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 The Endocrine Society Clinical Practice Guideline Prostate-Specific Antigen, Best Practice Statement: American Urological Association. 3.Guideline for the Management of Clinically Localized Prostate Cancer American Urological Association. 4.Campbell-Walsh Urology 10 TH Edition. chapter 29 – Androgen Deficiency in the Aging Male.

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.

Diagnosis of Hypogonadism?

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

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

Testosterone Replacement Step 2 What is next? Measurement of morning total 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.

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.

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

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

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

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

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)

Diagnosis of Hypogonadism?

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

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.

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

Recommendations

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

Testosterone Replacement Recommendation 2 Avoid labeling men with low testosterone levels due To: 1.SHBG abnormalities. 2.Natural variations in testosterone levels. 3.Transient disorders as requiring testosterone therapy.

Do we need any other tests?

Testosterone Replacement Sometimes, Step 4 What are those additional tests? If Total Testosterone <150 ng/dl LH, FSH, Prolactin and MRI of the sella Turcica 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.

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.

Do we need to screen the general population for hypogonadism?

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

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

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

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.

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.

What about symptoms Questionnaires?

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

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

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.

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.

Testosterone Replacement What are the benefits of TRT? Testosterone therapy of hypogonadal men is associated with improvements in: 1.Overall sexual activity, frequency of sexual thoughts 2.Increase in the frequency and duration of nighttime erections 3.Increases hair growth. 4.Increases fat-free mass and muscle strength 5.Increases bone mineral density 6.May improves the positive and reduces the negative aspects of mood 7.Data on the impact of testosterone replacement on insulin sensitivity have yielded conflicting results.

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.

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.

But

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.

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.

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.

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 % of men with low testosterone present with ED ED onset yo is associated 7 fold increase in risk for a CV in the next 7-10 years Chew KK et al, J Sex Med

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.

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.

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.

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

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

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 mg 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.

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

Testosterone Replacement Clinical Pharmacology TRT T Pellets 3-6 pellets implanted SC, 3-6 months Advantages: Correct symptoms. Disadvantages: Require surgical incision, pellets may extrude spontaneously.

Testosterone Replacement Clinical Pharmacology TRT T Patch (Androderm) 1-2 patches, 5-10mg Testosterone Advantages: Correct symptoms, easy application. Disadvantages: Serum T in the low normal range, skin irritation at the application site.

Testosterone Replacement Clinical Pharmacology TRT T Tablets (Striant) 30mg bioadhesive tablets BID, serum T peak after 1 month. Advantages: Correct symptoms. Disadvantages: Gum-related adverse events in 16% of treated men.

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

Prostate Cancer and TRT Clinicians should assess prostate cancer risk in men being considered for testosterone therapy: Family history, Race, PSA and digital rectal exam (DRE). Avoid testosterone therapy without further urological evaluation in patients with palpable prostate nodule or induration Avoid testosterone therapy if PSA is greater than 4 ng/ml or PSA greater than 3 ng/ml in men at high risk of prostate cancer, such as African-Americans or men with first-degree relatives with prostate cancer.

PSA and TRT Prostate Cancer and TRT In men 40 yr of age or older who have a baseline PSA greater than 0.6 ng/ml: Digital examination of the prostate. PSA measurement before initiating treatment, at 3 to 6 months.

Obtain urological consultation if there is: An increase in serum PSA concentration >1.4 ng/ml within any 12-month period of TRT. PSA velocity > 0.4 ng/ml yr after 6 months of TRT (only applicable if PSA data are available for a period exceeding 2 yr). Abnormal digital rectal examination. AUA/IPSS of 19. PSA and TRT

Prostate Cancer Risk and TRT Prostate Cancer and TRT We suggest estimating prostate cancer risk using the prostate cancer risk calculator Takes into consideration: Age, ethnicity, PSA. Findings of digital rectal examination. Family history. The use of a 5a- reductase inhibitor. Prior biopsy history.

Can I start my patients on TRT after prostate cancer treatments?

