Current Data and Considerations Novel Testosterone Formulations

Transcription

1 Current Data and Considerations Novel Testosterone Formulations 1

2 Diagnosis and Assessment Module 2 2

3 Objectives Identify clinical manifestations and symptoms of hypogonadism Describe components of comprehensive diagnostic assessment of hypogonadism Discuss challenges with testosterone assays Review recommended baseline testing parameters 3

4 Clinical Manifestations of Hypogonadism Physical Psychological 1,2 Sexual 1,2 Decreased bone mineral density 1,2 Decreased muscle mass and strength 1,2 Gynecomastia 1,2 Anemia 1,2 Frailty 3 Increased body fat or body mass index 1,2 Fatigue 1,2 Depressed mood Diminished energy, sense of vitality, or well-being Impaired cognition and memory Diminished libido Erectile dysfunction Difficulty achieving orgasm Decreased spontaneous erections 1. AACE Hypogonadism Task Force. Endocr Pract. 2002;8: Bhasin S et al. J Clin Endocrinol Metab. 2006;91: Mulligan T et al. Int J Clin Pract. 2006;60: A number of physical, psychological, and sexual symptoms and signs are suggestive of hypogonadism. Physical changes suggestive of hypogonadism include decreased bone mineral density and decreased muscle mass and strength, gynecomastia, anemia, frailty, increased body fat or body mass index, and fatigue. 1-3 Less specific psychological changes that may be associated with hypogonadism include depressed mood; diminished energy, sense of vitality, or well-being; and impaired cognition and memory. 1,2 Sexual changes that may be related to hypogonadism include diminished libido, erectile dysfunction, difficulty achieving orgasm, and decreased spontaneous erections. 1,2 1. AACE Hypogonadism Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients 2002 update. Endocr Pract. 2002;8: 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: Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60:

5 Diagnostic Evaluation of Adult Men With Suspected Hypogonadism History and physical symptoms and signs Morning Total T Low T <300 ng/dl Normal T Exclude reversible illness, drugs, nutritional deficiency Repeat T (use free or bio T, if suspect altered SHBG) LH+FSH SFA (if fertility issues) Follow-up Confirmed low T (eg, total T <300 ng/dl; or free or bio T < normal (eg, free T <5 ng/dl) Low T, low or normal LH+FSH (2º) Low T, high LH+FSH (1º) Normal T, LH+FSH FSH=follicle-stimulating hormone. LH=luteinizing hormone. SFA=seminal fluid analysis. SHBG=sex hormone-binding globulin. T=testosterone. Reprinted with permission from Bhasin S et al. Testosterone therapy in adult men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2006;91: Copyright 2006, The Endocrine Society. The diagnostic strategy recommended by The Endocrine Society Clinical Practice Guideline for adult men suspected of having androgen deficiency is shown here. Total testosterone levels should be measured in the morning. A testosterone value <300 ng/dl is low and requires further evaluation. Levels of serum luteinizing hormone and follicle-stimulating hormone should be measured to differentiate primary (testicular) from secondary (pituitary-hypothalamic) hypogonadism. Men with secondary hypogonadism require further evaluation to determine whether the condition is caused by hypothalamic or pituitary dysfunction. The presence of hyperprolactinemia and hemochromatosis can be determined by measurement of serum prolactin and iron saturation, respectively. Pituitary function testing can reveal deficiencies of other pituitary hormones. The cost-effectiveness of magnetic resonance imaging scanning to exclude a tumor of the pituitary or hypothalamus is unknown. A karyotype can be used to diagnose Klinefelter s syndrome, a common cause of primary testicular failure in patients with primary testicular failure of unknown etiology. 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:

6 Physical Examination of Adult Men With Suspected Hypogonadism Comprehensive history 1,2 Gynecomastia 1,2 Secondary sexual characteristics (decreased body hair, decreased beard growth) 1,2 Testicular examination, noting size and consistency 1,2 Approximate ranges of normal adult testes Prostate assessment, noting palpability Body mass index 2,3 1. AACE Hypogonadism Task Force. Endocr Pract. 2002;8: Bhasin S et al. J Clin Endocrinol Metab. 2006;91: Mulligan T et al. Int J Clin Pract. 2006;60: The American Association of Clinical Endocrinologists (AACE) guidelines recommend obtaining a comprehensive history and performing a complete physical examination to determine the cause and extent of hypogonadism. 1,2 The presence and degree of gynecomastia, the amount and distribution of body hair, and any decrease in body hair or beard growth should be examined. The length, width, and consistency of the testes should be measured. Adult testes are usually ml and cm long by cm wide. 1,2 A nonpalpable prostate suggests testosterone deficiency. 1 Because the risk of hypogonadism is greater in obese men, and waist circumference 102 cm is predictive of low testosterone levels, body mass index and waist circumference should also be measured AACE Hypogonadism Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients 2002 update. Endocr Pract. 2002;8: 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: Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60: Svartberg J, von Mühlen D, Sundsfjord J, Jorde R. Waist circumference and testosterone levels in community dwelling men: the Tromsø study. Eur J Epidemiol. 2004;19:

