Testosterone Replacement in Adults. John A. Seibel, MD, FACP, MACE

Transcription

1 Testosterone Replacement in Adults John A. Seibel, MD, FACP, MACE

2 Disclosures None! *Privately Authenticated

3 Definition of Male Hypogonadism inadequate gonadal function, as manifested by deficiencies in the secretion of gonadal hormones. American Association of Clinical Endocrinologists Guidelines (2002) Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6): Petak SM, et al. Endocr Pract. 2002;8(6):

4 Definition of Hypogonadism Male gonadal dysfunction Low levels of testosterone May be congenital or acquired Winters SJ. Arch Fam Med. 1999;8: ; Petak SM, et al. AACE Clinical Practice Guidelines. Available at: Accessed October 16, 2003; Tenover JL. Endocrinol Metab Clin North Am. 1998;27:

5 Low Testosterone Is Increasingly Common as Men Age 1 in 10 Men in their 40s and 50s 1 in 5 Men in their 60s 1 in 4 Men in their 70s Available at: Accessed March 20, 2009.

6 Hypogonadism Testosterone Naturally falls with Age! Really? Then how do you Explain that only 50% of Men Age 85+ are deficient in Testosterone? Or Does it Fall Because of: Illness (Diabetes, HTN, HBP, Obesity, etc) Medications Exposure to Endocrine Disruptors

7 Prevalence of Hypogonadism Prevalence of Low Testosterone Million Men in the US Overall, 38.7% of men 45 years had testosterone levels <300 ng/dl % 40.2% 39.9% 45.5% 50% 38.7% to to to to Total Patients recruited for study from Mulligan T, et al. Int J Clin Pract. 2006;60(7): Patient Age Range

8 Conditions Associated with Hypogonadism

9 Prevalence of Low Testosterone in Other Conditions ED = erectile dysfunction 1. Daniell HW. J Pain. 2002;3: ; 2. Mulligan T, et al. Int J Clin Pract. 2006;60: ; 3. Grinspoon S, et al. Ann Intern Med. 1998;129:18-26; 4. Dobs AS. Baillière s Clin Endocrinol Metab. 1998;12: ; 5. Bodie J, et al. J Urol. 2003;169:

10 Secondary Hypogonadism (Pituitary Failure): Acquired Causes or Conditions Pituitary adenoma Inflammatory diseases (rheumatoid arthritis, Crohn s disease, ulcerative colitis) Respiratory disorders (asthma, COPD, sleep apnea) Iatrogenic (ketoconazole, glucocorticoids, spironolactone, cimetidine, phenytoin, flutamide, opioids) Other endocrine disorders (hyperprolactinemia, hypothyroidism) Alcohol or anabolic steroid abuse Winters SJ. Arch Fam Med. 1999;8: ; Tenover JL. Endocrinol Metab Clin North Am. 1998;27: ; Gordon GG, et al. J Clin Endocrinol Metab. 1975;40: ; Doerr P, Pirke KM. J Clin Endocrinol Metab. 1976;43: ; Tengstrand B, Carlstrom K, Hafstrom I. Rheumatology (Oxford). 2002;41:

11 Should Aging Processes be Treated?

12 Should Aging Processes be Treated? Reasons To Treat: Prevention of Fractures Disfigurement Reasons Not To Treat: Medication side effects

13 Should Aging Processes be Treated? Reasons To Treat: Prevention of Heart Attacks & Strokes Prevention of PAD Reasons Not To Treat: Medication side effects

14 Should Aging Processes be Treated? Reasons To Treat: Prevention of Osteoporosis Symptom Relief Reasons Not To Treat: CV problem Cancer Medications

15 Should Aging Processes be Treated? Reasons To Treat: Osteoporosis Symptom relief No mood swings Feels better in general Increase in lean muscle Decrease in fat Reasons Not To Treat: Medication side effects

