Hypogonadism and testosterone replacement

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  • The testes are under the control of hormones released in the brain by the hypothalamus and the pituitary gland.
    At puberty, the hypothalamus increases secretion of gonadotrophin-releasing hormone (GnRH), which stimulates the pituitary gland to release the two gonadotrophins, leutinising hormone (LH) and follicle stimulating hormone (FSH). FSH controls the production of spermatozoa in the seminiferous tubules while LH stimulates the production of testosterone by the Leydig cells.GnRH is secreted in pulses every 1.5 to 2 hours. The frequency and amplitude of these pulses is under the control of several factors, including testosterone, oestradiol and inhibin B, which produce negative feedback effects. Two hormones released under stress – corticotrophin-releasing hormone and prolactin also produce a negative feedback effect on GnRH secretion; this effect of stress on reproductive health is well known. The frequency and amplitude of these pulses influence the amounts of LH and FSH that are secreted by the pituitary gland. Inhibin B shows a pronounced inverse correlation with FSH serum levels, however whether or not secretion of inhibin B is under the control of FSH remains to be clarified.1,2
    1. Nieschlag E & Behre HM. Andrology, Male reproductive health and dysfunction (2nd Edition). Springer, Heidelberg; 2002.
    2. Jöckenhovel F. Male Hypogonadism. UNI-MED, Bremen; 2004.
  • By itself, and via its main metabolites, dihydrotestosterone (DHT) and estradiol, testosterone exerts an influence on many physical and mental functions in men.
    Together, testosterone and its metabolites act by stimulation or inhibition of various target organs, such as the sex organs, accessory glands, bones, muscles, bone marrow, the brain, skin and hair.1,2
    How varied the effects of testosterone on the body can be is seen in the range of disorders which can appear as a result of testosterone deficiency.
    1. Jöckenhovel F. Male Hypogonadism. UNI-MED, Bremen; 2004.
    2. Nieschlag E & Behre HM. Andrology, Male reproductive health and dysfunction (2nd Edition). Springer, Heidelberg; 2002.
  • In the blood, 98% of testosterone is bound to transport proteins, and only 2% is free and hence biologically active.
    Approximately 60% of the circulating testosterone is bound with high affinity to the globulin sex hormone binding globulin (SHBG), and 38% is loosely bound and transported by albumin. SHBG shows a higher affinity for testosterone than estradiol. Thus, increased production of SHBG by the liver causes a shift in the ratio of testosterone to estradiol by reducing the amount of free testosterone.1
    Since androgens reduce SHBG production, men have lower serum concentrations of SHBG than women. However, SHBG may be raised in men with testosterone deficiency. Other factors that influence SHBG production include: oestrogen intake, growth hormone deficiency, cirrhosis, ageing, thyrotoxicosis, antiepileptic drugs (increase SHBG production); being overweight, hypothyroidism, hyperinsulinism (decrease SHBG production). 1
    Several lines of evidence suggest that not only free testosterone, but also albumin-bound testosterone is available to the target tissues, in case of an increased need for testosterone. Therefore, the non-SHBG-bound testosterone is called ‘bioavailable testosterone’ (i.e. bioavailable = free + albumin-bound).
    Free testosterone mediates androgenic effects, which are exerted at target organs via stimulation of the androgen receptor (a member of the superfamily of nuclear receptors).
    The actions of testosterone are also mediated through conversion to active metabolites such as dihydrotestosterone (DHT) and estradiol.1
    1. Jöckenhovel F. Male Hypogonadism. UNI-MED, Bremen;2004.
  • Hypogonadism is defined as an inadequate function of the testes in man.1
    1. Jöckenhovel F. Male Hypogonadism. UNI-MED, Bremen; 2004.
  • Male hypogonadism is a descriptive clinical syndrome complex arising from biochemical androgen deficiency characterised by impaired androgenic functions and reduced circulating levels of testosterone.
    The deficiency state adversely affects functions of multiple androgen-dependent organ systems, giving rise to short and long-term morbidity with loss of quality of life, which responds to testosterone replacement.
    Male hypogonadism is usually caused by disease conditions of the testis or dysfunction of the hypothalamic-pituitary-testicular axis.1
    1. Jöckenhovel F. Male Hypogonadism. UNI-MED, Bremen; 2004.
  • These physical symptoms experienced by men with hypogonadism are a consequence of androgen deficiency.In addition to the effects on the reproductive system, there are a number of general effects of testosterone deficiency as illustrated above. There are also several conditions associated with androgen deficiency including osteoporosis, CHD and diabetes.
    However, it is important to note that a man with hypogonadism will not necessarily present with all of these symptoms. Assessment of the above symptoms can be used as a guide in the diagnosis of hypogonadism.
  • Hypogonadism is classified depending on the underlying cause.If testicular failure has occurred, the condition is termed primary hypogonadism or primary testicular failure. Because there is no deficiency of gonadotrophins (levels are usually increased), it is also referred to as hypergonadotrophic hypogonadism.1Secondary hypogonadism or secondary testicular failure occurs as a result of hypothalamic-pituitary disease. Because there is a deficiency of gonadotrophins, it is also referred to as hypogonadotrophic hypogonadism.1A third type of hypogonadism is age-related, or related to systemic disease and is regarded as a combined condition of primary or secondary testicular failure. This is called Late-Onset Hypogonadism, or LOH for short.2 It is important to distinguish between the different types of hypogonadism, as the prognosis and therapy will differ.
    There is no single test for hypogonadism. Because classification of the disease is so important, there must be a full historical, physical and laboratory assessment before any diagnosis is made. Questionnaires may be a useful diagnostic tool in certain circumstances.
    1. Nieschlag E & Behre HM. Testosterone: action, deficiency, substitution (3rd Edition). Cambridge University Press, Cambridge; 2004.