7 Testosterone Binding Albumin-bound T 68% 30% SHBG-bound T 2% Free T SHBG=sex hormone-binding globulin. T=testosterone. Data from AACE Hypogonadism Task Force. Endocr Pract. 2002;8: Testosterone levels should be determined in the morning because peak testosterone levels occur during the early morning hours. In young adult men, most circulating testosterone is bound to either sex hormone-binding globulin (SHBG; 30%) or albumin (68%). Binding of testosterone to SHBG is tight, so that fraction is not biologically active. By contrast, testosterone is weakly bound to albumin and can readily dissociate to free active testosterone. AACE Hypogonadism Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients 2002 update. Endocr Pract. 2002;8:

8 Methods for Measuring Total Testosterone Immunoassay RIA RIA after extraction and chromatography ELISA CLIA Mass spectrometry GC LC CLIA=chemiluminescent immunoassay. ELISA=enzyme-linked immunosorbent assay. GC=gas chromatography. LC=liquid chromatography. RIA=radioimmunoassay. Rosner W et al. J Clin Endocrinol Metab. 2007;92: Recently, an Endocrine Society task force published a position statement on the usefulness of various methods for measuring testosterone. The methods most often used to measure plasma total testosterone (T) are radioimmunoassay (RIA) and chemiluminescent immunoassay (CLIA), which are performed directly on serum or plasma or after extraction and/or chromatography. Direct assay methods often overestimate T concentration, are not standardized, and have limited accuracy at T <300 ng/dl. RIA after extraction and/or chromatography is extensively used and is more accurate and sensitive than direct assay. However, it is more labor intensive and requires a high degree of technical proficiency. Any RIA generates radioactive waste. Mass spectrometry after extraction and liquid or gas chromatography is highly accurate when properly validated. However, it is relatively expensive, has a relatively long turnaround time, and has not been standardized. Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H. Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab. 2007;92:

9 Methods for Measuring Free Testosterone Unbound or Bioavailable Immunoassay via RIA Physical separation of protein-bound from FT Ammonium sulfate precipitation to measure bioavailable T* Calculation Free androgen index (T/SHGB) Using algorithms based on law of mass action *Separation by means of a membrane (eg, equilibrium dialysis) or filter (eg, centrifugal ultrafiltration). Requires TT, total SHBG, total albumin, and the use of the equilibrium constants (kd) for the binding of SHBG and T and albumin and T. FT=free testosterone. RIA=radioimmunoassay. SHBG=sex hormone-binding globulin. T=testosterone. TT=total testosterone. Rosner W et al. J Clin Endocrinol Metab. 2007;92: Unbound or free testosterone (FT) is generally thought to be the component that results in androgenic effects. Another important concept is bioavailable testosterone (bio-t), which is defined as FT plus testosterone (T) that is weakly bound to serum albumin. This measurement is widely used but requires a very accurate, precise assay because FT is such a small portion of total T. A number of methods have been used to measure FT or bio-t. Direct RIA is simple, rapid, relatively inexpensive, and can be automated. However, it has poor accuracy and sensitivity. Physical separation of protein-bound T from FT by a membrane (ie, equilibrium dialysis) or filter (ie, ultracentrifugation) is relatively accurate, sensitive, and reproducible,and the equilibrium dialysis method is considered the gold standard for quantifying FT. However, physical separation techniques are relatively expensive and technically cumbersome and difficult. For indirect measurement of FT, such as ammonium sulfate precipitation to measure bio-t, tritiated T (3H-T) is added to the sample, and bound and free 3H-T are separated after attaining equilibrium. Free 3H-T is then measured. The ammonium sulfate precipitation method is technically simple but can be inaccurate if impure 3H-T is used or if precipitation of globulins is incomplete. FT can also be calculated using the free androgen index (FAI, the unitless quotient T/SHBG) or by using algorithms based on the law of mass action. Both calculations are simple and highly dependent on the accuracy and sensitivity of the assays used to measure total T and SHBG. However, the FAI correlates poorly with physical separation measures in men. Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H. Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab. 2007;92:

10 Evaluation of Testosterone Levels in Adult Men Normal (TT >320 ng/dl) Diagnostic of hypogonadism (TT <200 ng/dl) Equivocal range of hypogonadism (TT 200 to 320 ng/dl) Determine FT or BT to differentiate eugonadism from hypogonadism (FT 6.5 ng/dl, BT 15 ng/dl) BT=bioavailable testosterone. FT=free testosterone. TT=total testosterone. Rosner W et al. J Clin Endocrinol Metab. 2007;92: According to the Endocrine Society Task Force position statement, in adult men, a normal total testosterone (TT) level is >320 ng/dl, and when TT is <200 ng/dl, hypogonadism is diagnosed. Values of TT between 200 and 320 ng/dl are considered equivocal. For values in this range, determination of free testosterone (FT) or bioavailable T (BT) is recommended to differentiate eugonadism from hypogonadism. The lower limits of normal are an FT of 6.5 ng/dl and a BT of 15 ng/dl. Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H. Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab. 2007;92:

