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Testosterone Replacement Therapy Urology - Update

Testosterone Replacement Therapy Urology - Update. Hugo H Davila, MD Urology Center St. Joseph Hospital. Objective. Objective: My objective is to update the guidelines for the evaluation and treatment of androgen deficiency syndromes in adult men published previously in 2006.

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Testosterone Replacement Therapy Urology - Update

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  1. Testosterone Replacement Therapy Urology - Update Hugo H Davila, MD Urology Center St. Joseph Hospital

  2. Objective • Objective: • My objective is to update the guidelines for the evaluation and treatment of androgen deficiency syndromes in adult men published previously in 2006. • The Endocrine Society Clinical Practice Guideline 2010 • Prostate-Specific Antigen, Best Practice Statement: 2009. American Urological Association. • Guideline for the Management of Clinically Localized Prostate Cancer 2007. American Urological Association. • Campbell-Walsh Urology 10TH Edition . chapter 29 – Androgen Deficiency in the Aging Male.

  3. Agenda • Diagnosis of Hypogonadism • Symptoms • Labs • Testosterone Replacement Therapy (TRT) • Indications • Benefits • Formulation • Contraindications • Prostate Cancer and TRT • PSA and TRT • Adverse Effect • Monitoring men in TRT • Androgen-Deprivation Therapy (ADT) in Prostate Cancer and Cardiovascular Risk.

  4. Diagnosis of Hypogonadism?

  5. Men with consistent symptoms and signs and unequivocally low serum testosterone levels.

  6. Testosterone Replacement Step 1 What are those symptoms and Signs? More specific symptoms and signs Incomplete or delayed sexual development, eunuchoidism Reduced sexual desire (libido) and activity Decreased spontaneous erections Breast discomfort, gynecomastia Loss of body (axillary and pubic) hair, reduced shaving Very small (especially 5 ml) or shrinking testes Inability to father children, low or zero sperm count Height loss, low trauma fracture, low bone mineral density Hot flushes, sweats Other less specific symptoms and signs Decreased energy, motivation, initiative, and self-confidence Feeling sad or blue, depressed mood, dysthymia Poor concentration and memory Sleep disturbance, increased sleepiness Mild anemia (normochromic, normocytic, in the female range) Reduced muscle bulk and strength Increased body fat, body mass index Diminished physical or work performance

  7. Testosterone Replacement Step 2 What is next? Measurement of morningtotal testosterone level by a reliable assay (mass spectrometry) as the initial diagnostic test. Confirmation of the diagnosis by repeating measurement of total testosterone. Evaluation of androgen deficiency should not be made during an acute or subacute illness.

  8. Testosterone Replacement Step 2 How low is low? The lower limit of the normal range for young men, i.e. approximately 300 ng/dl (10.4 nmol/liter), with a greater likelihood of having symptoms below this threshold than above it.

  9. Men with consistent symptoms and signs and unequivocally low serum testosterone levels.

  10. Low TT Predict the development of Metabolic Synd and Diabetes Population-based cohort study: 11 years follow up N= 702 TT <450 ng/dl After 11 years 45% of those men developed MS and DM Diabetes care. Vol 27.2004. 1036-1041

  11. Definition of Metabolic syndrome NHLBI and WHO need >3 of the following Obesity waist circumference >94cm (40 in) Triglycerides mg/dl >150 HDL mg/dl <40 BP mmHg >130/85 Glucose mg/dl >110

  12. Metabolic syndrome Hypogonadism and ED are commonly treated Associated with metabolic syndrome, type 2 diabetes and CVD, these condition are clearly linked to increase mortality and morbidity. Metabolic syndrome may be considered a risk factor for ED. ED may be considered a risk factor for CVD

  13. Low TT and CHF CHF is a complex multistep Disease Disrupt the endocrine and metabolic system Impaired exercise capacity and fatigue Associated with Low testosterone levels 25% of hypogonal men have CHF Aukrust P, et al. J Am Coll Cardiol 2009;54(10)928-929.

  14. Diagnosis of Hypogonadism?

  15. Testosterone Replacement Step 2 What is Total Testosterone? Serum total testosterone =SHBG bound (40-50%)+ Free T (2%) + Albumin bound (48%) Most of the circulating testosterone is bound to SHBG and to albumin. Only 2% of circulating testosterone is unbound or “free.” The term “bioavailable testosterone” refers to free testosterone plus testosterone bound loosely to albumin

  16. Testosterone Replacement Step 3 Do I need any other test? Measurement of free or bioavailable testosterone level, using an accurate and reliable assay, in some men in whom total testosterone concentrations are near the lower limit of the normal range and in whom alterations of SHBG are suspected.