    2. Nieschlag E et al. Eur Urol 2005;48:1-4.
    3. Bhasin et al. J Clin Endo Metab 2006;91:1995-2010.
  • Klinefelter’s syndrome is caused by one or more extra X-chromosomes, and 80% of patients display the classic karyotype 47, XXY. It is not known why the additional X-chromosome impairs testicular function. The signs of Klinefelter’s syndrome are almost unnoticeable in childhood, and the majority of patients undergo puberty normally and lead a normal social and married life. Gynaecomastia occurs in approximately half of all patients, and is associated with an increased incidence of breast cancer. There is no cure for the underlying chromosome disorder, however it is possible to help some men with Klinefelter’s syndrome to become fathers by assisted reproduction and surgical sperm recovery.2
    Androgen insensitivity
    A deficiency of androgen receptors in the target organs may present with the clinical features of hypogonadism. The hypothalamic-pituitary-testicular axis responds by secreting high levels of testosterone and LH
    2. Lanfranco F et al. Lancet 2004;364:273-283.
  • Kallman’s is a rare condition affecting the hypothalamus. When functioning normally, the hypothalamus secretes several releasing hormones to the pituitary gland. In Kallman’s syndrome, the hypothalamus is dysfunctional and cannot secret GnRH to the pituitary gland. As a result, the pituitary gland is unable to send either LH or FSH to the testes. Symptoms of Kallman’s syndrome are: absent sense of smell (anosmia), failure to enter puberty, lack of sexual drive and infertility.1
    Treatment of Kallman’s syndrome is directed at restoring the deficient hormones. Men are administered human chorionic gonadotrophin (hCG) or testosterone. To induce fertility in men, GnRH is administered by an infusion pump or hCG/FSH/LH combinations are administered through regular injections.
    1. Nieschlag E & Behre HM. Andrology, Male reproductive health and dysfunction (2nd Edition). Springer, Heidelberg; 2002.
  • In recent years, there has been increased awareness that many common systemic diseases as well as physiological states, such as ageing, can impair functions of the hypothalamic-pituitary-testicular axis resulting in low levels of circulating testosterone.
    The long-term consequences of these situations are still unclear. It is also unclear as to whether testosterone levels decrease as a consequence of aging in healthy males or the decrease is as a result of previous illness.
    The graph illustrates the decline in total testosterone and free testosterone levels with age, and the associated increase in SHBG levels. The factors that influence the increase in SHBG levels are still under discussion, but may include low levels of insulin-like growth factor I (IGF-1).1
    Recent guidelines for the treatment of late-onset hypogonadism (LOH) have been published jointly by the EAU (European Association of Urology), ISA (International Society of Andrology) and ISSAM (International Society for the Study of the Aging Male). These guidelines define LOH as ‘a clinical and biochemical syndrome associated with advancing age and characterised by typical symptoms and a deficiency in serum testosterone levels. It may result in significant detriment in the quality of life and adversely affect the function of multiple organ systems.1,2
    1. Vermeulen A et al. J Clin Endocrinol Metab 1996;81:1821-1826.
    2. Nieschlag E et al. Eur Urol 2005;48:1-4.
  • The Massachusetts Male Aging Study (MMAS) is an observational cohort study of health in a population-based, random sample of men. A total of 1709 respondents enrolled in the study and completed the baseline criteria.
    The slide presents the results of a study of MMAS aimed at providing estimates of the overall and age-specific prevalence and incidence of hypogonadism in a randomly sampled population-based cohort of middle-aged and older men. Data on androgen deficiency (defined using both signs/symptoms plus total and calculated free testosterone) were available for 1691 men at baseline (1987-1989) and 1087 at follow-up (1995-1997). The graph summarises the incidence of androgen deficiency by age and overall for 1087 men at follow-up.
    The data obtained were used to project the future number of cases of androgen deficiency.
    Estimates of prevalence of androgen deficiency at baseline and follow-up were 6.0 and 12.3% respectively. Both incidence and prevalence of hypogonadism increased significantly with age.
    Results were used to compute the expected annual incidence of hypogonadism in older men.1
    1. Araujo A et al. J Clin Endocrinol Metab 2004;89(12):5920-5926.
  • As discussed in the following slides, a number of recent epidemiological studies have revealed that hypogonadism often occurs concomitantly with other known risk factors that contribute to the metabolic syndrome, raising the question as to whether low testosterone itself may be a component of metabolic syndrome.
    The metabolic syndrome is an umbrella term for a cluster of cardiovascular risk factors, including type 2 diabetes, dyslipidaemia, abdominal obesity and hypertension. The definition of ‘the metabolic syndrome’ is hotly debated. The National Cholesterol Education Program’s Third Adult Treatment Panel (NCEP ATP III), World Health Organization (WHO) and the International Diabetes Federation (IDF) all offer different definitions of the metabolic syndrome.1-3
    However, there are certain similarities that can be extracted for practical use:4
    European men: Waist circumference ≥94cm plus two of the following:
    Raised triglyceride level >1.7mmol/l.
    Reduced high-density lipoprotein cholesterol (HDL-C) <1.0mmol/l.
    Blood pressure >130/85 mm Hg or on treatment for hypertension.
    Raised fasting glucose ≥ 5.6 mmol/l.
    1. Jackson G. Eur Urol 2006;50:426-7..
    2. Grundy SM et al. Circulation 2004;109:433-438.
    3. World Health Organisation. Definition, diagnosis and classification of diabetes mellitus and its complications. 1999;WHO, Geneva, Switzerland.
    4. International Diabetes Federation. The IDF consensus worldwide definition of the metabolic syndrome; online: www.idf.org/webdata/docs/Metac_syndrome_def.pdf. Accessed June 2006.
