Hypogonadism in Men CME Away India & Sri Lanka March 23 - April 7, 2018 Richard A. Bebb MD, ABIM, FRCPC Consultant Endocrinologist Medical Subspecialty Institute Cleveland Clinic Abu Dhabi
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Barriers To Change
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Learning Objectives: Recognition of hypogonadism in men Treatment of hypogonadism in men Safety Issues CVD, Prostate & Thrombotic Risk
Hypothalamus GnRH Pituitary Testosterone LH FSH Testis Adapted from Bagatell CJ, Bremner WJ. N Engl J Med. 1996;334:707-715. Testosterone Sperm
Hypogonadism sub-types: Primary (testicular) Low T, high LH and FSH Secondary (pituitary/hypothalamic) Low T, low or inappropriately normal LH and FSH Mixed primary and secondary (eg age related hypogonadism)
Clinical Approach to Hypogonadism Primary: Secondary: Irreversible Replace T if indicated Fertility is not possible a) Structural: Irreversible Replace T if indicated Fertility is possible b) Functional: May be reversible Replace T if indicated Fertility is possible
Secondary Hypogonadism Structural Pituitary tumor Pituitary radiation Traumatic brain injury Hemochromatosis (most) Functional Hyperprolactinemia Obesity Sleep Apnea (some) Opioids Post exogenous T exposure Medication exposure (eg prednisone)
Hypogonadism: Signs & symptoms Loss of strength, energy, motivation 1,2 Decrease in lean body mass, muscle volume; increased visceral fat 1,2 Fatigue, lethargy, sleep disturbance 1,2 Decrease in body hair; skin alterations 2 Diminished libido, erectile dysfunction 1,2 Mood and cognitive changes 1,2 1. Practice Committee (ASRM).Fertil Steril 2004;81:1437-1440. 2. Nieschlag E, Swerdloff R, Behre HM et al. The Aging Male 2005;8(2):56-8.
Clinical Manifestations 1,2 Decreased libido Decreased vitality Fatigue Mood changes Insomnia Anemia Delayed ejaculation Flushes Erectile dysfunction Decreased muscle mass Increased visceral body fat Testicular atrophy Weakness Osteopenia/osteoporosis Loss of facial, axillary and pubic hair Degree of Deficiency Manifestations may present alone or in combination 1. Liu PY, et al. J Clin Endocrinol Metab. 2004; 89:4789-4796. 2. Zitzmann M, et al. J Clin Endocrinol Metab. 2006;91:4335-4343.
ACTION SITES OF TESTOSTERONE Brain: hippocampus, frontal lobes Skin: hair growth, sebaceous glands Liver: protein synthesis Adipose tissue: control of leptin Muscles: volume and strength Marrow: hematopoietic cells Joints: synovial sheaths Bone: protein matrix Kidney: erythropoietin Prostate: development and function
Hypogonadism: Prevalence HIM Study Prevalence rate and odds ratio for hypogonadism by risk factors Mulligan T et al. Int J Clin Pract 2006;60:762-769.
Testosterone: When to measure Presence of symptoms 1,2 Unexplained anemia 1 Osteopenia/Osteoporosis 1 Type 2 Diabetes 3 1. Practice Committee (ASRM).Fertil Steril 2004;81:1437-1440. 2. Nieschlag E, Swerdloff R, Behre HM et al. The Aging Male 2005;8(2):56-8. 3. Bhasin S, et al. J Clin Endocrinol Metab. 2006;91:1995-2010.
Diurnal Cycle of Testosterone Bremner et al. J Clin Endocrinol Metab 1983;56:1278-81.
Testosterone: Measuring & testing Bioavailable testosterone Total Testosterone
Initial Diagnosis 1 Tests to be included: Repeat T FSH CBC SHBG LH Ferritin Prolactin TSH PSA/DRE 1. Morales A, et al. CUAJ. 2010;4(4);268-274.
Diagnostic Triad for Hypogonadism Signs & Symptoms + Biochemical Confirmation Evidence + Response to Therapy Modified from Nieschlag E, Swerdloff R, Behre HM et al. The Aging Male 2005;8(2):56-8.
It is not just in the numbers.. Endocrine Society Guidelines: low levels (alone) do not establish a diagnosis of hypogonadism Canadian Guidelines: Androgen deficiency is a Clinical Diagnosis supplemented by Laboratory Testing (Dr. Dan Holmes) A Syndromic Diagnosis compared to: - Outcome Defined Normal Range: BP, Cholesterol, HgA1c - Normal Population Distribution: Calcium, CBC, folate
Benefits of Testosterone Replacement: (in Hypogonadal men) Sexual function Mood Energy Lean body mass Bone mineral density Fat mass Wang C et al. J Clin Endocrinol Metab 2004;89:2085-2098.
