LeRoy A. Jones, M.D. President Society Urologic Prosthetic Surgeons Urology San Antonio Clinical, Associate Professor Urology University of Texas HSC San Antonio Hormone replacement therapy in Men

San Antonio, Texas 2

Testosterone Replacement Progressive decline in serum testosterone with aging Pharmaceutical industry involvement Multibillion dollar industry! 3+ million men on US on T replacement! Fountain of Youth?

4 FT-01423/June 2011 Testosterone Regulation: Hypothalamic-Pituitary-Gonadal (HPG) Axis Testosterone Spermatozoa LH FSH 1. Gonadotropin-releasing hormone (GnRH) secreted from the hypothalamus stimulates anterior pituitary 2. Anterior pituitary releases follicle stimulating hormone (FSH) and luteinizing hormone (LH) 3. LH stimulates Leydig cells in the testes to produce testosterone 4. FSH stimulates Sertoli cells in the testes to produce spermatozoa GnRH Dandona P, Rosenberg MT. Int J Clin Pract. 2010;64(6): (-) Hypothalamus Pituitary gland Hypothalamus Posterior pituitary Anterior pituitary Testes (-)

Free 2% The Distinction Between Bioavailable and Total Testosterone: Why It Matters 5 Total testosterone Bioavailable testosterone SHBG, sex hormone–binding globulin. Braunstein GD. In: Basic & Clinical Endocrinology. 5th ed. Stamford, CT: Appleton & Lange; 1997: Albumin-bound 38%60% SHBG-bound

Testosterone Deficiency Testosterone deficiency (TD) is a clinical and biochemical syndrome characterized by a deficiency of testosterone, or testosterone action, and relevant symptoms and signs. ISSM 2014

Symptomatic Hypogonadism T< 15nmol/L loss libido/ energy T< 12nmol/L (346ng/dL) obesity T< 10nmol/L depression, sleep disturbance, poor concentration

8 FT-01423/June 2011 In the Hypogonadism in Males (HIM) Study, the Prevalence of Hypogonadism Was Estimated to Be Nearly 40% Mulligan T et al. Int J Clin Pract. 2006;60(7): % 34% 40% 46% 50% Total (45+) 45–5455–6465–7475–8485+ Age Range, years Prevalence of Hypogonadism, % The HIM study estimated the prevalence of hypogonadism (< 300 ng/dL) in 2165 men over 45 presenting to 95 primary care practices in the United States Reprinted from Int J Clin Pract, 60, Mulligan T, Prevalence of hypogonadism in males aged at least 45 years: the HIM study, , 2006, with permission of John Wiley & Sons, Inc.

9 FT-01423/June 2011 Common Comorbidities Among Hypogonadal Men in the HIM study Mulligan T et al. Int J Clin Pract. 2006;60(7): A history of hypertension, hyperlipidemia, diabetes, and obesity were each reported significantly more often by hypogonadal men compared with eugonadal men in the HIM study p<0.001 Patients, %

10 FT-01423/June 2011 Endocrine Society Guidelines for Screening for Low T Screening for low T is not recommended in all patients Bhasin S et al. J Clin Endocrinol Metab. 2010;95: Recommended Patients to Screen NOT Recommended to Screen Type 2 diabetes mellitus Treatment with medications, including opioids and glucocorticoids HIV-associated weight loss End-stage renal disease and maintenance hemodialysis Moderate to severe chronic obstructive lung disease Infertility Osteoporosis or low trauma fracture Sellar mass General population

11 FT-01423/June 2011 Low T Screening Tools While the general population should not be screened, the following tools can aid in diagnosis for patients where screening is recommended Endocrine Society guidelines recommend testing total testosterone by 2  Morning blood draw  No role for free testosterone (assay variability)  LH, PRL with repeat Testosterone  SHBG in obese and elderly 2. Bhasin S et al. J Clin Endocrinol Metab. 2010;95: Gavrilova N, Lindau ST. J Gerontol B Psychol Sci Soc Sci. 2009;64 (suppl 1):i94-i105.

