Testosterone Replacement Therapy Urology - Update

Hugo H Davila, MDUrology Center

St. Joseph Hospital

ObjectiveObjective: My objective is to update the guidelines for the evaluation and treatment of androgen deficiency syndromes in adult men published previously in 2006.

1.The Endocrine Society Clinical Practice Guideline 2010

2.Prostate-Specific Antigen, Best Practice Statement: 2009. American Urological Association.

3.Guideline for the Management of Clinically Localized Prostate Cancer 2007. American Urological Association.

4.Campbell-Walsh Urology 10TH Edition . chapter 29 – Androgen Deficiency in the Aging Male.

AgendaDiagnosis of Hypogonadism

SymptomsLabs

Testosterone Replacement Therapy (TRT) IndicationsBenefitsFormulation• 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 ReplacementStep 1

What are those symptoms and Signs?More specific symptoms and signs

Incomplete or delayed sexual development, eunuchoidismReduced sexual desire (libido) and activity

Decreased spontaneous erectionsBreast discomfort, gynecomastia

Loss of body (axillary and pubic) hair, reduced shavingVery small (especially 5 ml) or shrinking testes

Inability to father children, low or zero sperm countHeight loss, low trauma fracture, low bone mineral density

Hot flushes, sweats

Other less specific symptoms and signs

Decreased energy, motivation, initiative, and self-confidenceFeeling sad or blue, depressed mood, dysthymia

Poor concentration and memorySleep disturbance, increased sleepiness

Mild anemia (normochromic, normocytic, in the femalerange)

Reduced muscle bulk and strengthIncreased body fat, body mass index

Diminished physical or work performance


What is next?

Measurement of morning total testosteronelevel by a reliable assay (mass spectrometry) as the initial diagnostic test.

Confirmation of the diagnosis by repeatingmeasurement 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 upN= 702TT <450 ng/dlAfter 11 years 45% of those men developed

MS and DM

Diabetes care. Vol 27.2004. 1036-1041

Definition of Metabolic syndrome

NHLBI and WHO need >3 of the following

Obesity waist circumference >94cm (40 in)Triglycerides mg/dl >150HDL mg/dl <40BP mmHg >130/85Glucose mg/dl >110

Metabolic syndromeHypogonadism 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 CHFCHF is a complex multistep Disease

Disrupt the endocrine and metabolic systemImpaired exercise capacity and fatigueAssociated with Low testosterone levels

25% of hypogonal men have CHF

Aukrust P, et al. J Am Coll Cardiol 2009;54(10)928-929.

Diagnosis of Hypogonadism?


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


Do I need any other test?

Measurement of free or bioavailable testosteronelevel, using an accurate and reliable assay, in somemen in whom total testosterone concentrations are near the lower limit of the normal range and in whom alterations of SHBG are suspected.


What are the conditions that affects SHBG?

Conditions associated with decreased SHBG concentrations

Moderate obesityNephrotic syndromeHypothyroidismUse of glucocorticoids, progestins, and androgenic steroidsAcromegalyDiabetes mellitus

Conditions associated with increased SHBG concentrations

AgingHepatic cirrhosis and hepatitisHyperthyroidismUse of anticonvulsantsUse of estrogensHIV disease

Recommendations


Recommendation 1

Avoid treatment in men without unequivocally low testosterone levels and symptoms.


Recommendation 2

Avoid labeling men with low testosterone levels dueTo:1.SHBG abnormalities.2.Natural variations in testosterone levels. 3.Transient disorders as requiring testosterone therapy.

Do we need any other tests?

Testosterone ReplacementSometimes,

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)

Infertility2 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.


Recommendation 3

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

Do we need to screen the general population for hypogonadism?


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 ReplacementYes,

Patients in whom there is high prevalence of low testosteroneLevels:

•Sellar mass, radiation to the sellar region, or other diseases ofthe sellar region•Treatment with medications that affect testosteroneproduction or metabolism, such as glucocorticoids andopioids•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


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.


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

What about symptoms Questionnaires?


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


Recommendation 4

The recommendation in favor of measurement testosterone levels in those conditions in which there is a high prevalence of low testosterone levels


SymptomsLabs






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 ReplacementWhat are the benefits of TRT?

Testosterone therapy of hypogonadal men isassociated with improvements in:1.Overall sexual activity, frequency of sexual thoughts 2.Increase in the frequency and duration of nighttime erections3.Increases hair growth. 4.Increases fat-free mass and muscle strength5.Increases bone mineral density6.May improves the positive and reduces the negative aspects of mood7.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.

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.


•Bone mineral densityThe panel did not find any trials reporting the effect of testosterone on bone fractures.

•Body compositionTRT was associated with a significantly greater increase in lean body mass (LBM) (2.7kg; 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 functionTRT 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 functionTwo placebo-controlled trials yielded imprecise resultsregarding 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.