16 Role of Testosterone in Male Health

17 The Impact of Testosterone Skin Hair growth, balding, sebum production Liver Synthesis of serum proteins Male Sexual Organs Penile growth, spermatogenesis, prostate growth, and function Bone Accelerated linear growth, closure of epiphyses Brain Libido, mood Muscle Increase in strength and volume Kidney Stimulation of erythropoietin production Bone Marrow Stimulation of stem cells Guyton AC. In: Textbook of Medical Physiology. 8th ed. 1991:

18 Role of Testosterone in Erectile Function Screening 19% of men with ED are known to have low testosterone % of patients are non-responsive to PDE5 inhibitors 2 Patients failing PDE5 inhibitors may warrant screening for low testosterone Causes of ED include several factors 3 Psychogenic Neurogenic Endogenic Vasculogenic Animal models suggest that the erectile pathway is testosterone dependent 4 Nitric oxide is necessary for penile erection Super beats won t help 1. Bodie J, et al. J Urol. 2003;169: ; 2. Salonia A, et al. Curr Med Res Opin. 2003; 19: ; 3. Yassin AA, Saad F. J Androl. 2008; 29: ; 4. Shabsigh R. Aging Male. 2004; 7:

19 Symptoms of Androgen Deficiency Reduced libido and sexual activity Fatigue Reduced muscle mass and strength Depressed mood Decreased energy or vitality Hot flashes, sweats Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6): Morelli A, et al. J Endocrinol Invest. 2007;30(10):

20 Signs of Low Testosterone Incomplete sexual development Breast discomfort, gynecomastia Increased body fat Reduced muscle bulk and strength Lack of effect of PDE5 inhibitors for erectile dysfunction Low BMD Loss of body hair (auxiliary and pubic), reduced shaving Low or zero sperm count Adapted from Bhasin S, et al. J Clin Endocrinol Metab. 2006;91:

21 Total Testosterone (ng/dl) Diurnal Variation in Serum Total 800 Testosterone Levels 700 Young Men Older Men am noon 4 pm 8 pm midnight 4 am 8 am Time Bremner WJ et al. J Clin Endocrinol Metab. 1983;56:

22 Circulating Testosterone 2% 38% 60% SHBG = sex-hormone binding globulin. Adapted from Braunstein GD. In: Basic & Clinical Endocrinology. 5th ed. Stamford, Conn: Appleton & Lange; 1997:

23 Diagnosing Low Testosterone Signs and symptoms 1 Clinical laboratory diagnostic tests 1 Total testosterone levels (<300 ng/dl)* Bioavailable testosterone (<70 ng/dl) Free testosterone (<50 pg/ml) Screening tools ADAM (Androgen Deficiency in the Aging Male) Questionnaire 2 AMS (Aging Males' Symptoms) Scale 3 MMAS (Massachusetts Male Aging Study) Questionnaire 4 *Most frequently used lab test for the diagnosis of hypogonadism. 1. AACE Hypogonadism Task Force. Endocrinol Pract. 2002;8: ; 2. Morley JE, et al. Metabolism. 2000;49: ; 3. Moore C, et al. Eur Urol. 2004;46:80-87; 4. Smith KW, et al. Clin Endocrinol. 2000;53:

24 Diagnosing Low Testosterone Signs and symptoms 1 Clinical laboratory diagnostic tests 1 T-3 Trials have established new normal Total testosterone levels ( ) *Most frequently used lab test for the diagnosis of hypogonadism. 1. AACE Hypogonadism Task Force. Endocrinol Pract. 2002;8: ; 2. Morley JE, et al. Metabolism. 2000;49: ; 3. Moore C, et al. Eur Urol. 2004;46:80-87; 4. Smith KW, et al. Clin Endocrinol. 2000;53:

25 Diagnostic Testosterone Testing: LH and FSH Additional Tests To ascertain whether cause is primary or secondary Serum prolactin High prolactin levels may suggest presence of pituitary tumor Braunstein GD. Testes. In: Basic & Clinical Endocrinology. 5th ed. Stamford, CT: Appleton & Lange; 1997: Tenover JL. Endocrinol Metab Clin North Am. 1998;27:

26 Testosterone-Replacement Therapy Dosing and Administration Intramuscular Injection Testosterone enanthate or cypionate mg weekly or mg every 2 week Transdermal Patches (Nonscrotal) mg applied nightly for 24 hours Nasal Inhalation Must inhale 2-3 times daily Transdermal Gels 1% 5-10 g applied daily (5-10 mg testosterone systemically absorbed) Buccal Tablets 30 mg tablet applied to the buccal mucosa every 12 hours Pellets mg implanted subcutaneously every 3-6 monts * Androderm [package insert]. Watson Pharma, Inc; Testopel [prescribing information]. Slate Pharmaceuticals, Inc; Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6):

27 Nasal Testosterone 73% of subjects achieving target levels of total T ( ng/dl) at 90 days Compliance as frequent dosing (BID, TID) is needed 11% had nasal symptoms (discomfort, dryness, congestion, epistaxis, rhinorrhea)

28 Testosterone Undecanoate TU has a longer half life due to a longer hydrophobic side chain In the United States it is only available through a REMS program TU (750 mg) is administered in 3 ml by a nurse in a clinic with a certified provider The patient needs to wait for 30 minutes after the injection to see if he develops a Reaction.

29 Testosterone Undecanoate Reaction anaphylaxis or a Pulmonary Oil Microembolism (POME) reaction which typically presents with a cough Dosing in United States is time 0, 4 weeks, every 10 weeks thereafter Number of IM injections/year: 26 with T esters (TE) versus 4-5 with TU

30 Transdermal Gels Are the Most Commonly Prescribed Form of TRT Gels Injectables 17% 10% Patches Other (includes buccal) 70% 3% IMS NPA; 2008.

31 Testosterone Levels After Replacement With Gel or Injection* Testosterone Gel Injection 1000 ng/dl Normal range of testosterone 300 ng/dl Time (d) Sub-therapeutic levels of testosterone *Schematic representation; not an actual study.

32 Monitoring After Initiation of Testosterone Replacement Therapy Adapted from Bhasin, et al. J Clin Endocrinol Metab. 2006;91: and Rhoden EL, et al. N Engl J Med. 2004;350:

33 What About Prostate Cancer? Geriatric patients may be at an increased risk for prostatic hyperplasia and prostatic carcinoma PSA levels in hypogonadal men are often abnormally low 1,2 TRT may increase PSA levels reflecting normalization and typically plateau within 12 months of initiating therapy Increases in PSA levels beyond this warrant further screening 1. Bhasin, et al. J Clin Endocrinol Metab. 2006;91: ; 2. Miner M, et al. Postgrad Med. 2008;120:

34 Reasons for Urological Consultation Serum PSA concentration >4 ng/ml An increase in serum PSA >1.4 ng/ml within any 12-month period of T replacement A PSA velocity of >0.4 ng/ml/yr using the PSA level at 6 months after initiation of T replacement as the reference Only applicable if PSA data are available for a period >2 years Detection of prostatic abnormality on DRE AUA = American Urological Association; DRE = digital rectal exam; IPSS = International Prostate Symptom Score; PSA = prostate specific antigen. Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6):

35 Benefits of TRT

36 Testosterone-Replacement Therapy Contraindications and Precautions Contraindications Male breast cancer Prostate cancer (known or suspected) Use in pregnant or breast-feeding women Known or suspected sensitivity to ingredients used in T delivery systems Precautions Benign prostatic hyperplasia (BPH) Lower urinary tract symptoms (LUTS) Edema in patients with preexisting cardiac, renal, or hepatic disease Gynecomastia Precipitation or worsening of sleep apnea Azoospermia Testicular atrophy BMD = bone mineral density; DRE = digital rectal exam; PSA = prostate specific antigen; TRT = testosterone-replacement therapy. Bhasin S, et al. J Clin Endocrinol Metab. 2006;91(6):

37 Discontinuation of IM Testosterone leads to Restoration of Sperm Production Restoration of Baseline Sperm Count Baseline 54% (46-60) Within 6 months 10 Mill/ml 83% (75-89) within 12 months 20 Mill.ml 95% (89-98) within 16 months 100% within 24 months Liu PY, et al. Lancet. 2006;367(9520):