  • This study was conducted in the United States among men with type 2 diabetes, who were being seen for management of their diabetes. Men previously identified as hypogonadal were excluded.1
    Free testosterone, total testosterone and bioavailable testosterone were measured for all patients. Depending on the testosterone measure, prevalence of hypogonadism ranged from 33% to 44% among this cohort of 103 patients.1
    Results of this study demonstrate the importance of carefully monitoring testosterone levels and verifying clinical symptoms prior to diagnosis of hypogonadism.1
    1. Dhindsa S et al. J Clin Endocrinol Metab 2004; 89(11): 5462-5468.
  • This study demonstrates the increased risk associated with having multiple risk factors, a fact which is well known from cardiovascular studies. The previous slides have demonstrated the increased prevalence of hypogonadism (defined as total testosterone ≤12 nmol/l) associated with having type 2 diabetes, or with having ED. This slide shows the cumulative effect of having both conditions: just over one-fifth of non-diabetic ED patients have testosterone levels within the hypogonadal range, whereas this figure increases to just over one-third in patients who have diabetes and ED.1
    1. Corona G et al. Eur Urol 2004; 46(2): 222-228.
  • Testosterone release is pulsatile (f=~2hrs) and exhibits diurnal variation
    Blood samples should be taken between 7.00 and 11.00 am, and repeated at an interval of 2 weeks when a low level is identified.
    Consistent results are needed to make a diagnosis.
    Laboratory “reference” ranges for testosterone are statistically derived.
    Most statistically-derived reference ranges do not take into account emergence of deficiency symptoms as levels decline.
    Symptom emergence is variable between individuals, at least in part because of the variable nature of the testosterone receptor.
    Different symptoms seem to emerge at different threshold levels, even with levels as high as 15 nmol/l.
    It is also important to bear in mind the effects of ageing on testosterone levels, which show a decline with age.1
    1. Nieschlag E & Behre HM. Andrology, Male reproductive health and dysfunction (2nd Edition). Springer, Heidelberg; 2002.
  • This slide presents a potential algorithm to guide diagnosis of hypogonadism.
    There is no reliable index of androgen action in vivo, therefore measurement of testosterone is the main index to guide clinical decision making in these patients.
    Total testosterone level is the most common starting point towards diagnosis. Testosterone should be measured in the morning to avoid the diurnal variation which can cause misdiagnosis.1,2
    To date, there is no general consensus regarding the threshold level of total testosterone below which hypogonadism can be diagnosed.
    A total testosterone level of <8nmol/l is generally regarded as compatible with hypogonadism.1,2
    The Endocrine Society guidelines (USA) recommend that pituitary imaging (MRI) should be performed to exclude pituitary and/or hypothalamic tumour or infiltrative disease in patients with severe secondary hypogonadism (testosterone <150 ng/dl (<5.2 nmol/l)), panhypopituitarism, persistent hyperprolactinaemia, or symptoms or signs of tumour mass effect (such as headache, visual impairment, or visual field defect).2
    A total testosterone level of >12nmol/l is considered unlikely as indicating presence of hypogonadism.1,2
    A total testosterone level of between 8-12nmol/l is indicative of hypogonadism, but further investigation and laboratory tests are required to facilitate diagnosis.1,2
    1. Nieschlag E et al. Eur Urol 2005;48:1-4.
    2. Bhasin S et al. J Clin Endocrinol Metab 2006;91(6):1995-2010.
  • Where clinical features of hypogonadism are present, measuring prolactin and gonadatrophins may facilitate the diagnosis. Measurement of SHBG and assessment of comorbid conditions (e.g. ageing, hypothyroidism, hepatic cirrhosis, obesity) may also be useful. It is important to consider factors that may increase SHBG levels (e.g. ageing), when interpreting laboratory test results, as the free testosterone level depends on this.1,2
    Free testosterone can also be calculated from SHBG, total testosterone and albumin (see www.issam.ch/freetesto.htm). Consistently low levels of free testosterone may assist diagnosis.
    It is generally agreed that total T levels >12 nmol/L (>346 ng/dL) or free T >250 pmol/L (72 pg/dL) do not require testosterone therapy. There is consensus that serum total T <8 nmol/L (<231 ng/dL) or free T <180 pmol/L (52 pg/dL) require substitution. However, symptoms of testosterone deficiency may become manifest below 12-15 nmol/L3
    The decision to treat symptomatic patients with no identifiable cause of hypogonadism within the hypothalamic-pituitary-testicular axis remains a difficult clinical challenge, due to lack of widespread evidence concerning the benefits and risks of treatment.
    Following discussion with the patient, a trial of treatment for 6 months could be considered followed by evaluation of response and reappraisal of diagnosis.
    1. Nieschlag E et al. Eur Urol 2005;48:1-4.
    2. Bhasin S et al. J Clin Endocrinol Metab 2006;91(6):1995-2010
    3. Zitzmann M et al. JCEM 2006;91:4335-4343
  • Correction of the symptoms of androgen deficiency is the central treatment goal, and this can be achieved by administering testosterone therapy.Primary hypogonadism may be treated with testosterone treatment alone. It is usually not possible to restore fertility in men with primary testicular failure.Men with secondary hypogonadism may benefit from treatment with gonadotrophins or GnRH if fertility is required, otherwise they should also receive testosterone replacement.
    The contraindications and recommended monitoring guidelines for patients on testosterone therapy are discussed in a later section.
  • This randomised, placebo-controlled, double-blind study compared the efficacy of testosterone gel (Androgel®) versus placebo as adjunctive therapy to sildenafil 100mg in hypogonadal men with ED who did not respond to sildenafil alone.1
    Seventy-five hypogonadal men (total testosterone 400 ng/dl), with a confirmed lack of response to sildenafil 100mg, were randomised to receive a daily dose of 1% testosterone gel or placebo, in addition to their sildenafil treatment.
    The primary efficacy measure was the erectile function domain of the IIEF.
    Throughout the study patients receiving testosterone gel with sildenafil had greater improvement in erectile function than those who received sildenafil and placebo gel. This difference reached statistical significance at week 4.
    1. Shabsigh R et al. J Urol 2004;172:658-663
  • Testosterone therapy has been in use since the 1930’s, and can largely reverse the effects of androgen deficiency.This slide presents the European launch dates for the products: availability in the UK may have been slightly later.
