatic intraepithelial neoplasia. J Urol 2003; 170: 2348e51. 29 Morgentaler A. Testosterone therapy for men at risk for or with history of prostate cancer. Curr Treat Options Oncol 2006; 7: 363e9.
Practice points C C C C
C C C C
C
449
Repeated 9 a.m. testosterone levels used to guide therapy Definition of normal, low and borderline testosterone levels Use only when clearly indicated Consider a finite trial of testosterone for those with symptoms and a borderline testosterone Use appropriate route for the patient Use appropriate blood monitoring for each route Must monitor testosterone FBC, PSA and liver function Consider alternative routes of administration if patient develops side effects Testosterone does not have a major impact on prostate health but is contraindicated in invasive prostate cancer
Ó 2009 Elsevier Ltd. All rights reserved.
Testosterone replacement therapy
What’s new? C C
Leighton J Seal
C C C
Abstract
C
Testosterone replacement therapy is a well-tolerated and established treatment for hypogonadism, providing excellent clinical and biochemical relief from the effects of sex steroid deficiency. This review gives a practical clinical guide to managing testosterone replacement therapy. It outlines the indications for testosterone replacement, including the relevant testosterone threshold levels for treatment. There is also discussion of its use in non-gonadal illness such as HIV. Recent studies looking at the use of testosterone in cardiometabolic disease are discussed. The routes of administrating testosterone replacement therapy are summarized, with emphasis on the newer delivery systems that have become available recently. There is a discussion of the side effects of testosterone treatment including its effects on the prostate and haematological parameters. Finally, an outline of both safety and clinical testosterone level monitoring is presented.
C
result in hypoactive sexual desire disorder, which is characterized by low libido.5,6 Paediatrics In childhood, testosterone treatment causes growth of the genitalia. In boys with microphallus this has been utilized to assess the potential of penile growth and to improve penile size in infancy. Testosterone induces and maintains male secondary sexual characteristics and causes fusion of the epiphyses during growth. It can therefore be used to induce puberty when there is delay of this process and also to stop growth if a child is excessively tall.
Keywords ADAM; delayed puberty; hypogonadism; liver dysfunction; polycythaemia; prostate cancer; sarcopenia; testosterone; testosterone replacement therapy
Sarcopenia In HIV-related wasting, testosterone supplementation has been show to improve muscle strength7 and functional status.8 Therefore in HIV-related weight loss and sarcopenia it is recommended that a 3-month treatment with testosterone can be given but it should be no longer than this.9 In age-related sarcopenia, the evidence supporting the use of testosterone is contradictory and the risks of complications are higher, which means that the use of testosterone supplementation purely to improve functional status is questionable unless the patient has demonstrated hypogonadism.9
Indications There are many indications for testosterone replacement therapy but by far the most common is the treatment of male hypogonadism. Adult hypogonadism Testosterone therapy reverses the clinical features of hypogonadism. There is an increase in lean body mass and upper body strength1; there is a concurrent decrease in body fat, with increased muscle definition and a decrease in hip to waist ratio. In susceptible individuals, there is a loss of capital hair in a male pattern baldness distribution. There is an improvement in visio-spatial ability.2 General energy and drive increases and depression when present is reduced.3 Testosterone increases libido in both men and women.4,5 Testosterone can be very successful in treating libido disturbance in the context of hypogonadism, even in females where the testosterone deficiency seen post menopausally can
Female-to-male transsexualism Hormonal treatment is intrinsic to the management of gender dysphoria. Treatment should not be initiated without approval from a mental health practioner with a special interest in gender dysphoria.10 In female-to-male transsexuals, testosterone administered as an i.m. injection, once every 2e4 weeks, results in masculinization over 2e5 years. The aim of treatment is to get the testosterone levels into the normal male range.11 Sustanon has recently been licenced in the UK for this purpose. Osteoporosis Testosterone increases mineral deposition in the skeleton. It can increase bone mineral density in hypogonadism by 3.7%12 and there is a doseeresponse relationship between testosterone replacement therapy and the increase in bone mineral density.13
Leighton J Seal PhD FRCP is a consultant and Honorary Senior Lecturer in Endocrinology and Diabetes at St George’s Hospital, Tooting and also Consultant Endocrinologist at the Gender Identity Clinic at Charing Cross Hospital, London, UK. Competing interests: The author has been a speaker for Bayer Schering Pharmaceuticals and received fees for consulting for that company.