Symptom Improvement Timeline of Symptom Improvement 1 Enhanced libido Improved emotional well-being Increased energy Reduced ED Increased strength Enhanced BMD Improved cognition Enhanced cardiovascular health Decreased body fat Improvement in some components of MetS 0 3 6 12 Duration of Treatment (months) 1. Morales A, et al. CUAJ. 2010;4:268-274.
Healthy Man Study Serum Testosterone (nmol/l) 40 35 30 25 20 15 10 5 0 Testosterone Serum T did not vary with age n=325 men, 2900 serum specimens 40 50 60 70 80 90 Age (years) Sartorius G et al Clin Endocrinol 2012 ;77:755
European Male Aging Study (EMAS) Relationship between Age and Testosterone in 3220 Men 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 Wu FCW et al. J Clin Endocrin Metab 93(7): 2737-2745 (2008)
European Male Aging Study (EMAS) Relationship between Age and Testosterone in 3220 Men BMI <25 BMI 25-29 BMI 30 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 Wu FCW et al. J Clin Endocrin Metab 93(7): 2737-2745 (2008)
European Male Aging Study (EMAS) Relationship between Age and Testosterone in 3220 Men BMI <25 BMI 25-29 BMI 30 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 At BMI ~35, ½ of men in 2 0 hypogonadal range Wu FCW et al. J Clin Endocrin Metab 93(7): 2737-2745 (2008)
European Male Aging Study (EMAS) Relationship between Age and Testosterone in 3220 Men Co-morbidities and fall in serum T at any age Wu FCW et al. J Clin Endocrin Metab 93(7): 2737-2745 (2008)
Effect of weight loss on testosterone levels in Men with Type 2 Diabetes (n=10 to 58 men, 5 to 50 kg loss). Testosterone and the Metabolic Syndrome Grossmann M JCEM 2011;96:2341-2353
T Trial population Men > 65 years Serum total T <275 ng/dl plus 2 nd <300 ng/dl One or more symptoms potentially related to low testosterone
T Trials General enrolment criteria plus specific criteria for some trials; Physical Function Trial Sexual Function Trial Vitality Trial Cognitive Function Trial Anemia Trial Cardiovascular Trial Bone Trial Testosterone target range 500-800 ng/dl
Outcomes of T Trial in Aging (co-morbid) Men Sexual Function - Modest & transient benefits in some aspects ED: PDE5 inhibitors are more effective. Cognition and memory - not improved Vitality and fatigue -no benefits Physical function - some benefits in some testing procedures Bone - density improved: not compared to established therapies
GnRH Testosterone: Three hormones in one LH Testosterone 6 mg/day aromatase (0.2%) Hepatic oxidation & conjugation Renal excretion 5α-reductase (5-10%) Amplification (prostate, skin) DHT Direct pathway (muscle) Estradiol Diversification (brain, bone) Androgen receptor Androgen receptor Y Estrogen receptor Inactivation pathway D Handelsman www.endotext.org
T and E 2 needed for optimal male health 400 healthy men 20-50 years: GnRH agonist down-regulation Te (or placebo) gel 1.25-10 g daily for 16 weeks +/- anastrozole to block E2 synthesis Androgen deficiency: lean mass, muscle size, and strength Estrogen deficiency: increases in body fat Both contributed to decline in sexual function. Finkelstein JS et al N Engl J Med. 2013;369:1011
Implications of Three hormones in one Relative estrogen deprivation using nonaromatizable androgens (SARMs) or aromatase inhibitors can produce osteoporosis so: DO NOT USE!! Native testosterone is the treatment of choice
Current Treatment Options Intramuscular - Depo-Testosterone (T cypionate) - Delatestrel (T enanthate) - Nebido (T undecanoate) - Sustanon (30 mg Testosterone propionate. - 60 mg Testosterone phenylpropionate. - 60 mg Testosterone isocaproate. - 100 mg Testosterone decanoate) Oral - Andriol / Testocaps (T undecanoate) Testosterone patch Androderm (Testosterone) Testosterone gels - Androgel (1%, 1.6% Testosterone) - Testim (1% Testosterone) - Axiron (2% Testosterone) Other: T Pellets, T buccal, T nasal
Injectable Testosterone Advantages Infrequent administration Lower cost T undecanoate can be clinic administered Disadvantages Fluctuating blood level effects on libido, energy, and mood with short acting esters No diurnal cycle Polycythemia more common The Needle
Testosterone Undecanoate (oral) Advantages Oral Invisible Convenient Not hepatotoxic Disadvantages Variable absorption No diurnal cycle 2 to 3 times per day Must be taken with fatty foods Expense
Androderm Advantages Consistently Testosterone levels Mimics diurnal cycle Convenient, oncedaily therapy Disadvantages Visible Skin irritation can occur Expense
Androgel / Testim / Axiron Advantages Consistently Testosterone levels Mimics diurnal cycle Convenient, oncedaily therapy Disadvantages Potential for partner transfer (? Not Axiron) Expense Aroma (Testim)
Other T Methods T Pellets: surgical, extrusion, infection, cost Buccal: Frequent dosing, irritation Nasal: Cost, potential to limit transference
Contraindications suspected or confirmed carcinoma of the prostate or breast 1,2 significant polycythemia (hematocrit>50%) 1,2 untreated sleep apnea 1,2 severe heart failure (eg, class III or IV) 1,2 severe symptoms of lower urinary tract obstruction 1,2 clinical evidence of bladder outflow obstruction 1 undiagnosed prostate nodule or induration 2 unexplained elevation in PSA 2 1. Nieschlag E, Swerdloff R, Behre HM et al. The Aging Male 2005;8(2):56-8. 2. Bhasin S, Cunningham GR, Hayes FJ et al. J Clin Endocrinol Metab 2006;1995-2010.