    As well as restoring the male secondary sexual characteristics, testosterone may prevent complications of androgen deficiency such as osteoporosis.
    What do we require from a testosterone therapy?To reproduce physiological testosterone levels, and ideally we also want to maintain the normal daily fluctuation whilst minimising excursions outside the normal physiological range.Testosterone therapy alleviates the symptoms of androgen deficiency, and plays a role in preventing long-term complications such as osteoporosis.And finally, something that should not be overlooked is ease of administration and patient compliance. An ideal preparation is suited to the patient, allowing him to receive therapy with little or no disruption to his normal life.
  • Free, unesterified testosterone is biologically inactive. Although it is absorbed well from the gut, it is effectively metabolised and inactivated in the liver (first-pass effect) before it reaches the target organs. Only when a high dose (such as 200mg of free testosterone) is ingested, do serum testosterone levels become measurable. This dosage of testosterone exceeds the physiological production rate of testosterone by some 30-fold, which involves a heavy hepatic load. The hepatic capacity to metabolise testosterone is age and sex dependent.1
    When esterified in the 17β-position with the long chain fatty acid, undecanoic acid, and incorporated into a capsule with oleic acid (Restandol®), the route of absorption from the gastrointestinal tract is shifted from the portal vein to the thoracic duct. Because of its long aliphatic chain it travels with lipids in the lymph and reaches the general circulation via the subclavian vein, avoiding a first pass through the liver and subsequent metabolism. For adequate absorption from the gastrointestinal tract it is essential that oral testosterone undecanoate is taken with a meal that contains dietary fat. Without dietary fat the resorption and the resulting serum levels are minimal.1
    After oral ingestion of 40mg Restandol, the maximum serum testosterone level is reached in 2-6 hours. Therapeutic testosterone levels can be achieved by taking 40mg three times daily,2 which results in fluctuating serum testosterone levels, that show great intra- and inter-individual variability.1
    A new formulation of testosterone undecanoate in castor oil rather than oleic acid (Andriol® TestocapsTM) has improved the stability of this compound.
    1. Gooren LJG et al. Drugs 2004. 64(17):1861-1891.
    2. Organon Laboratories Limited. Restandol® SPC; May 1998.
  • One buccal testosterone preparation is available (Striant®). Striant is a mucoadhesive buccal system applied twice daily, which is designed to adhere rapidly to the buccal mucosa and to gellify (but not dissolve), releasing testosterone steadily into the circulation, and thereby bypassing the liver.1
    The tablets are curved on one side and have one flat side.
    In a pharmacokinetic study of 82 men applying 30mg tablets twice daily at 12-hour intervals, 86.6% patients reached an average testosterone concentration over 24 hours within the physiological range.2
    1. Ardana Bioscience. Striant® SPC; March 2005
    2. Wang C et al. J Clin Endo Metab 2004;89(8):3821-3829
  • Implants of crystalline testosterone have been used for androgen replacement for nearly five decades.
    Implants are cylindrical and inserted under local anaesthetic into subcutaneous tissue by means of a trochar through a small skin incision either in the abdominal wall or buttock. Testosterone is released by surface erosion from the implant and absorbed into the systemic circulation. Between 600mg and 1.2g (3 to 6 pellets) can maintain serum testosterone concentrations in the middle to high-normal range for four to six months.2
    1. Organon Laboratories Ltd. Testosterone implant 200mg – Summary of Product Characteristics. May 1999.
    2. Nieschlag E et al. Human Reproduct Update 2004; 10(5):409-419.
  • Various transdermal patches are available, including scrotal patches.
    Andropatch® (2.5 or 5mg) applied daily provides a circadian profile of testosterone delivery.1
    Andropatch is applied at night (10pm) to clean, dry, unbroken skin on the back, abdomen, upper arms or thighs, removed after 24 hours and the replacement patch put on in a different area (recommended interval of 7 days before re-using the same application site).1
    Initially patches are applied equivalent to 5mg testosterone/24 hours, but the dose can be increased or decreased according to plasma testosterone levels.1
    Skin irritation is not uncommon, affecting >50% of patients.2
    1. GlaxoSmithKline UK. Andropatch® 5mg SPC; August 2002.
    2. Gooren LJG et al. Drugs 2004. 64(17):1861-1891.
  • Topical gel preparations also provide physiological profiles of testosterone, with regimens that mimic the natural diurnal patterns of testosterone release.
    Both Testogel® and Testim ® are easy to apply, although there are restrictions in the first six hours after application in terms of showering and swimming, as these could interfere with the bioavailability.1,2
    The gel is applied thinly onto clean, dry healthy skin, such as shoulders, arms or abdomen, immediately after the pack is opened. Gel should not be applied to the genital area as the high alcohol content may cause local irritation. The gel should be allowed to dry for 3-5 minutes prior to dressing.1,2
    Daily administration is necessary. Following a single daily application onto the skin, Testogel provides continuous delivery of testosterone into the bloodstream for 24 hours. After steady-state testosterone levels have been achieved, the daily variation in testosterone level will be of a similar magnitude to the normal daily variation in healthy men.1
    There is a risk of passive transfer within the first six hours, and patients should be instructed on how to avoid contact with gel application sites by other people, especially pregnant women and children.1,2
    The blood testosterone level begins to increase in the first hour after treatment with Testogel or Testim, and from day 2 it will have reached steady state.1,2
    1. Schering Health Care Limited. Testogel ® 50mg SPC; February 2004.
    2. Ipsen Ltd. Testim ® 50mg SPC; August 2004.
  • Sustanon 250 (testosterone propionate 30mg, testosterone phenylpropionate 60 mg, testosterone isocaproate 60 mg, testosterone decanoate 100mg/ml in arachis [peanut] oil) is the more widely used short-acting injectable preparation, which has been available in the UK since 1973.1
    Sustanon 250 is injected every 3 weeks, although some patients may require more/less frequent injections depending on testosterone levels. Similarly to Sustanon 250, testosterone enanthate (Testoviron) is a 250mg injectable preparation, which is injected every 3 weeks3. Testosterone enanthate is the most widely used injectable preparation throughout Europe, although it is little used in the UK.
    Following injection, the peak testosterone level is reached within 24-48 hours1 and this tends to be within the high normal or supraphysiological range, gradually declining into the hypogonadal range over the inter-injection interval. A two- or three-weekly regimen results in peaks and troughs in testosterone levels that may be associated with changes in mood, sexual desire and energy levels.2
    1. Organon Laboratories Limited. Sustanon® 250 SPC; January 2006.
    2. Barass BJR et al. BJU International 2004;93:1183-1187.
    3. Schering Health Care Limited. Testoviron ® SPC; July 2003.
  • Testosterone levels for Sustanon 250 (green line) are taken from a study of 10 hypogonadal men, who received 1 Sustanon injection. Serum testosterone levels were measured weekly for 4 weeks. Testosterone levels are supraphysiological at day 7.1 Since tmax for Sustanon 250 is approximately day 2, testosterone levels can be seen to be above the normal range for approximately 1 week following injection. No baseline measures were made for patients on Sustanon 250. By week 3, the average testosterone level is within the hypogonadal range.2
    1. Lane HA et al. Endocrine Abstracts 2006;11:P677.
    2. Organon Laboratories Limited. Sustanon® 250 SPC; January 2006.
  • Nebido® (testosterone undecanoate 1000 mg in castor oil) is a 4ml injection, which has been available in the UK since 2005.
    Most patients require a loading dose at 6 weeks, and thereafter an inter-injection interval of 10-14 weeks is recommended.1
    Steady-state serum testosterone levels are achieved between the 3rd and the 4th injection. It is therefore recommended that following the loading dose, injections are given every 12 weeks. Measurement of testosterone levels at approximately week 30 (serum trough level of testosterone prior to 4th injection) and clinical symptoms should be considered for individualisation of treatment, i.e. increasing or decreasing the inter-injection interval.1
    Serum testosterone levels are maintained within the normal range, avoiding the supraphysiological levels of testosterone that may be seen with other testosterone therapies.1,2,3
    The most common adverse reaction is pain at the injection site (approximately 10% of patients).1
    1. Schering Health Care Limited. Nebido ® SPC; October 2004.
    2. Von Eckardstein S et al. J Androl 2002;23(3):419-425.
    3. Schubert M et al. J Clin Endocrinol Metab 2004;89:5429-5434.
  • The yellow line represents a study of 14 hypogonadal men who received one injection of long-acting testosterone undecanoate (Nebido). Testosterone levels remain within the physiological range for the 6-week period. This study highlights the need for a loading dose of testosterone undecanoate at 6 weeks, to avoid testosterone levels falling into the hypogonadal range.1
    The orange line represents a study of 7 hypogonadal men receiving long-acting testosterone undecanoate for up to 3.2 years. These data are the testosterone levels after injection number 13 (i.e. approximately 2.5 years of treatment). Following upward titration of the inter-injection interval from 6-weekly in this dose-finding study, all patients were on 12-weekly injections by injection number 13, illustrating that 12-weekly injections of long-acting testosterone undecanoate maintains testosterone levels within the physiological range.2
    1. Von Eckardstein S et al. J Androl 2002; 23(3):419-425.
    2. Behre HM et al. Eur J Endocrinol 1999;140:414-419.
  • Regular monitoring of all patients on testosterone replacement therapy is required to minimise the risk of adverse effects.1,2 Examination of the prostate gland should be performed at intervals, along with full investigation of any urinary symptoms. Men should also have PSA levels determined regularly, as this sensitive marker may help to detect prostate cancer at an early stage. Cancer can disrupt the structure and arrangement of the prostate cells. As a result the PSA is able to leak into the surrounding blood vessels more readily than in a healthy prostate, and the PSA rises above normal. The greater the damage to the prostate gland, the more leaky it becomes and the higher the level of the resulting PSA in the blood stream. Timing-wise, it is recommended to check PSA levels after 3 months, 6 months and 1 year of therapy, and then yearly after that (6-monthly for older patients).1,2
    Testosterone stimulates the production of red blood cells, and overproduction of these may result in an increased risk of blood clots. For this reason, the haematocrit level in the blood should be determined at regular intervals.1,2 The most reliable indicator of clinical response in symptom areas such as sexual function and mood can be the patient’s own report.
    1. Nieschlag E et al. Eur Urol 2005;48:1-4.
    2. Bhasin S et al. J Clin Endocrinol Metab 2006;91(6):1995-2010.
  • The recent Endocrine Society Guidelines (2006),1 recommend evaluating the patient 3 months after initiation of testosterone treatment and then annually to assess whether symptoms have responded to treatment and whether the patient is suffering any adverse effects. In addition, European guidelines recommend monitoring every 3 months in the first year, then annually.2
    Prostate
    PSA and DRE should be measured prior to treatment initiation and at three months. Thereafter, they should be measured in accordance with evidence-based guidelines for prostate cancer screening, according to the age and race of the patient. Bladder symptoms may be monitored by recording the International Prostate Symptom Score (IPSS).
    Haematocrit
    If haematocrit is greater than 54%, the Endocrine Society guidelines recommend to stop treatment until haematocrit decreases to a safe level. The patient should be evaluated for hypoxia and sleep apnoea, and therapy should be re-initiated at a reduced dose.
    Bone Mineral Density (BMD)
    The guidelines suggest that BMD of the lumbar spine, femoral neck, and hip should be repeated after 1 to 2 years of testosterone treatment in hypogonadal men with osteoporosis or low trauma fracture. European guidelines recommend monitoring BMD every 2 years.2
    1. Bhasin S et al. J Clin Endocrinol Metab 2006;91(6):1995-2010.
    2. Nieschlag E et al. J Androl 2006;27:135-137
  • PSA velocity should be calculated using the PSA level after 6 months of testosterone administration as the reference. PSA velocity should only be used if there are longitudinal (>2 years) PSA data available.