MEDICINE 37:9
New routes of administration Topical gel Long acting testosterone injection Use of testosterone in cardiometabolic disease Licensing of testosterone for transsexualism Use in HIV sarcopenia Testosterone appears not to increase the risk of prostate cancer
Cardiometabolic disorders Recent studies have shown that in heart failure, testosterone supplementation for men with borderline or low testosterone can
445
Ó 2009 Elsevier Ltd. All rights reserved.
SEX HORMONES
significantly improve their function capacity, improving by one or two New York Heart Association categories with treatment.14,15 In diabetes mellitus, testosterone supplementation for similar testosterone levels has resulted in improvement of HbA1C by 0.5e2.5%.16,17 It is too soon to recommend the general use of testosterone in these situations, but these areas are under active investigation.
testosterone levels, it can cause significant skin rashes due to an excipient that is included in the patch. This often limits its use. Testosterone in an alcohol-based gel gives good delivery of testosterone, with levels maintained in the physiological range throughout the day. With gels there is the risk of transfer of testosterone to other people for 6 hours after the gel is applied to the skin and so patients should be advised not to come into skinto-skin contact with another person during this time, especially with a female or prepubertal child. Testosterone tablets are rapidly absorbed from the gut but have a low bioavailablity. There is activation of the testosterone to dihydrotestosterone (DHT) by 5-alpha reductase, which is present in the gut lacteals, giving high DHT:testosterone levels. It can be effectively monitored only by measuring plasma DHT, not testosterone levels, and this assay is not widely available. It results in large testosterone swings on a daily basis which can have adverse effects on mood, energy and libido.
Initiation of testosterone therapy Because of the circadian rhythm of testosterone, levels must be measured in the morning at 9 a.m. to ensure they are reliable. It is also important to measure the testosterone on more than one occasion as up to 40% of abnormal testosterone values normalize on repeat testing. A total testosterone value of greater than 12 nmol/litre (providing there is normal sex hormone-binding globulin production) is normal and testosterone replacement is not indicated.18 Similarly a total testosterone level of less than 8 nmol/litre is considered hypogonadal and testosterone replacement is appropriate.18 This leaves a borderline plasma testosterone level between 8 and 12 nmol/litre, where testosterone replacement may be considered. In this situation the calculation of a free testosterone level can be useful. Using plasma total testosterone, albumin and SHBG levels it is possible to calculate both free and bioavailable testosterone levels. An easy-to-use calculator can be found at the website of the International Society for the Study of the Ageing Male.19 Free testosterone levels below 180 pmol/litre are hypogonadal and in those with levels of 180e250 pmol/litre a 12week trial of testosterone can be given, but it is important to review whether the patient has gained benefit from the treatment before continuing it on a more permanent basis.18
Monitoring The aim of monitoring is to maintain the plasma testosterone level within the physiological range for as long as possible with that particular preparation. Monitoring should be performed in the steady state, i.e. following at least four treatments. The monitoring requirements of each preparation are summarized in Table 1.
Safety monitoring The safety monitoring for this ongoing treatment is outlined in Table 2. This monitoring is designed to detect the major side effects of hormonal therapy.