TRT After Prostate Cancer Treatment Prostate Cancer and TRT Organ-confined prostate cancer Who have undergone radical prostatectomy. Have been disease-free 2 or more years Who have undetectable PSA levels May be considered for testosterone replacement on an individualized basis. Note: The lack of data from randomized trials precludes a general recommendation.

Contraindications for TRT Avoid testosterone therapy in patients With: Hematocrit above 50%. Untreated severe obstructive sleep apnea. Severe lower urinary tract symptoms (AUA/ IPSS > 19). Uncontrolled or poorly controlled heart failure. In those desiring fertility.

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

Adverse Effect of TRT 37 randomized controlled testosterone trials were reviewed: Increases in hemoglobin. Increase hematocrit. Increase PSA. Decrease in high-density lipoprotein (HDL) Gynecomastia (breast exam)

Adverse Effect of TRT Not different among testosterone- and placebo-treated men: Overall mortality. Cardiovascular event rates. Systolic and diastolic blood pressure.

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.

Evaluate the patient 3 to 6 months after treatment initiation 1.Testosterone Injection: T level midway between injections = ng/dl. 2.Transdermal Gel: assess testosterone level any time after patient has been on treatment for at least 1 wk; adjust dose to achieve serum testosterone level in the mid-normal range. 3.Testosterone pellets: measure testosterone levels at the end of the dosing interval. Adjust the number of pellets and/or the dosing interval to achieve serum testosterone levels in the normal range. Monitoring Men Receiving TRT

Hematocrit at baseline, at 3 to 6 months, and then annually. If hematocrit is >54%, stop therapy until hematocrit decreases to a safe level; evaluate the patient for hypoxia and sleep apnea; reinitiate therapy with a reduced dose. Measure bone mineral density of lumbar spine and/or femoral neck after 1–2 yr of testosterone therapy in hypogonadal men with osteoporosis or low trauma fracture, consistent with regional standard of care. Monitoring Men Receiving TRT

Evaluate formulation-specific adverse effects at each visit: Injectable testosterone (enanthate, cypionate, and undecanoate): ask about fluctuations in mood or libido, and rarely cough. Testosterone gels: advise patients to cover the application sites with a shirt and to wash the skin with soap and water before having skin-to- skin contact, can be transferred to a woman or child who might come in close contact. T levels are maintained when the application site is washed 4–6 h after application of the testosterone gel. Testosterone pellets: look for signs of infection, fibrosis, or pellet extrusion. Monitoring Men Receiving TRT

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.

Androgen-Deprivation Therapy in Prostate Cancer and Cardiovascular Risk A Science Advisory From the American Heart Association, American Cancer Society, and American Urological Association Endorsed by the American Society for Radiation Oncology

Androgen-Deprivation Therapy in Prostate Cancer and Cardiovascular Risk There is a substantial amount of data demonstrating that ADT adversely affects traditional cardiovascular risk factors: Including serum lipoproteins. Insulin sensitivity. Obesity.

Androgen-Deprivation Therapy in Prostate Cancer and Cardiovascular Risk Despite the metabolic effects of ADT and the possible increased cardiovascular risk. There is no clear indication for patients for whom ADT is believed to be beneficial to be referred to: Internists, endocrinologists, or cardiologists for evaluation before initiation of ADT

Androgen-Deprivation Therapy in Prostate Cancer and Cardiovascular Risk Given the metabolic effects of ADT, it is advisable that patients in whom ADT is initiated be referred to their primary care physician for periodic follow-up evaluation

Androgen-Deprivation Therapy in Prostate Cancer and Cardiovascular Risk The American Heart Association and other expert organizations, recommend, when appropriate: Lipid-lowering therapy. Antihypertensive therapy. Glucose lowering therapy. Antiplatelet therapy.

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.

