Testosterone deficiency leads to
multiple problems but can be difficult
to diagnose. However, replacement
therapy can be rewarding and a life
changer for the patient.peer-reviewe

Cachia, Mario J.

English

OAR@UM

Throughout the ages, the search for eternal youth has led down many paths. The discovery of testosterone was, many believed the elixir which had, at long last, been found.  The medical use of testosterone, however, proved to be very challenging indeed and not quite the epitome of eternal youth as had been hoped for.1Physiological functions of testosterone include protein synthesis with anabolic effects on muscle, erythropoiesis and bone.2 It also favourably alters glucose and lipid metabolism.3 Testosterone promotes energy, drive, motivation, concentration and endurance.  It is also important in promoting psychosexual health and activity. All these are very important in promoting the well-being of the male individual.Men are usually considered not to be subject to andropause4,5 but testosterone levels do decline with age (about 1.2% per annum from the age of 40, with about 12% of men above the age of 50 reaching 50% by 80 years of age). The level at which testosterone deficiency in adults occurs is a hotly debated issue.  There are several reasons for this:1. different testosterone assays can give very variable testosterone levels; 2. investigators use different assays in their studies whilst also taking different cut-off points; 3. decreased libido and erectile dysfunction can occur at testosterone levels which vary from one individual to another. Matters are further complicated as testosterone levels, besides changing with age, are known to decrease with increasing body mass index; as well as increase for several hours after intercourse and also show diurnal variation. Given all the above problems, it is surprising that testosterone replacement therapy is ever initiated.6 Judicial use of testosterone replacement therapy will, however, improve the person’s well being, decrease the person’s cardiovascular risk parameters (although no large study has so far shown a decreased cardiovascular morbidity or mortality with therapy),7 improve muscle bulk, increase libido, correct erectile dysfunction (if there are no other causes e.g. long standing diabetes with neuropathy) and halt the decline of, or even improve, bone mineral density.Conditions which are increasingly being identified as associated with low testosterone levels include diabetes8-11 and the metabolic syndrome,8 increasing age,5 heart failure,12 and obesity.13,14 Given the variability of the assays and other variations as already mentioned above, the  indiscriminate clinical testing for testosterone deficiency is inappropriate.15 Targeting the correct, high risk individuals is the logical approach. Patients complaining of decreased libido and impotence should have a thorough history taking and examination looking for iatrogenic (e.g. beta-blocker therapy) or psychological causes prior to embarking on testosterone assay.  High risk conditions include:a. diabetes with another complaint e.g. impotence, decreased libido, decreased bone density, lethargy not explained by other causes;MEN’S HEAlTHTestosterone deficiency in the adult males“No, you rest now. Just to have you lift a finger was a great step forward.”MARIO J CACHIAAbstractTestosterone deficiency leads to multiple problems but can be difficult to diagnose. However, replacement therapy can be rewarding and a life changer for the patient.G.GM.MH.11.2011.0111 Date of preparation: November 2011.The long-lasting dose of  testosterone•   Nebido®  is the only long-acting  testosterone  injection  providing physiological  testosterone  levels with  4–5  injections  per year. 1•   Nebido®  treatment  reduces body fat  and waist  circumference. 2,3•   Nebido®  signicantly  improves  signs and symptoms  of testosterone  deciency syndrome,  such as libido, morning  erections  and mood changes. 