  17. Testosterone Replacement Step 3 What are the conditions that affects SHBG? Conditions associated with decreased SHBG concentrations Moderate obesity Nephrotic syndrome Hypothyroidism Use of glucocorticoids, progestins, and androgenic steroids Acromegaly Diabetes mellitus Conditions associated with increased SHBG concentrations Aging Hepatic cirrhosis and hepatitis Hyperthyroidism Use of anticonvulsants Use of estrogens HIV disease

  18. Recommendations

  19. Testosterone Replacement Recommendation 1 Avoid treatment in men without unequivocally low testosterone levels and symptoms.

  20. Testosterone Replacement Recommendation 2 Avoid labeling men with low testosterone levels due To: SHBG abnormalities. Natural variations in testosterone levels. Transient disorders as requiring testosterone therapy.

  21. Do we need any other tests?

  22. Testosterone Replacement Sometimes, Step 4 What are those additional tests? If Total Testosterone <150 ng/dl LH, FSH, Prolactin and MRI of the sellaTurcica If testicular Vol<6ml (small testes) Karyotype (Klinefelter syndrome) Infertility 2 semen analyses Bone mineral density by using dual-energy x-ray absorptiometry (DEXA) scanning in men with severe androgen deficiency or low trauma fracture Note: I recommend measurement of serum LH and FSH levels to distinguish between primary (testicular) and secondary (pituitary-hypothalamic) hypogonadism.

  23. Testosterone Replacement Recommendation 3 The diagnostic strategy places a relatively higher value on detecting conditions (e.g. pituitary neoplasia or other treatable pituitary disorders) for which effective treatment or counseling is available.

  24. Do we need to screen the general population for hypogonadism?

  25. Testosterone Replacement NO, The benefits and adverse consequences of long term testosterone therapy in asymptomatic men with presumed hypogonadism remain unclear.

  26. Can We measure Testosterone Level in patients with other medical problems?

  27. Testosterone Replacement • Yes, • Patients in whom there is high prevalence of low testosterone • Levels: • Sellar mass, radiation to the sellar region, or other diseases of • the sellar region • Treatment with medications that affect testosterone • production or metabolism, such as glucocorticoids and • opioids • HIV-associated weight loss • End-stage renal disease and maintenance hemodialysis • Moderate to severe chronic obstructive lung disease • Infertility • Osteoporosis or low trauma fracture, especially in a young man • Type 2 diabetes mellitus

  28. Testosterone Replacement Long-acting opioid analgesics suppress the hypothalamic-pituitary gonadal axis in men, produce symptomatic androgen deficiency (up to 74%), and are associated with increased risk of osteoporosis.

  29. Testosterone Replacement Androgen deprivation therapy using GnRH analogs in men with prostate cancer has emerged as an important cause of therapeutically induced androgen deficiency that is associated with increased risk of sexual dysfunction, fatigue, fractures, cardiovascular disease, and diabetes.

  30. What about symptoms Questionnaires?

  31. Testosterone Replacement • There is limited information about the performance properties of case-detection instruments that rely on self report, namely: • Androgen Deficiency in Aging Males . • the Aging Males’ Symptoms Rating Scale. • Massachusetts Male Aging Study Questionnaire

  32. Testosterone Replacement Recommendation 4 The recommendation in favor of measurement testosterone levels in those conditions in which there is a high prevalence of low testosterone levels

  33. Agenda • Diagnosis of Hypogonadism • Symptoms • Labs • Testosterone Replacement Therapy (TRT) • Indications • Benefits • Formulation • Contraindications • Prostate Cancer and TRT • PSA and TRT • Adverse Effect • Monitoring men in TRT • Androgen-Deprivation Therapy (ADT) in Prostate Cancer and Cardiovascular Risk.

  34. Testosterone Replacement • Indications/contraindications for TRT • Testosterone therapy for symptomatic men with classical androgen deficiency syndromes and low TT • Avoid testosterone therapy in patients with breast or prostate cancer.

  35. Testosterone Replacement What are the benefits of TRT? Testosterone therapy of hypogonadal men is associated with improvements in: Overall sexual activity, frequency of sexual thoughts Increase in the frequency and duration of nighttime erections Increases hair growth. Increases fat-free mass and muscle strength Increases bone mineral density May improves the positive and reduces the negative aspects of mood Data on the impact of testosterone replacement on insulin sensitivity have yielded conflicting results.

  36. TRT in men with Sexual Dysfunction • Recommendation #5 • TRT in men with low testosterone levels and low libido to improve libido • TRT men with ED who have low testosterone levels after evaluation of underlying causes of ED and consideration of established therapies for ED. • Note: A decision to treat older men depends on the physician’s and the patient’s assessment of risks and benefits and costs.

  37. TRT in Older Men with Low Testosterone Recommendation #6 We recommend against a general policy of offering TRT to all older men with low testosterone levels.

  38. But

  39. TRT in Older Men with Low Testosterone • Several studies demonstrate that serum total and free testosterone concentrations in men fall with increasing age • By the eighth decade, according to one study, 30% of men had total testosterone values in the hypogonadal range, and 50% had low free testosterone values . • Note: Depending on the severity of clinical manifestations, some panelists favored treating symptomatic older men with a testosterone level below the lower limit of normal for healthy young men 280–300 ng/dl , others favored a level less than 200 ng/dl.

  40. Testosterone Replacement • Bone mineral density • The panel did not find any trials reporting the effect of testosterone on bone fractures. • Body composition • TRT was associated with a significantly greater increase in lean body mass (LBM) (2.7 • kg; 95% CI, 1.6, 3.7) and a greater reduction in fat mass(2.0 kg; 95% CI, 3.1, 0.8) than placebo.

  41. Testosterone Replacement • Muscle strength and physical function • TRT was associated with a greater improvement in grip strength than placebo. Most of the studies included men who had no functional limitations and used measures of physical function that had a low ceiling. • Sexual function • Two placebo-controlled trials yielded imprecise results • regarding the effect of testosterone on overall sexual satisfaction.

  42. Interval from manifestation of ED to initial atherosclerotic cardiovascular event. • Atherosclerotic cardiovascular event subsequent to manifestation of ED • 5-10 years after ED onset 37% will have CV event. • 20-25% of men with low testosterone present with ED • ED onset 20-40 yo is associated 7 fold increase in risk for a CV in the next 7-10 years • Chew KK et al, J Sex Med. 2010.7.192-202.

  43. Testosterone Replacement • Quality of life • The results were inconsistent across trials and imprecise. • Depression • The effects of testosterone therapy on depression have been inconsistent across trials. • Cognition • Three placebo-controlled, randomized trials, reported imprecise effects on several dimensions of cognition, none of which was significant after pooling.

  44. Testosterone Replacement • HIV-infected men with weight loss • Clinicians should consider short-term TRT as an adjunctive therapy in HIV-infected men with low testosterone levels and weight loss to promote weight maintenance and gains in LBM and muscle strength.

  45. Testosterone Replacement • Glucocorticoid-treated men • We suggest that clinicians offer TRT to men receiving high doses of glucocorticoids who have low testosterone levels to promote preservation of LBM and bone mineral density.

  46. Agenda • Diagnosis of Hypogonadism • Symptoms • Labs • Testosterone Replacement Therapy (TRT) • Indications • Benefits • Formulation • Contraindications • Prostate Cancer and TRT • PSA and TRT • Adverse Effect • Androgen-Deprivation Therapy (ADT) in Prostate Cancer and Cardiovascular Risk. • Monitoring men in TRT

  47. Testosterone Replacement • Clinical Pharmacology TRT • T enanthete or Cypionate Injections • 150-200 mg IM every 2 wk or 75-100mg/wk • Advantages: Correct symptoms, inexpensive, self-administered • Disadvantages: IM injection, peaks and valleys in serum T.

  48. Testosterone Replacement • Clinical Pharmacology TRT • Testosterone Gel (Androgel 1.6%, Fortesta 2%, Axiron, Testim 1%) • Androgel = Arm • Fortesta = Upper Thigh • Axiron = Axilla • 5-10 g T gel containing 50-100mg T QDay • Advantages: Correct symptoms, flexibility, ease of application, good skin tolerability • Disadvantages: Potential of transfer, skin irritation in some PT, moderately high DHT levels.

  49. Testosterone Gel • Testosterone Gel • Single center, randomized, double-blinded placebo-controlled study. • >65 yo men (N=274) • 6 months Test gel 50 mg • TT levels= 500-700 ng/dl • Effect on: Muscle mass and strength, QoL • Results • Improved muscle mass, physical function and QoL • Sriniva-Smankar et al. J ClinEndocrinoMetab, 2010; 409-420

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