  • Hypogonadism and testosterone replacement

    1. 1. 8NEBI68 Hypogonadism and Testosterone Replacement Jamie Smith
    2. 2. 8NEBI68 Testosterone and its metabolites Sexual differentiation Musculature Bone mass Erythropoiesis Psychotropic action Potency/libido Lipid metabolism Bone mass Epiphyseal closure Psychotropic action Lipid metabolism Feedback action Prostate Sexual differentiation Secondary hair Sebum production Prostate TestosteroneTestosterone DihydrotestosteroneDihydrotestosterone OestradiolOestradiol Arom atase Arom atase 5Ω - Reductase 5Ω - Reductase
    3. 3. 8NEBI68 Binding of testosterone (T) T firmly boundT firmly bound to SHBGto SHBG 60%60% BIOAVAILABLE TESTOSTERONEBIOAVAILABLE TESTOSTERONE == Albumin-bound TAlbumin-bound T ++ Free TFree T Free TFree TT loosely boundT loosely bound to albuminto albumin 2%2%38%38%
    4. 4. 8NEBI68 Clinical picture of testosterone deficiency1 • Decreased muscleDecreased muscle bulk/powerbulk/power • Abdominal obesityAbdominal obesity • Loss of libidoLoss of libido • Hot flushes/palpitationsHot flushes/palpitations • Decreased body hairDecreased body hair • AnaemiaAnaemia • SubfertilitySubfertility • Subnormal genital sizeSubnormal genital size • Loss of pubic hairLoss of pubic hair • Erectile dysfunctionErectile dysfunction • Sexual dysfunctionSexual dysfunction • DepressionDepression • Reduced well-beingReduced well-being • Low self esteemLow self esteem • Poor concentration/drivePoor concentration/drive General body effectsGeneral body effects Reproductive systemReproductive system EmotionalEmotional ComplicationsComplications • OsteoporosisOsteoporosis • Raised lipidsRaised lipids • Insulin resistanceInsulin resistance • SarcopaeniaSarcopaenia 1. Nieschlag E and Behre HM. Testosterone: action, deficiency, substitution (3rd Edition). Cambridge University Press; 2004.
    5. 5. 8NEBI68 Sex hormones and hypogonadism 1. Jöckenhovel F. Male Hypogonadism. UNI-MED, Bremen; 2004. LHLHFSHFSH GnRHGnRH HypothalamusHypothalamus PituitaryPituitary TestisTestis SECONDARYSECONDARY HYPOGONADISMHYPOGONADISM Secondary testicular failureSecondary testicular failure Hypogonadotrophic hypogonadismHypogonadotrophic hypogonadism PRIMARY HYPOGONADISM Primary testicular failure Hypergonadotrophic hypogonadism
    6. 6. 8NEBI68 Causes of primary hypogonadism1 • Congenital – Chromosomal defects e.g. Klinefelter's syndrome – Congenital anorchia – Androgen receptor/enzyme defects • Acquired – Testicular trauma/torsion – Surgical removal – Chemotherapy/irradiation • Complications of illness – e.g. diabetes, renal failure, alcoholic liver disease, cirrhosis 1. Nieschlag E et al. Human Reprod Update 2004;10(5):409-419.
    7. 7. 8NEBI68 Causes of secondary hypogonadism1,2 • Congenital – Kallmann’s syndrome – Idiopathic hypogonadotrophic hypogonadism (IHH) – Prader-Willi syndrome • Acquired – Prolactinoma – Pituitary adenoma – Hypothalamic tumour – Anabolic steroid abuse • Complications of illness – e.g. AIDS, haemochromatosis 1. Nieschlag E & Behre HM. Andrology, Male reproductive health and dysfunction (2nd Edition). Springer, Heidelberg; 2002. 2. Nieschlag E et al. Human Reproduct Update 2004;10(5):409-419.
    8. 8. 8NEBI68 Late-onset hypogonadism • A clinical and biochemical syndrome associated with advancing age and characterised by typical symptoms and a deficiency in serum testosterone levels1,2 1. Nieschlag E et al. Eur Urology 2005;48:1-4. 2. Vermeulen A et al. J Clin Endocrinol Metab 1996;81:1821-1826. SHBGSHBG Free T (x100)Free T (x100) TestosteroneTestosteroneSHBGSHBG Free T (x100)Free T (x100) TestosteroneTestosterone 0 25 50 75 25-34 (n=45) 35-44 (n=22) 45-54 (n=23) 55-64 (n=43) 65-74 (n=47) 75-84 (n=48) 75=100 (n=21) Hormonelevel(nmol/L) Age
    9. 9. 8NEBI68 Hypogonadism incidence and age (US data) 0 5 10 15 20 25 Overall 48-59 60-69 70-79 Incidence per1,000person-years Age (years) • Expected 481,000 new cases p.a. in US men 40-69 yrs 1. Araujo A et al. J Clin Endocrinol Metab 2004;89(12):5920-5926.