11 Difficulties With Testosterone Assays Vary depending on age, gender, and presence of comorbid conditions 1 Vary with time of day 1,2 Interference from other circulating steroids 1 No universally recognized testosterone-calibrating standard 1 1. Rosner W et al. J Clin Endocrinol Metab. 2007;92: AACE Hypogonadism Task Force. Endocr Pract. 2002;8: A number of difficulties complicate testosterone assays and their interpretation. Total testosterone concentrations vary according to age, gender, and the presence of any comorbid conditions. 1 Testosterone concentrations exhibit diurnal variations, with highest levels occurring early in the morning. 1,2 Other circulating steroids with similar structures may interfere with the assays. 1 In addition, there is no universally recognized testosterone-calibrating standard, and normal ranges corrected for age and gender, using a standardized assay, are generally lacking Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H. Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab. 2007;92: AACE Hypogonadism Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients 2002 update. Endocr Pract. 2002;8:

12 Other Hormone Assays and Baseline Tests Sex hormone-binding globulin 1 Follicle-stimulating hormone 1 Luteinizing hormone 1 Hematocrit 2 Lipid profile 1 1. AACE Hypogonadism Task Force. Endocr Pract. 2002;8: Bhasin S et al. J Clin Endocrinol Metab. 2006;91: Other hormone assays and baseline tests that should be considered in the evaluation of the male patient with suspected hypogonadism are listed here. Sex hormone-binding globulin (SHBG) levels should be measured when clinical findings suggest hypogonadism but total testosterone levels are normal or borderline low. Male patients with hypogonadism often have high SHBG levels. 1 Determination of luteinizing hormone and follicle-stimulating hormone in a patient with low testosterone will help determine whether the underlying problem is a primary testicular disorder (hypergonadotropic hypogonadism) or a pituitary disease (hypogonadotropic hypogonadism). In hypogonadotropic hypogonadism, levels of these gonadotropins should be increased. 1 Hematocrit should be measured at baseline because testosterone therapy is not recommended for patients with erythrocytosis (hematocrit >50%). 2 Lipid imbalances with testosterone therapy are unusual but can occur when anabolic steroids are not aromatized from testosterone to estradiol. An initial lipid profile should be recorded, with subsequent profiles obtained after 6 to 12 months of treatment and yearly thereafter AACE Hypogonadism Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients 2002 update. Endocr Pract. 2002;8: 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:

13 Prostate Health Assessment DRE PSA Consult with urologist if PSA >4.0 ng/ml PSA velocity >0.4 ng/ml/year (using PSA level after 6 months of therapy) Detection of prostate abnormality on DRE AUA prostate symptom score >19 AUA=American Urological Association. DRE=digital rectal examination. PSA=prostate-specific antigen. Bhasin S et al. J Clin Endocrinol Metab. 2006;91: The Endocrine Society Clinical Practice Guideline recommends a digital rectal examination (DRE) of the prostate and measurement of prostate-specific antigen (PSA) before initiating testosterone therapy. A urologic consultation is recommended if the PSA is >4.0 ng/ml, the PSA velocity is >0.4 ng/ml per year (using the PSA level after 6 months of testosterone therapy), a prostatic abnormality is detected on DRE, or the patient has an American Urological Association prostate symptom score of >19. 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:

14 Relationship of PSA Levels to Prevalence of Prostate Cancer Total PSA (ng/ml) to to to to 4.0 Probability of Prostate Cancer (%) N=2,950 men aged 62 to 91 years. PSA=prostate-specific antigen. Reprinted with permission from Thompson IM et al. N Engl J Med. 2004;350: The prevalence of prostate cancer was determined in 2,950 men (aged 62 to 91 years) in the placebo arm of the Prostate Cancer Prevention Trial who never had a prostate-specific antigen (PSA) level >4.0 ng/ml or an abnormal annual digital rectal examination result during 7 years in the study. Prostate cancer was diagnosed in 15.2% (449) of the 2,950 men, and 14.9% (67) of these cancers were high grade (Gleason score of 7 or higher). As shown here, the prevalence of prostate cancer increased as the PSA level increased, ranging from 6.6% among men with a PSA 0.5 ng/ml to 26.9% among men with a PSA of 3.1 to 4.0 ng/ml. Although PSA levels 4.0 ng/ml are generally considered normal, these findings show that prostate cancer is not uncommon in men with these levels. Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level 4.0 ng per milliliter. N Engl J Med. 2004;350:

15 Summary Clinical manifestations of hypogonadism may include low libido, fatigue, sexual and erectile dysfunction, gynecomastia, and frailty Diagnostic assessment should include physical examination and laboratory tests of testosterone and prostate-specific antigen levels A number of physical, psychological, and sexual signs and symptoms may suggest hypogonadism, such as diminished libido, fatigue, sexual and erectile dysfunction, gynecomastia, and diminished physical capacity or work performance. 1,2 The diagnostic assessment of men with suspected hypogonadism should include a physical examination and laboratory tests of testosterone and prostate-specific antigen levels. 1,2 1. AACE Hypogonadism Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients 2002 update. Endocr Pract. 2002;8: 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: