Testosterone Therapy in the 21st Century Man.! Wayne Kuang MD MD for Men LLC 505 Urology LLC

Transcription

1 Testosterone Therapy in the 21st Century Man! Wayne Kuang MD MD for Men LLC 505 Urology LLC

2 Disclosures Wayne Kuang MD MenMD Theralogix United Therapies No testosterone products

3 MD for Men LLC Enlarged Prostate Prostate Cancer Screening No-Needle Vasectomy Erectile Dysfunction Testosterone Therapy

4 MD for Men / 505 Urology

5 MD for Men & 505 Urology LLC Dr. Alberto Corica! Robotics General Urology Prostate Cancer Kidney Cancer Bladder Cancer Female Urology Neurourology Advanced Stone Care

6 Low T

7 Testosterone Therapy T use in the US has increased by 300% from 1997 to 2012 Sales of T products in 2011: $1.6 billion Number of T prescriptions in 2011: 5.6 million Does NOT include Internet sales not requiring prescriptions

8 Testosterone Steroid hormone primarily made by the Leydig cells in the testicles 3-10mg/day is produced that corresponds to serum levels of ng/dl Small percentage is produced in the adrenals Activates Androgen Receptor

9 Circadian Rhythms tt peaks in the morning & troughs in the evening The rhythm flattens out after the age of 60 Young 27yo n=10 Elderly 70yo n=10 Bremner 1983 JCEM 56:1278 Plymate 2003 Clin Endo 58:710

10 Definition of Low T! "Hypogonadism in men is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone (androgen deficiency) and a normal number of spermatozoa due to a disruption of one or more levels of the hypothalamic-pituitary-testicular axis." -Endocrine Society Clinical Practice Guideline 2010 Bhasin 2010

11 Prevalence Hypogonadism in Males (HIM) (n=2165; <300ng/dL) % 50% % Low T % 40.2% 39.9% 38.7% Total Age Mulligan 2006

12 Associated Conditions Chronic opioid use: 74% Obesity: 52% Diabetes: 50% AIDS: 50% HTN: 42% Hyperlipidemia: 40% ED: 19%! Bodie 2003 J Urol 169: 2262; Daniel 2002 Pain 3:377; Dobs 1998 Ballieres Clin Endo Metab 12:379; Grinspoon 1998 Ann Intern Med 129:18; Mulligan 2006 Int J Clin Practice 60:762

13 Diagnosing Low T Look for signs & symptoms Test for a serum morning total T If normal, then stop here Confirm with a 2nd morning serum total T with LH & FSH If normal, then can stop here Consider SHBG Free T Semen analysis Consider Prolactin Bhasin 2010: Endocrine Society Clinical Guidelines

14 HPG Axis Hypothalamus GnRH Pituitary LH Testes T uptodate.com

15 Hypogonadism Primary Klinefelter syndrome Cryptorchidism Post-orchitis Testicular trauma Autoimmune testicular failure Testicular irradiation After chemotherapy Hemochromatosis Secondary Kallmann s syndrome Hypothalamic GnRH deficiency Prader-Willi syndrome Laurence-Moon-Biedel syndrome Acquired hypogonadotropic hypogonadism Severe systemic illness Uremia Hemochromatosis!

16 2001 Baltimore Longitudinal Study on Aging n=850 / tt < 325 ng/dl 50% 49% 37.5% % Low T 25% 28% 12.5% 10% 12% 19% 0% Harmon 2001 Age

17 MAN-o-pause T declines as men age. A result of rising Sex Hormone Binding Globulin (SHBG) and therefore a decrease in Free/ Bioavailable T. Also increased hypothalamus/pituitary sensitivity to T which enhances the negative feedback inhibition (Decreased GnRH & LH). Carruthers 2009; Morales 2006

18 Protein-Bound T 1/3 T bound to Albumin Weakly bound so bioavailable 2/3 T bound to SHBG Tightly bound so NOT bioavailable Seidman

19 Bioavailable T NORMAL AGING MALE BIOAVAILABLE! (Free T + Weakly Bound to Albumin) 60% (2% Free T) 25% Vermeulen 1999 JCEM 84:3666 UNAVAILABLE! (Tightly Bound to SHBG) 40% 75%