Route
Side effects
There are many routes for the delivery of testosterone replacement. The active moiety is testosterone and so the pros and cons of each route are related to the differing pharmacokinetics of the preparations, which result in varying plasma testosterone levels with time (Table 1). The mainstays of testosterone replacement have been shortacting testosterone esters. They have many disadvantages, however, especially mood swings due to the constant waxing and waning of the testosterone levels they induce. They also have the highest incidence of polycythaemia, which is related to the amount of time that the plasma testosterone level is above the normal range. Recently a longer-acting preparation, testosterone undecanoate (NebidoÔ, Bayer Schering), has become available. This produces a much smoother testosterone profile and consequently a patient’s mood is generally more stable. There is a lower incidence of polycythaemia. Testosterone implants are small wax pellets that are inserted into a deep subcutaneous position, usually over the abdominal wall. The treatment involves a minor operative procedure using aseptic technique under local anaesthesia. There is a delay in the onset of action of 1e2 weeks post insertion but the procedure is very infrequent and plasma levels are kept within the physiological range for most of the 6-month period. There is only one patch preparation available in the UK: AndropatchÔ (Glaxo Smith Kline). Although it gives good
Polycythaemia Testosterone induces the production of erythropoietin and so red blood cells. The increase in blood viscosity can lead to an increased incidence of stroke in those who have a haematocrit above 50%.20 The development of polycythaemia appears to be proportional to the amount of supraphysiological testosterone that is administered. Polycythaemia usually responds to a decrease in the dose of testosterone, especially if this is changed to a non-injectable formulation. When this is inadequate, regular venesection to bring the haematocrit down into the normal range can be instituted.
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Liver dysfunction The incidence of hepatic dysfunction with alkylated steroid preparations such as methyl testosterone is high. There have been reported cases of fulminant hepatic failure.21 These anabolic steroids are no longer used in routine testosterone replacement. Abnormalities of liver function, with an incidence of up to 4.4%, has been reported in patients taking testosterone, so liver function test monitoring is required.22 Lipid profile In hypogonadism, reduced high-density lipoprotein, increased triglyceride and increased low-density lipoprotein cholesterol are present and these abnormalities are corrected when
446
Ó 2009 Elsevier Ltd. All rights reserved.
SEX HORMONES
A summary of the routes of administration of testosterone and required monitoring Preparation Short-acting testosterone injection C Testosterone enthanate (Proviron Ô) C Mixed testosterone esters (SustenonÔ) C Testosterone proprionate (VirormoneÔ) Long-acting testosterone
Dose Intramuscular injection 100e250 mg 2e4 weeks
Advantages Rapid onset Adequate plasma levels Avoids daily dosing
1000mg/12 weeks Loading: C Short-acting testosterone and Nebido 1000 mg C 6 weeks later Nebido 1000 mg C 6 weeks after that Nebido 1000 mg C Then 1000 mg/12 weeks Testosterone 600e 1200 mg/4e8 months Deep subcutaneous wax pellets inserted via a minor operation
Reduced frequency of injection Smoother testosterone profile Mood more stable Less polycythaemia
Testosterone patch AndropatchÔ.
Patch 5e10 mg per day
Testosterone gel TestogelÔ, TestimÔ, ProstrakenÔ
5e10 mg (1e2 packs)
Testosterone undecanoate C RestandolÔ
40e120 mg tds orally
No needles Testosterone level in physiological range Mimics circadian rhythm No needles Testosterone level in physiological range Mimics circadian rhythm Orally active
C
Testosterone undecanoate (NebidoÔ)
Testosterone implant
C
C
Very infrequent Smooth testosterone profile Low polycythaemia risk Good mood stability
Disadvantages Supra-physiological levels for 3e5 days Aggression Hypersexuality Polycythaemia Rapid decline in testosterone Variable mood Loading phase Oil embolism if injection is administered too quickly
Monitoring Peak levels (1 week after the injection) 25e30 nmol/litre Trough level (day the injection due, before the injection given) 8e12 nmol/litre
Delayed onset Minor operation 1 cm scar Bleeding Infection Extrudation of pellets Lack of energy and reduced libido prior to next pellet insertion Daily dosing Skin allergies Large patch
Testosterone levels 4, 5 and 6 months after pellet insertion Aim: 10e15 nmol/litre by next insertion
Testosterone level 4e6 hours after application Aim: 15e20 nmol/litre
Daily Time needed for gel to dry Transfer of testosterone
Testosterone level 4e6 hours after application Aim: 15e20 nmol/litre
Monitoring by DHT (assay not widely available) Large testosterone swings Variable:
DHT 4 hours after a dose Aim: 1e3 nmol/litre
C C C
Testosterone levels week 10, 11 and 12 before the 1st 12-week injection 10e15 nmol/litre
mood energy levels libido.