4BSP02J11016_Nebido_Ad_A4_Master_V6_FAW.indd   1 28/11/2011   15:57urinary retention, prostatic intraepithelial neoplasia and prostatitis. Pulmonary microembolism of oily solutions can in rare cases lead to signs and symptoms such as cough, dyspnoea, malaise, hyperhidrosis, chest pain, dizziness, paraesthesia or syncope. Suspected anaphylactic reactions after Nebido injection have been reported. Other side effects - The following adverse reactions have been reported under treatment with testosterone-containing preparations: nervousness, hostility, sleep apnoea, various skin reactions including seborrhoea, increased frequency of erections, in rare cases, priapism, and, in very rare cases, jaundice. Therapy with high doses of testosterone preparations commonly reversibly interrupts or reduces spermatogenesis, thereby reducing the size of the testicles. Prescribers should consult the SmPC in relation to other side effects. Overdose: Reduce dose or terminate therapy. Incompatibilities: Must not be mixed with other medicinalproducts. Legal Category: POM. MA Number(s): 185/02701. MA Holder: Bayer plc, Bayer House, Strawberry Hill, Newbury, Berkshire, RG14 1JA, United Kingdom. Date of preparation: July 2012.References: 1. Minnemann T et al. Comparison of a newlong-acting testosterone undecanoate formulation vs testosterone enanthate for intramuscular androgen therapy in male hypogonadism. J Endocrinol Invest 2008;31(8):718–723. 2. Aversa A et al. Effects of testosterone undecanoate on cardiovascular risk factors and arthrosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study. J Sex Med 2010;7(10):3495–3503. 3. Saad F et al. An exploratory study of the effects of 12 month administration of the novel long-acting testosterone undecanoate on measures of sexual function and the metabolic syndrome. Arch Androl 2007;53(6):353–357. 4. Giltay EJ et al. Effects of testosterone supplementation on depressive symptoms and sexual dysfunction in hypogonadal men with the metabolic syndrome. J Sex Med 2010;7(7):2572–2582.Nebido® 1000 mg/4 ml, solution for injection (testosterone undecanoate)  Prescribing Information(Refer to full Summary of Product Characteristics (SmPC) before prescribing)Presentation: 1ml of solution contains 250 mg of testosterone undecanoate, corresponding to 157.9 mg of testosterone. Each 4ml ampoule of solution contains 1000 mg of testosterone undecanoate. Indication: Testosterone replacement therapy for male hypogonadism when testosterone deficiency has been confirmed by clinical features and biochemical tests. Posology and method of administration: Strictly for intramuscular use. Application: Inject Nebido® extremely slowly. One ampoule (1000mg) is injected intramuscularly every 10 to 14 weeks. Nebido® should be injected deeply into the gluteal muscle, and must be administered very slowly. Special care should be taken to avoid intravasal injection. The contents of an ampoule should be injected intramuscularly immediately after opening the ampoule – refer to the SmPC or PIL for instructions on openingthe ampoule safely. Starting treatment: Measure serum testosterone levels before the start and during initiation of treatment. If appropriate, first injection interval may be reduced to a minimum of 6 weeks. Maintenance: Injection interval within 10 to 14 week range. Monitor serum testosterone and symptoms regularly; adjust injection interval as appropriate. Paediatric population: Not for use in children. Not evaluated clinically in males under 18. Geriatric patients: Based on limited data, no dose adjustment is considered necessary. Contraindications: Androgen-dependent prostate cancer or breast cancer. Past or present liver tumours. Hypersensitivity to testosterone or any of the excipients. Not for use in women. Warnings and precautions: Use only if hypogonadism has been demonstrated and if other etiology has been excluded. Limited experience in patients over 65. Before therapy exclude prostate cancer. Examine prostate and breast at least annually, or twice yearly in elderly or at risk patients (clinical or familial factors). Periodically check testosterone concentrations, haemoglobin, haematocrit and liver function tests. Androgens may accelerate the progression of sub-clinical prostate cancer and benign prostatic hyperplasia. Use with caution in cancer patients at risk of hypercalcaemia (and associated hypercalciuria), due to bone metastases. Regular monitoring of serum calcium concentration is recommended in these patients. Rarely, liver tumours (both benign and malignant) have been reported. Include liver tumour in differential-diagnostic considerations if severe upper abdominal complaints, liver enlargement or signs of intra-abdominal haemorrhage occur. Efficacy and safety of Nebido® has not been demonstrated in patients with hepatic and renal impairment, therefore testosterone replacement therapy should be used with caution in these patients. Nebido® may cause oedema with or without congestive cardiac failure in patients with severe cardiac, hepatic or renal insufficiency, or in patients with ischaemic heart disease. In this case, stop treatment immediately. Use with caution in patients predisposed to oedema, with epilepsy, migraine or