Take Home Message

Take Home Message Recommendation 1: Definition Hypogonadism is a clinical and biochemical syndrome associated with advancing age and characterized by symptoms and a deficiency in serum T levels. Recommendation 2: Clinical Diagnosis The diagnosis of hypogonadism requires symptoms and signs suggestive of T deficiency. Most common symptom is low libido. Others include ED, sarcopenia, osteopenia/osteoporosis, increased body fat, decreased vitality, and low mood. None of them is specific for T deficiency and must be corroborated with a low T level. Questionnaires such as AMS and ADAM are not recommended for diagnosis of hypogonadism because of low specificity.

Take Home Message Recommendation 3: Laboratory Diagnosis Patients suspected of low T need a biochemical workup. Risk factors for hypogonadism in older men include chronic illnesses (diabetes, chronic obstructive lung disease, and renal and HIV-related diseases), obesity, metabolic syndrome, and hemochromatosis. A sample for T determination should be obtained between 7:00 and 11:00 AM. The most widely accepted test is serum total T. Measurement of free or bioavailable T should be considered when the total T is not diagnostic, particularly in obese men.

Take Home Message Recommendation 4: Assessment of Treatment Outcome and Decisions on Continued Therapy Failure to benefit within a reasonable interval (3 months is adequate for sexual function, others require a longer interval) should result in discontinuation of treatment. Seeking other causes of symptoms is then mandatory. Recommendation 5: Body Composition T administration improves body composition in hypogonadal men (decrease fat mass, increase lean body mass). Recommendation 6: Bone Density and Fracture Rate Osteopenia/osteoporosis and fracture prevalence rates are greater in hypogonadal men. Bone density in hypogonadal men increases under T treatment.

Take Home Message Recommendation 7: Testosterone and Sexual Function The initial assessment of all men with ED and/or diminished libido should include determination of serum T. Men with ED and/or diminished libido and documented T deficiency are candidates for therapy. There is evidence suggesting therapeutic synergism with combined use of T and phosphodiesterase-5 inhibitors in hypogonadal men. Recommendation 8: Testosterone and Obesity, Metabolic Syndrome, and Type 2 Diabetes Several components of the metabolic syndrome are also present in hypogonadal men.

Take Home Message Recommendation 9: Carcinoma of the Prostate and Benign Prostatic Hyperplasia There is no conclusive evidence that T therapy increases the risk or carcinoma of the prostate or benign prostatic hyperplasia. Prior to TRT, the risk of carcinoma of the prostate must be assessed using, as a minimum, direct rectal examination and PSA screening. During treatment, patients should be monitored for prostate disease at 3 to 6 months, 12 months, and at least annually thereafter. Severe lower urinary tract symptoms (>19 in IPSS) due to benign prostatic hyperplasia represent a temporary contraindication. After successful treatment of these symptoms this contraindication is lifted. Men successfully treated for prostate carcinoma and suffering from confirmed low T are potential candidates for TRT after a prudent interval if there is no clinical or laboratory evidence of residual cancer.

Take Home Message Recommendation 10: Treatment and Delivery Systems Available intramuscular, subdermal, transdermal, oral and buccal preparations of testosterone are safe and effective. Recommendation 11: Adverse Effects and Monitoring TRT is contraindicated in men with prostate or breast cancer. Men with significant erythrocytosis, untreated obstructive sleep apnea, and untreated severe congestive heart failure should not be treated with T until resolution of the comorbid condition. Erythrocytosis might develop during treatment, especially with injectable preparations. Periodic hematologic assessment is indicated. Dose adjustments and/or periodic phlebotomy may be necessary. Recommendation 12: Age Age is not a contraindication to initiate testosterone treatment. Individual assessment of comorbidities and potential risks versus benefits of treatment is particularly important in elderly men.

Objective Objective: My objective was to update the guidelines for the evaluation and treatment of androgen deficiency syndromes in adult men published previously in The Endocrine Society Clinical Practice Guideline Prostate-Specific Antigen, Best Practice Statement: American Urological Association. 3.Guideline for the Management of Clinically Localized Prostate Cancer American Urological Association. 4.Campbell-Walsh Urology 10 TH Edition. chapter 29 – Androgen Deficiency in the Aging Male.

Thank you