DHT, Dihydrotestosterone. Drug manufacturers: Proviron, Cambridge Laboratories; Sustenon, Organon; Virormone, Nordic; Nebido, Bayer Schering; Testosterone implant, Organon; Andropatch, Glaxo Smith Kline; Testogel, Bayer Schering; Testim, Ipsen; Tostran, ProStraken; Restandol, Organon.
Table 1
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Ó 2009 Elsevier Ltd. All rights reserved.
SEX HORMONES
Summary
Investigations and safety monitoring for testosterone replacement therapy
Testosterone replacement therapy is a well tolerated and established treatment for hypogonadism, which provides excellent clinical and biochemical relief from the effects of sex steroid deficiency. Recent advances in the delivery systems have made its use much more comfortable, convenient and capable of delivering more physiological levels of testosterone. A
Test Initial visit Diagnostic
Safety
LH FSH Testosterone SHBG Prolactin LFTs FBC (polycythaemia) PSA Lipid profile
REFERENCES 1 Wang C, Swerdloff RS, Iranmanesh A, et al. Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab 2000; 85: 2839e53. 2 Slabbekoorn D, Van Goozen SH, Megens J, Gooren LJ, CohenKettenis PT. Activating effects of cross-sex hormones on cognitive functioning: a study of short-term and long-term hormone effects in transsexuals. Psychoneuroendocrinology 1999; 24: 423e47. 3 Pope Jr HG, Cohane GH, Kanayama G, Siegel AJ, Hudson JI. Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial. Am J Psychiatry 2003; 160: 105e11. 4 Anastasiadis AG, Davis AR, Salomon L, Burchardt M, Shabsigh R. Hormonal factors in female sexual dysfunction. Curr Opin Urol 2002; 12: 503e7. 5 Buster JE, Kingsberg SA, Aguirre O, et al. Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Obstet Gynecol 2005; 105: 944e52. 6 Simon J, Braunstein G, Nachtigall L, et al. Testosterone patch increases sexual activity and desire in surgically menopausal women with hypoactive sexual desire disorder. J Clin Endocrinol Metab 2005; 90: 5226e33. 7 Bhasin S, Storer TW, Asbel-Sethi N, et al. Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels. J Clin Endocrinol Metab 1998; 83: 3155e62. 8 Kong A, Edmonds P. Testosterone therapy in HIV wasting syndrome: systematic review and meta-analysis. Lancet Infect Dis 2002; 2: 692e9. 9 Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2006; 91: 1995e2010. 10 Seal LJ. The practical management of adults with gender dysphoria. In: Barrett J, ed. Transsexual and other disorders of gender identity: a practical guide to management. Oxford: Radcliffe, 2007. 11 Mahmoud A, Comhaire FH. Mechanisms of disease: late-onset hypogonadism. Nat Clin Pract Urol 2006; 3: 430e8. 12 Isidori AM, Giannetta E, Greco EA, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol (Oxf) 2005; 63: 280e93. 13 Aminorroaya A, Kelleher S, Conway AJ, Ly LP, Handelsman DJ. Adequacy of androgen replacement influences bone density response to testosterone in androgen-deficient men. Eur J Endocrinol 2005; 152: 881e6. 14 Malkin CJ, Pugh PJ, West JN, et al. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial. Eur Heart J 2006; 27: 57e64.
Glucose Weight Blood pressure DRE (over 45 years) Follow-up visit Every 3 months titration Every 12 months stable Testosterone levels LFTs FBC (polycythaemia) PSA Lipids Weight Blood pressure DRE (over 45 years) DRE, digital rectal examination; LH, luteinizing hormone; FSH, folliclestimulating hormone; SHBG, sex hormone binding globulin; LFT, liver function test; FBC, full blood count; PSA, prostrate specific antigen.