blood clotting irregularities. Improved insulin sensitivity may occur. Irritability, nervousness, weight gain, prolonged or frequent erections may indicate excessive androgen exposure requiring dose adjustment. Preexisting sleep apnoea may be potentiated. Testosterone may produce a positive reaction in anti-doping tests. Not suitable for developing muscles or increasing fitness in healthy individuals. Withdraw treatment if symptoms of excessive androgen exposure persist or reappear. Interactions: Interactions reported with oral anticoagulants (requires dose monitoring), ACTH or corticosteroids, and thyroxin binding globulin in laboratory tests. Pregnancy and lactation: Not for use in women. Effects on ability to drive and use machines: None known. Undesirable effects: Common – injection site pain, acne, polycythaemia, increased weight, hot flush, increased prostate specific antigen, abnormal prostate examination, benign prostate hyperplasia and various injection site reactions. Serious side effects – cf. CI/Warnings and Precautions – in addition, hypersensitivity, cardiovascular disorder, depression, aggression, hypertension, liver function test abnormalities,                                                           MT G.GM.MH.11.2011.011110b. obese individuals with erectile dysfunction;c. ‘non-intermittent’ impotence or lack of morning tumescence;  d. osteoporosis. In a male this should always lead to an evaluation of testosterone levels as part of the investigations.Most recent studies consider a total testosterone level of around 8 nmol/l as being the cut-off point for testosterone deficiency16,17 if certain criteria are met i.e. the sample is taken at around 10am and the individual has refrained from sexual activity for the past 24 hours. Once the diagnosis is made, then appropriate therapy has to be initiated.  Testosterone replacement may not always be the appropriate therapy. For example, consider the case of a widowed 74 year old male with osteoporosis and prostate problems. The appropriate therapy here is treatment directed at the osteoporosis – testosterone therapy may exacerbate the prostate problem, and if he has no desire for sexual activity, may be totally inappropriate. For patients for whom testosterone therapy has been considered appropriate, then there are several options available, not all of which are available locally. Testosterone by oral route, although once popular has now References1. Shalender Bhasin GRC, Frances J. Hayes. Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline. 2010.2. Tuck SP, Francis RM. Testosterone, bone and osteoporosis. Frontiers of Hormone Research. 2009;37:123-32. PubMed PMID: 19011293. 3. Volpato S, Vigna GB, Fellin R. The benefit and risk of testosterone replacement therapy in older men: effects on lipid metabolism. Acta Bio-Medica de l Ateneo Parmense. 2010;81 Suppl 1:95-9. PubMed PMID: 20518198. 4. Wu CY, Yu TJ, Chen MJ. Age related testosterone level changes and male andropause syndrome. Chang Gung Med J. 2000 Jun;23(6):348-53. PubMed PMID: 10958037. 5. Leifke E, Gorenoi V, Wichers C, Von Zur Muhlen A, Von Buren E, Brabant G. Age-related changes of serum sex hormones, insulin-like growth factor-1 and sex-hormone binding globulin levels in men: Cross-sectional data from a healthy male cohort. Clinical Endocrinology. 2000;53(6):689-95. PubMed PMID: 2001037037. 6. Behre HM, Christin-Maitre S, Morales AM, Tostain J. Transversal European survey on testosterone deficiency diagnosis. Aging Male. 2012;15(2):69-77. PubMed PMID: 22380815. 7. Nigro N, Christ-Crain M. Testosterone treatment in the aging male: myth or reality? Swiss Medical Weekly. 2012;142:w13539. PubMed PMID: 22430839. 8. Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: Prospective results from the Massachusetts Male Aging Study. Diabetes Care. 2000;23(4):490-4. PubMed PMID: 2000124275.  9. Schipf S, Haring R, Friedrich N, Nauck M, Lau K, Alte D, et al. Low total testosterone is associated with increased risk of incident type 2 diabetes mellitus in men: results from the Study of Health in Pomerania (SHIP). Aging Male. 2011;14(3):168-75. PubMed PMID: 21039324.10. Ogbera OA, Sonny C, Olufemi F, Wale A. Hypogonadism and subnormal total testosterone levels in men with type 2 diabetes mellitus. Jcpsp, Journal of the College of Physicians & Surgeons - Pakistan. 2011;21(9):517-21. PubMed PMID: 21914405.11. Li H, Kong XB, Zhang HL, Wu J. Testosterone Levels in Males with Type 2 Diabetes and Their Relationship with Cardiovascular Risk Factors and Cardiovascular Diseases. Journal of Sexual Medicine. 