•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.

Testosterone Replacement•Quality of lifeThe results were inconsistent across trials and imprecise.

•DepressionThe effects of testosterone therapy on depression have been inconsistent across trials.

•CognitionThree placebo-controlled, randomized trials, reported imprecise effects on several dimensions of cognition, none of which was significant after pooling.


•HIV-infected men with weight lossClinicians 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.


•Glucocorticoid-treated menWe 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.


SymptomsLabs



• Adverse Effect • Androgen-Deprivation Therapy (ADT) in Prostate Cancer

and Cardiovascular Risk. • Monitoring men in TRT


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.

Testosterone ReplacementClinical Pharmacology TRT•Testosterone Gel (Androgel 1.6%, Fortesta 2%,

Axiron, Testim 1%)Androgel = ArmFortesta = Upper Thigh Axiron = Axilla 5-10 g T gel containing 50-100mg T QDayAdvantages: Correct symptoms, flexibility,

ease of application, good skin tolerabilityDisadvantages: Potential of transfer, skin irritation in some PT, moderately high

DHT levels.

Testosterone Gel•Testosterone Gel

Single center, randomized, double-blinded placebo-controlled study.>65 yo men (N=274)6 months Test gel 50 mgTT levels= 500-700 ng/dlEffect on: Muscle mass and strength, QoLResultsImproved muscle mass, physical function and

QoL

Sriniva-Smankar et al. J Clin Endocrino Metab, 2010; 409-420


Clinical Pharmacology TRT•T Pellets

3-6 pellets implanted SC, 3-6 monthsAdvantages: Correct symptoms.Disadvantages: Require surgical

incision, pellets may extrude spontaneously.


Clinical Pharmacology TRT•T Patch (Androderm)

1-2 patches, 5-10mg TestosteroneAdvantages: Correct symptoms, easy application.Disadvantages: Serum T in the low

normal range, skin irritation at the application site.


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.


SymptomsLabs





Prostate Cancer and TRTProstate 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 relativeswith prostate cancer.

PSA and TRT

Prostate Cancer and TRT

In men 40 yr of age or older who have a baseline PSAgreater 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 TRTProstate Cancer and TRT

We suggest estimating prostate cancer risk using the prostate cancer risk calculator

http://deb.uthscsa.edu/URORiskCalc/Pages/calcs.jsp

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 TRTContraindications for TRT

Avoid testosterone therapy in patientsWith:

Hematocrit above 50%.Untreated severe obstructive sleep

apnea. Severe lower urinary tract symptoms (AUA/

IPSS > 19).Uncontrolled or poorly controlled

heartfailure. In those desiring fertility.


SymptomsLabs





Adverse Effect of TRTAdverse Effect of TRT

37 randomized controlled testosteronetrials were reviewed:

Increases in hemoglobin.Increase hematocrit.Increase PSA.Decrease in high-density lipoprotein (HDL)Gynecomastia (breast exam)

Adverse Effect of TRT

Adverse Effect of TRT

Not different among testosterone- and placebo-treated men:

•Overall mortality.•Cardiovascular event rates.•Systolic and diastolic blood pressure.


SymptomsLabs





• Evaluate the patient 3 to 6 months after treatment initiation1. Testosterone Injection: T level midway

between injections = 400-700ng/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.


•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.



SymptomsLabs





Androgen-Deprivation Therapy in Prostate Cancer and Cardiovascular Risk

A Science Advisory From the American Heart Association, AmericanCancer 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.


Risk •Despite the metabolic effects of ADT

and the possible increased cardiovascular risk.

•There is no clear indication for patientsfor whom ADT is believed to be beneficial to be referred to:Internists, endocrinologists, or cardiologists for evaluation before initiation of ADT


Risk Given the metabolic effects of ADT, it

is advisable that patients in whom ADT is initiated be referred to their primary carephysician for periodic follow-up evaluation


Risk The American Heart Association

andother expert organizations, recommend, when appropriate:

•Lipid-lowering therapy.•Antihypertensive therapy.•Glucose lowering therapy.•Antiplatelet therapy.


SymptomsLabs





Take Home Message

Take Home MessageRecommendation 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 MessageRecommendation 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 MessageRecommendation 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 MessageRecommendation 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 MessageRecommendation 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 MessageRecommendation 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.

ObjectiveObjective: My objective was to update the guidelines for the evaluation and treatment of androgen deficiency syndromes in adult men published previously in 2006.

1.The Endocrine Society Clinical Practice Guideline 2010

2.Prostate-Specific Antigen, Best Practice Statement: 2009. American Urological Association.

3.Guideline for the Management of Clinically Localized Prostate Cancer 2007. American Urological Association.

4.Campbell-Walsh Urology 10TH Edition . chapter 29 – Androgen Deficiency in the Aging Male.

Thank you

Testosterone Replacement Therapy Urology - Update

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