Table 2
appropriate testosterone replacement is given.12,23 When supraphysiological treatment is used, as is seen in athletes who abuse testosterone, there is a reversal of the lipid parameters back to the adverse profile.24,25 Obstructive sleep apnoea Testosterone therapy exacerbates the symptoms of obstructive sleep apnoea and, more worryingly, increases the occurrence of cardiac arrhythmia in this condition.25,26 It is relatively contraindicated in this condition. Prostate neoplasia Prostate cancer is often considered the most worrying side effect of testosterone treatment but reassuringly, there is very little evidence that testosterone replacement to appropriate values in the physiological range is causative in prostate cancer development.27e29 Testosterone is contraindicated in active hormonal cancer, including breast and prostate cancer. In men who are taking testosterone replacement therapy, the development of prostate cancer must be routinely screened for by PSA and DRE monitoring.9
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SEX HORMONES
15 Pugh PJ, Jones RD, West JN, Jones TH, Channer KS. Testosterone treatment for men with chronic heart failure. Heart 2004; 90: 446e7. 16 Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006; 154: 899e906. 17 Boyanov MA, Boneva Z, Christov VG. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male 2003; 6: 1e7. 18 Nieschlag E, Swerdloff R, Behre HM, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males. ISA, ISSAM, and EAU recommendations. Eur Urol 2005; 48: 1e4. 19 Free & bioavailable testosterone calculator. International Society for the Study of the Ageing Male. Also available at: http://www.issam.ch/ freetesto.htm (accessed 28 Apr 2009). 20 Krauss DJ, Taub HA, Lantinga LJ, Dunsky MH, Kelly CM. Risks of blood volume changes in hypogonadal men treated with testosterone enanthate for erectile impotence. J Urol 1991; 146: 1566e70. 21 Wilder EM. Death due to liver failure following the use of methandrostenolone. Can Med Assoc J 1962; 87: 768e9. 22 van Kesteren PJ, Asscheman H, Megens JA, Gooren LJ. Mortality and morbidity in transsexual subjects treated with cross-sex hormones. Clin Endocrinol (Oxf) 1997; 47: 337e42. 23 Whitsel EA, Boyko EJ, Matsumoto AM, Anawalt BD, Siscovick DS. Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis. Am J Med 2001; 111: 261e9. 24 Hurley BF, Seals DR, Hagberg JM, et al. High-density-lipoprotein cholesterol in bodybuilders v powerlifters. Negative effects of androgen use. JAMA 1984; 252: 507e13. 25 Bhasin S. Effects of testosterone administration on fat distribution, insulin sensitivity, and atherosclerosis progression. Clin Infect Dis 2003; 37(Suppl 2): S142e9.
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26 Matsumoto AM, Sandblom RE, Schoene RB, et al. Testosterone replacement in hypogonadal men: effects on obstructive sleep apnoea, respiratory drives, and sleep. Clin Endocrinol (Oxf) 1985; 22: 713e21. 27 Barqawi A, Crawford ED. Testosterone replacement therapy and the risk of prostate cancer. Is there a link? Int J Impot Res 2006; 18: 323e8. 28 Rhoden EL, Morgentaler A. Testosterone replacement therapy in hypogonadal men at high risk for prostate cancer: results of 1 year of treatment in men with prostatic intraepithelial neoplasia. J Urol 2003; 170: 2348e51. 29 Morgentaler A. Testosterone therapy for men at risk for or with history of prostate cancer. Curr Treat Options Oncol 2006; 7: 363e9.
Practice points C C C C
C C C C
C
449
Repeated 9 a.m. testosterone levels used to guide therapy Definition of normal, low and borderline testosterone levels Use only when clearly indicated Consider a finite trial of testosterone for those with symptoms and a borderline testosterone Use appropriate route for the patient Use appropriate blood monitoring for each route Must monitor testosterone FBC, PSA and liver function Consider alternative routes of administration if patient develops side effects Testosterone does not have a major impact on prostate health but is contraindicated in invasive prostate cancer
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