Treatment Safety
Vigen R et al. J Am Med Assoc 310(17): 1829-1836 (2013)
Retrospective, non-randomized, observational study of 8,709 men, 61 to 64 yrs, who had undergone coronary angiography with a low serum total testosterone. Study Group Testosterone Rx Control Group Number of Subjects Deaths MI CVA Total Events/ group Event Rate before stats Event Rate after stats 1223 67 23 33 123 10.1% 25.7% 7486 681 420 486 1587 21.2% 19.9%
INCORRECT EXCLUSION SKEWED RESULTS Once MI or stroke occurred, men were no longer in the riskset Irrelevant whether or not they received T If included, this increases number of events in no-t group by 71% (1132 + 1587)
It gets worse. 9% of Vigen cohort found to be female!! Take Home Point: The Vigen Study is Rubbish
Shores M., et al. Arch Intern Med. 2006;166:1660-1665. Hazard Ratio: 1.88 95% CI: 1.34-2.63 P < 0.001 Low T associated with increased mortality Testosterone level Mortality 95% CI Normal 20.1% 16.2-24.1% Equivocal 24.6% 19.2-30.0% Low 34.9% 28.5-41.4% After adjusting for age, medical morbidity and other clinical covariates, low testosterone levels continued to be associated with increased mortality.
Survival of treated vs untreated T-deficient men N=1031 Men>40y T<250 ng/dl Mortality: 20.7% untreated 10.3% T treated P<0.0001 Shores et al, JCEM 2012
T Deficiency in DM Associated With Increased Mortality, Reversed with T Therapy 581 men T2DM F/u 5.8y Low T defined <300ng/dl (10.4 nmol/l Men with low T untreated HR 2.3 (CI95% 1.3-3.5; p=0.004) T therapy- Reduced from 19.2% to 8.4% Muraleedharan V et al. Eur J Endocrin 2013
Endocrine Society Guidelines There have been no RCTs that were large enough or long enough to determine the effects of T replacement therapy on major adverse cardiovascular events (MACE). In addition, there is no conclusive evidence that T supplementation is associated with increased cardiovascular risk in hypogonadal men.
Prostate Safety: Historical review Does exogenous testosterone cause prostate cancer to grow? based on result from one patient Current evidence no increase in cancer rates in clinical trials of TRT in normal men or men at increased risk no relationship of cancer risk with serum testosterone levels no reduced risk of cancer in men with low testosterone Morgentaler, A. Euro Urol 2006;50:935-939.
ng/dl ng/g Median serum [DHT] but no Δ in prostate [DHT] with Im T rx in older hypogonadal * 90 80 70 60 50 40 30 20 10 0 Baseline prostate [DHT] Treatment prostate [DHT] JAMA. 2006;296:2351-2361
Prostate Conclusions: No increase in prostate cancer rates in clinical trials of TRT in normal men or men at increased risk for PCa 1 Low serum free testosterone may be a marker of more aggressive prostate cancer 2 TRT results in: Modest in gland size (to eugonadal level) 3 No deterioration in urine flow, obstructive symptoms or other prostate symptoms 3 1 Morgentaler, A. Euro Urol 2006;50:935-939. 2 Hoffman et al. J Urol 2000;163:824-827. 3 Tremblay RR, Morales A. Aging Male 1998;1:213-218.
Testosterone and risk of venous thromboembolism VE: case-control study across 370 general practices in UK 19, 215 confirmed VEs (DVT, PE) 909, 530 age matched controls 10.0 additional VEs above the base rate of 15.8 per 10 000 person years. Starting testosterone Rx is associated with increased risk of VE peaking in 1 st six months Many of these patient may have a hereditary thrombophilia Martinez et al BMJ 2016 355:i5968
Monitoring Men on Testosterone Therapy For first year, patients should be monitored at 3, 6 and 12 months Assessment should include: Evaluate response to therapy Conduct DRE Measure: serum testosterone level selectively PSA Hematocrit (target <52%) liver function selectively HDL and cholesterol/hdl ratio Patients who remain stable may subsequently be followed up annually