12 FT-01423/June 2011 The Endocrine Society Clinical Practice Guideline (2010) for Evaluation of Adult Men With Suspected Hypogonadism BT, bioavailable testosterone; FSH, follicle-stimulating hormone; FT, free testosterone; LH, luteinizing hormone; SFA, seminal fluid analysis; SHBG, sex hormone-binding globulin; T, testosterone. Bhasin S et al. J Clin Endocrinol Metab. 2010;95: History and physical (signs and symptoms) Morning total T Low T value Exclude reversible illness, drugs, nutritional deficiency Repeat T [use FT or BT if suspect altered SHBG] LH + FSH SFA [if fertility issue] Exclude reversible illness, drugs, nutritional deficiency Repeat T [use FT or BT if suspect altered SHBG] LH + FSH SFA [if fertility issue] Confirmed low T (eg, total T 280–300 ng/dL) or FT or BT < normal (eg, FT 5–9 ng/dL) Confirmed low T (eg, total T 280–300 ng/dL) or FT or BT < normal (eg, FT 5–9 ng/dL) Low T, low or normal LH + FSH (Secondary) Low T, high LH + FSH (Primary) Normal T, LH + FSH Follow-upFollow-up Normal T Bhasin S, Journal of Clinical Endocrinology & Metabolism, Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline, 95, 6, 2010, Copyright 2010, The Endocrine Society.

13 FT-01423/June 2011 Testosterone Deficiency Treatment Current TRT modalities Application site and dose are not interchangeable across products 1. Dandona P et al. Int J Clin Pract. 2010;64(6): FORTESTA™ Gel [Prescribing Information]. Chadds Ford, PA: Endo Pharmaceuticals Inc; Axiron ® [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; TRT Modality Topicals Gel Patch Solution Injection Buccal system Subcutaneous pellets

Testoterone preparations Nieschleg E. Best Pract and Research Clinical Endo/Meta 29 (2015) 77-90

Testopel

Testosterone Therapy Delivery Systems: Adverse Effects Oral tablets Effects on liver and cholesterol (methyltestosterone) Pellet implants Require surgical procedure Infection, expulsion of pellet Intramuscular injections Fluctuation in mood or libido Polycythemia (especially in older patients) Transdermal patches Skin reactions at application site Transdermal gel Potential risk for testosterone transference to partner Tenover JL. Endocrinol Metab Clin North Am. 1998;27: Arver S, et al. J Urol. 1996;155: Parker S, et al. Clin Endocrinol (Oxf). 1999;50:57-62.

Follow-up 3-6 months for the first 1-2 years, yearly thereafter Laboratory evaluation: PSA, lipids, Hematocrit, testosterone

Testosterone Replacement Positive effects: Obesity Metabolic Syndrome Diabetes Osteoporosis

Hypogonadism and Infertility Exogenous testosterone will suppress spermatogenesis AUA survey- 25% of urologist will treat infertile man with testosterone! Recovery of spermatogenesis 5-9 months

Hypogonadism and Infertility HCG combination therapy for recovery of spermatogensis due to T use 49 men azoospermia/ severe oligospermia Combination HCG (3000 units SQ qod) supplement with clomophene citrate, anastrozole or recombinant FSH 47 (95.9%) recovered by 4.6 months, density 22.6 million/mL J Sex Med 2015 Jun;12(6)

Hypogonadism and Infertility Selective Estrogen Receptor Modulators: Clomiphene citrate- off label use 2 dia-stereoisomers: zuclomiphene and enclomiphene (half-life) Enclomiphene Citrate- correction of serum testosterone promote spermatogenesis

Prostate Cancer Prostate cancer stimulated by testosterone based on one patient (Huggins/Hodges 1941)! No evidence the T replacement causes prostate cancer Saturation Model (120ng/dl) Pts with Pca being treated

Conclusion Testosterone replacement therapy is safe Evidence based guidelines for follow up is important Determine reproductive status of the patient Treatment in the Pca pt should be by specialist in this area Need large randomized controlled trials

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