    10. 10. 8NEBI68 Hypogonadism and CV risk factors • Low testosterone levels in men frequently co-exist with – Type 2 diabetes mellitus – Erectile dysfunction – Abdominal obesity – Other CV risk factors • Component of the metabolic syndrome? CV, cardiovascular
    11. 11. 8NEBI68 Prevalence of hypogonadism in diabetes 0 10 20 30 40 50 Free T Total T Bioavailable T Percentageofpatients 1. Dhindsa S et al. J Clin Endocrinol Metab 2004; 89(11): 5462-5468. • n=103 men with type 2 diabetes
    12. 12. 8NEBI68 Hypogonadism in diabetic vs nondiabetic men with ED1 22.3 34.0 All ages EDno diabetes Diabetes 0 10 20 30 40 50 30-39 40-49 50-59 60-69 >70 Age (Years) %Hypogonadism(T<12nmol/L) p <0.0001 p <0.0001 1. Corona G et al. Eur Urol 2004; 46(2): 222-228. n=1027 men with ED with and without type 2 diabetes mellitus + ED
    13. 13. 8NEBI68 Diagnosing hypogonadism
    14. 14. 8NEBI68 GP (Pre-referral): ASSESSMENT General HistoryGeneral History Drug HistoryDrug History Physical examinationPhysical examination Past Medical HistoryPast Medical History Symptom duration and social history Previous testicular or head injury? Chronic illness? General exam + BMI, testicular size, secondary sexual hair Prescription drugs? Drug abuse?
    15. 15. 8NEBI68 When should you measure testosterone?1 Circadian rhythm of testosterone 1. Nieschlag E & Behre HM. Andrology, Male reproductive health and dysfunction (2nd Edition). Springer, Heidelberg; 2002.
    16. 16. 8NEBI68 Patient history and physical examinationPatient history and physical examination Measure serum testosterone levels between 7-11amMeasure serum testosterone levels between 7-11am Patient presents with symptomsPatient presents with symptoms T >12nmol/lT >12nmol/l Consider alternativeConsider alternative diagnosesdiagnoses TT ≤≤12nmol/l12nmol/l Repeat T levelRepeat T level Measure LH, FSH,Measure LH, FSH, ProlactinProlactin Repeat testsRepeat tests HYPOGONADISMHYPOGONADISM T >12nmol/L,T >12nmol/L, normalnormal Prolactin andProlactin and FSH/LHFSH/LH T 8-12nmol/LT 8-12nmol/L normalnormal Prolactin andProlactin and FSH/LHFSH/LH T 8-12nmol/L,T 8-12nmol/L, andand ProlactinProlactin or abnormalor abnormal FSH/LHFSH/LH T <8nmol/LT <8nmol/L
    17. 17. 8NEBI68 Patients with borderline testosterone levels (8-12 nmol/l)1,2 • Consider additional biochemical tests – Gonadotrophins, SHBG, prolactin • Careful consideration of comorbidities • Calculate free testosterone (see online calculator at www.issam.ch/freetesto.htm) • Counsel patient regarding treatment options 1. Nieschlag E et al. Eur Urol 2005;48:1-4. 2. Bhasin S et al. J Clin Endocrinol Metab 2006;91(6):1995-2010.
    18. 18. 8NEBI68 Who should receive testosterone treatment? • Men with clinical symptoms and testosterone <8 nmol/l1 • Men with clinical symptoms and testosterone 8-12 nmol/l where additional investigations indicate presence of hypogonadism1 • Older men with significant symptoms – Long-term risks /benefits have yet to be clearly demonstrated 1. Nieschlag E et al. Int J Androl 2005;28:125-127
    19. 19. 8NEBI68 Who should receive testosterone treatment? Contraindications to testosterone treatment • Untreated or suspected carcinoma of prostate • Moderate to severe symptoms of BPH • Breast cancer • Liver tumour • Significant polycythaemia • Severe cardiac failure • Untreated sleep apnoea
    20. 20. 8NEBI68 Treating hypogonadism
    21. 21. 8NEBI68 Goals of testosterone replacement therapy1,2 • Restore physiological testosterone levels • Alleviate symptoms of androgen deficiency • Induce or restore physiological functions • Prevent long-term health risks of androgen deficiency 1. Nieschlag E et al. Eur Urol 2005;48:1-4. 2. Bhasin S et al. J Clin Endocrinol Metab 2006;91(6):1995-2010.
    22. 22. 8NEBI68 0 1 2 3 4 5 Week 4 Week 8 Week 12 Endpoint Placebo + Sildenafil 100mg Testosterone + Sildenafil 100mg 1. Shabsigh R et al. J Urol 2004; 172: 658-663 p=0.029 Testosterone converts sildenafil non-responders to responders in men with hypogonadism and erectile dysfunction1 p=ns p=ns p=ns Meanchangefrombaseline IIEFerectilefunctiondomain n=75 hypogonadal men with ED
    23. 23. 8NEBI68 Treatment options
    24. 24. 8NEBI68 19401940 Testosterone implantTestosterone implant 19541954 Short-acting injectableShort-acting injectable testosteronetestosterone 19771977 Oral testosteroneOral testosterone 19921992 Testosterone patchTestosterone patch 19951995 Testosterone patchTestosterone patch 19981998 Testosterone patchTestosterone patch 20022002 Testosterone gelTestosterone gel 20042004 Buccal testosterone tabletBuccal testosterone tablet 20042004 Long-acting injectableLong-acting injectable testosteronetestosterone
    25. 25. 8NEBI68 Oral testosterone (Restandol® ;Andriol® /TestocapsTM )1,2 • Tablets containing 40mg testosterone undecanoate as a maintenance dose taken 2-3 times a day • Route of absorption is via lymphatic system – Therefore needs to taken with a meal containing dietary fat – Without dietary fat absorption is minimal, and pharmacokinetics unreliable 1. Nieschlag E et al. Human Reproduct Update 2004; 10 (5):409-419. 2. Organon Laboratories Limited. Restandol® SPC; May 1998.
    26. 26. 8NEBI68 Buccal testosterone1,2 (Striant® ) • 30mg testosterone tablet placed above incisor tooth twice daily • Avoids hepatic inactivation – Absorbed across oral mucosa • Good pharmacokinetics, achieving normal testosterone levels • May be application difficulties • Risk of site reactions 1. Nieschlag E et al. Human Reproduct Update 2004; 10(5):409-419. 2. Ardana Bioscience. Striant® SPC; March 2005.