38 HUMAN CHORIONIC GONADOTROPIN (hcg) Placental glycoprotein homologue of LH Because of its similarity to LH, HCG can be used to induce testosterone production in the testes Products from urine Pregnyl, Follutein, Profasi, Choragon and Novarel Recombinant: Ovidrel

39 Clomiphene Citrate Effectively Raises Testosterone Levels Use instead of Testosterone Raise serum T levels comparable to gels May improve semen parameters, but the effect is inconsistent Side effects: gynecomastia, weight gain, hypertension, acne

40 Treatment Testosterone enanthate 200mg/week AND hcg 0, 125, 250 or 500 IU qod Measure serum gonadotropin should be above normal Spermatogenesis can be preserved Tung-Chen Heish, et al J Urol Feb;189(2):

41 Clomiphene Effective Baseline Post Treatment LH, IU/mL 2.6 IU 6.8 IU FSH, IU/mL 1.9 IU 7.6 IU Total testosterone ng/dl 192ng/ml 485 ng/ml Katz DJ, et al. BJU Int Nov 1. doi: /j X x.

42 Clomaphene Side Effects Psoratic Arthropathy Depression Erythrocytosis Ischemic stroke

43 AROMATASE INHIBITORS (AI) Drug Aromatase Inhibition Half Life Dosing Male Clinical Data Anastrozole (Arimidex) Non-steroidal, Competitive 47 h 0.5-1mg PO QD-QOD Hypogonadism Gynecomastia Letrozole (Femara) Non-steroidal, Competitive 48 h mg PO QD-QOD Hypogonadism Gynecomastia Infertility Exemestane (Aromasin) Steroidal, Irreversible 24 h mg PO QD Male breast cancer J Clin Endocrinol Metab. 2006; 91: 3324

44 Letrozole in Males: Gynecomastia and Infertility J Clin Endocrinol Metab. 2014; 99: E2673. Asian J Androl. 2011; 13: 895. Male Infertility - 27 infertile men, mean age 35 yo, T <330 ng/dl - Letrozole 2.5 mg/d for 6 months Results: - Increases in T, LH, decreases in E - Increases in sperm count, motility, ejaculate volume J Clin Endocrinol Metab. 2014; 99: E2673. Asian J Androl. 2011; 13: 895.

45 Aromatase Inhibitors Side effects Decrease in bone mineral density PE within 2 days of last dose Joint and tendon Pain Limb swelling Depression and breast tenderness

46 Judge Sets 19 Trial Dates for Androgel Cases Between October 2018 and March 2019 Unless agreements are reached to resolve Androgel cases filed by thousands of men who claim they have suffered heart attacks, strokes and other injuries following use of the testosterone gel, AbbVie will face 21 different bellwether trials over the next year, with at least 19 cases set to begin between October 2018 and March There are currently more than 6,500 product liability lawsuits filed against AbbVie and pharmaceutical companies in the federal court system, each raising similar allegations that the drug makers failed to adequately warn about the side effects of the testosterone treatments, which plaitiffs also claim were widely over-marketed to men without any real medical need

47 FDA Concerns Prompt New Warning FDA Concerns Use of TRT Risk of CVD, VTE and stroke FDA requires boxed warning on all TRT products since 6/14, 3/15. Decision made based on 4 trials (Vigen, Finkle, Basaria, Xu). All with methodological flaws or misleading results. Concern with inappropriate use and use in aging men

48 Corona Meta-analysis of TRT and CV events (MACE) Available evidence does not support a causal role between testosterone supplementation and adverse CV events when hypogonadism is properly diagnosed and replacement therapy correctly performed. Corona G, et al. Expert Opin Drug Saf. 2014;13:

49 Morganthaler Analysis Mayo Clinic Reviewed over 100 studies. Found the same 4 suggesting Increased CV Risk The rest had no evidence of increased CV risk. Showed improved CV Function. Increased Benefit for older men. Morganthaler, A et al Mayo Clin Proceed Feb 2015;2:p

50 Thank You!