2011 April;8(4):1260. PubMed PMID: 2011184024.12. Florvaag A, Oberle V, Fritzenwanger M, Kretschmar D, Betge S, Goebel B, et al. Testosterone deficiency in male heart failure patients and its effect on endothelial progenitor cells. Aging Male. 2012 September;15(3):180-6. PubMed PMID: 2012471670.13. Biswas M, Hampton D, Newcombe RG, Rees DA. Total and free testosterone concentrations are strongly influenced by age and central obesity in men with type 1 and type 2 diabetes but correlate weakly with symptoms of androgen deficiency and diabetes-related quality of life. Clinical Endocrinology. 2012 May;76(5):665-73. PubMed PMID: 2012209658.14. Mogri M, Dhindsa S, Ghanim H, Dandona P, Quattrin T. Testosterone concentration in obese young males. Diabetes. 2011 July;60:A345. PubMed PMID: 70629016.15. Bain J. Testosterone and the aging male: to treat or not to treat? Maturitas. 2010;66(1):16-22. PubMed PMID: 20153946.  16. Anawalt BD, Hotaling JM, Walsh TJ, Matsumoto AM. Performance of total testosterone measurement to predict free testosterone for the biochemical evaluation of male hypogonadism. Journal of Urology. 2012 April;187(4):1369-73. PubMed PMID: 2012165588.17. Crewther BT, Lowe TE, Ingram J, Weatherby RP. Validating the salivary testosterone and Cortisol concentration measures in response to short high-intensity exercise. Journal of Sports Medicine and Physical Fitness. 2010 March;50(1):85-92. PubMed PMID: 20308978.18. Feneley MR, Carruthers M. Is Testosterone Treatment Good for the Prostate? Study of Safety during Long-Term Treatment. Journal of Sexual Medicine. 2012 August;9(8):2138-49. PubMed PMID: 2012455538.  lost favour because of problems with hepatic first pass metabolism and erratic serum levels.  Testosterone gels and patches utilise the cutaneous route of administration and are fairly popular, but require at least a daily application.  The main problem is transfer of testosterone to a female partner (possibly also to minors in the family) if the proper precautions are not taken.  Parenteral testosterone esters are perhaps the most popular, although not always legitimately used e,g, in body building and other performance sports.  Most companies are now discontinuing most of these esters, causing supply and therapy problems. This has mainly arisen as a consequence to the ‘hacking’ of the Chinese undecanoate ester to the European market. This product only requires an injection at approximately three monthly intervals. Its rise in popularity has resulted in companies discontinuing production of other esters. Various other modes of administration are at present under review, such as implants. Side effects are relatively few and mild if used appropriately. The most common is polycythaema, which often requires a decrease in dose and sometimes necessitates discontinuation of therapy. Liver dysfunction is probably the second most common side-effect.  Uncontrollable rage and aggression has been reported, but is usually related to supra-pharmacological doses in abuse.   Prostate problems, although often cited, are probably not an issue. No study has really shown an increase in prostate problems, including prostate cancer.  In addition some studies have shown that the testosterone receptors on the prostate are easily saturated, so testosterone therapy does not really increase prostatic stimulation.18 Testosterone replacement can be a rewarding therapy, however, the pitfalls in diagnosis are such that specialist advice should be sought prior to initiation of any such therapy.  Testosterone deficiency leads to multiple problems but can be difficult to diagnose. However, replacement therapy can be rewarding and a life changer for the patient12

Is Testosterone Treatment Good for the Prostate? Study of Safety during Long-Term Treatment.

Performance of total testosterone measurement to predict free testosterone for the biochemical evaluation of male hypogonadism.

Rees Clinical Endocrinology.

Testosterone and the aging male: to treat or not to treat?

Testosterone concentration in obese young males. Diabetes.

Testosterone deficiency in male heart failure patients and its effect on endothelial progenitor cells. Aging Male.

Testosterone Levels

Validating the salivary testosterone and Cortisol concentration measures in response to short high-intensity exercise.

Testosterone deficiency in the adult males

https://www.um.edu.mt/library/oar/bitstream/handle/123456789/12953/Testosterone%20deficiency%20in%20the%20adult%20males.pdf?sequence=1&isAllowed=y

Testosterone deficiency in the adult males

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