    27. 27. 8NEBI68 Subdermal (Testosterone implants) • Testosterone pellets (100-600mg) implanted subdermally2 – Three to six pellets (600mg to 1.2g) usually maintain plasma testosterone concentrations for 4-6 months1 • Risk of supraphysiological testosterone levels • Minor surgical procedure – Can be painful/infection risk/scarring – 8.5% extrusion of pellets3 – Previous implants are not removed – A new insertion site is used each time 1. Nieschlag E et al. Human Reproduct Update 2004; 10(5):409-419. 2. Organon Laboratories Limited. Testosterone Implant 200mg SPC; May 1999. 3. Handelsman DJ et al. Clin Endocrinol 1997;47:311-316.
    28. 28. 8NEBI68 Transdermal patches1,2 (e.g. Andropatch® ) • 2.5-7.5mg testosterone delivered, starting dose • Daily circadian profile of testosterone delivery3,4 • Alcohol base to enhance permeation • Skin reactions common (>50% patients)3,4 • Size of patch can be obtrusive • May make crinkling noise 1. Nieschlag E et al. Human Reproduct Update 2004; 10(5):409-419. 2. GlaxoSmithKline UK. Andropatch® 5mg SPC; August 2002. 3. Wang C et al. J Clin Endocrinol Metab 2000; 85(8):2839-2653. 4. Gooren LJG et al. Drugs 2004.64(17):1861-1891.
    29. 29. 8NEBI68 Transdermal gels1-5 (Testogel® , Tostran® , Testim® ) • 50-100 mg testosterone gel applied each morning to shoulders, back, or abdomen* • Daily circadian profile of testosterone delivery2,4 • Skin reactions in 4-10% patients2,3* • Avoid washing for 6 hours* • Risk of transfer to another person via skin contact • Daily patient compliance required *Details may vary; refer to product information 1. Nieschlag E et al. Human Reproduct Update 2004; 10(5):409-419. 2. Schering Health Care Limited. Testogel ® 50mg SPC; February 2004. 3. Ipsen Ltd. Testim ® 50mg SPC; August 2004. 4. Wang C et al. J Clin Endocrinol Metab 2000; 85(8):2839-2653. 5. ProStrakan Ltd. Tostran ® SPC; April 2007.
    30. 30. 8NEBI68 Intramuscular injections - short acting1,2 (Sustanon® 100; Sustanon® 250; Testoviron® ) • Currently the most widely used form of testosterone • Two short-acting preparations widely available in UK – Sustanon 100 (testosterone: propionate/phenylpropionate/ isocaproate in arachis oil) – Sustanon 250 (testosterone: propionate/phenylpropionate/ isocaproate/decanoate in arachis oil) • Injection every 2 weeks (Sustanon 100) or 3 weeks (Sustanon 250)2,3 • Peak and trough testosterone levels • Injection site reactions/patient discomfort • Reaction to excipients (nut allergy) 1 Nieschlag E et al. Human Reproduct Update 2004; 10(5):409-419. 2. Organon Laboratories Limited. Sustanon® 100 SPC; February 2004 3. Organon Laboratories Limited. Sustanon® 250 SPC; January 2006.
    31. 31. 8NEBI68 Pharmacokinetics of UK available injectable testosterone preparations: Sustanon 2501 1. Lane HA et al. Endocrine Abstracts 2006;11:P677. 0 10 20 30 40 1 2 3 4 Sustanon 250 Weeks
    32. 32. 8NEBI68 Intramuscular injections - long acting1 (Nebido® ) • 1000 mg testosterone undecanoate in 4 ml castor oil • Loading dose at 6 weeks, and then every 10 to 14 weeks1 • Testosterone levels maintained within the physiological range2 – Avoids frequent peaks and troughs in testosterone levels that may be seen with short-acting injections3 • Increased patient convenience (quarterly injections) • Injection site reactions/patient discomfort 1. Schering Health Care Limited. Nebido ® SPC; October 2004. 2.Von Eckardstein S et al. J Androl 2002;23(3):419-425. 3.Schubert M et al. J Clin Endocrinol Metab 2004;89:5429-5434.
    33. 33. 8NEBI68 0 10 20 30 40 0 1 2 3 4 5 6 7 8 9 10 11 12 Weeks Serumtestosterone(nmol/L) T undecanoate (1st injection) T undecanoate (13th injection) Pharmacokinetics of UK available injectable testosterone preparations: Nebido1-3 1. Von Eckardstein S et al. J Androl 2002; 23(3):419-425. 2. Behre HM et al. Eur J Endocrinol 1999;140:414-419. Data are from 2 separate studies, i.e. not a comparative trial
    34. 34. 8NEBI68 Monitoring patients on testosterone therapy
    35. 35. 8NEBI68 Parameters to monitor or to be aware of during therapy1,2 • Prostate • Haematocrit and haemoglobin – Increased levels particularly associated with supraphysiological levels of testosterone • Blood lipids • Liver function • Miscellaneous adverse effects of testosterone – E.g. gynaecomastia, acne, oily skin, priapism, sleep apnoea • Clinical response to therapy 1. Bhasin S et al. J Clin Endocrinol Metab 2006;91(6):1995-2010. 2. Nieschlag E et al. Human Reproduct Update 2004; 10(5):409-419.
    36. 36. 8NEBI68 Endocrine Society: recommendations1 ParameterParameter BaselineBaseline 3 month3 month AnnualAnnual PSA Y Y Y DRE Y Y Y Haematocrit Y Y Y Testosterone - Y Y BMD Y - Y 1. Bhasin S et al. J Clin Endocrinol Metab 2006;91(6):1995-2010.
    37. 37. 8NEBI68 Endocrine Society: Prostate monitoring1 • Urological consultation should be sought if there is: – Verified PSA >4.0 ng/ml – Increase in PSA concentration >1.4ng/ml within any 12-month period of testosterone treatment – PSA velocity >0.4ng/ml/year – Detection of a prostatic abnormality on DRE 1. Bhasin S et al. J Clin Endocrinol Metab 2006;91(6):1995-2010.

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