20 Man-o-pause SHBG tt ft

21 Symptoms Depressed mood Impaired cognition / memory Decr strength Decr energy, motivation & self-confidence Decr joy Decr work performance Decr libido Erectile/orgasmic dysfunction!! Decr AM erections Bhasin 2010 J Clin Endo Metab 95:2536 Bassil 2009 Ther Clin Risk Manag 5:427 - Insulin resistance

22 Screening for Low T Three most common symptoms to predict Low T: ED Loss of AM erections Low sex drive Wu 2010 NEJM 363:123

23 Signs Low bone mineral density Oligospermia Azoospermia Anemia Incr body fat & BMI/truncal obesity Decr muscle mass Gynecomastia

24 Normal tt (ng/dl) Reference Range Lower Limit Upper Limit Quest ! TriCore Singulex Society of Endocrinology * FDA 300

25 Benefits

26 Benefits of T

27 DM2 -TIMES2 STUDY European multicenter study (R DB PC Pr) tt<350 ng/dl! 220 hypogonadal men with DM2 &/or metabolic syndrome! 6 months of TRT improved insulin resistance, glycemic control, body composition & libido! Jones 2011 Diabetes Care 34:828

28 Type II DM BLAST study in the UK First double -blind, placebo-controlled intervention study for type II DM 211 men Long acting T undecanoate 1000mg Hackett 2014 JSM 11:840

29 Type II DM Weeks HbA1c Testosterone Undecanoate Placebo Hackett 2014 JSM 11:840

30 Hip Fractures Case control study! Avg age 73yo! 28 cases fracture (last 25mos)! 28 matched controls! Jackson 1992 Ann J Med Sci 304(1): 4 % Hypogonadal % 32% 0 Hip Fracture None

31 DEXA in Low T Men Natl Osteoporosis Foundation recommends men with Low T to have Bone Marrow Density measurement. National Osteoporosis Foundation 2010

32 Muscle Mass Adipose Tissue 60 men (60-75yo) in a randomized double blind trial TE weekly x 20 weeks Increased fat-free mass, skeletal muscle mass and leg press strength Decreased fat mass Bhasin 2006 JCEM 90:678 Srinivas-Shankar 2010 JCEM 95:639

33 Risks

34 Lawsuits

35 Risks of TRT Polycythemia Edema Heart failure Liver dysfunction Gynecomastia Acne Azoospermia/Infertility Major Adverse Cardiac Event (MACE) Prostate enlargement Prostate cancer Worsening OSA Thrombosis (DVT/PE)

36 PSA & Supraphysiologic T Suppression of endogenous T with LHRH agonist Then IM T weekly (25-600mg) for 20 weeks No significant PSA rise despite supraphysiologic T levels Bhasin 2005 JCEM 90:678; Bhasin 2001 AJPEM 281: E1172; Morgantaler 2009 Eur Urol 55:310

37 PSA Rise with TRT Author # Months of Rx mg/day PSA Rise Morgantaler >= Wang Wang Steidle Dean Morgantaler Axiron

38 PSA Baseline PSA Final PSA Gels (n=47) Injections (n=57) Pastuszak Pellets (n=74)

39 Saturation Model 2006 JAMA At physiologic T levels, supplemental tesosterone has minimal effects on intraprostatic androgen levels and cell proliferation. A biphasic relationship between prostate growth & testosterone There is a threshold above which more testosterone does not result in more prostate growth. Marks 2006 JAMA 296:2351 Morgantaler 2009 Eur Urol 55:310 Tan 2014 Sex Med Rev 2: 112

40 Saturation Model Water for the Thirsty Tumor, t Food for the HHungry Tumor! Morgantaler 2009 Eur Urol 55:310

41 PSA & Prostate Ca Subset of Men with Prostate Cancer Baseline PSA ng/ml Final PSA ng/ml Gels (n=6) Injections (n=4) Pellets (n=8) Pastuszak

42 Polycythemia Defined as a hgb more than 18.5g/dL (approximately hct of 56.4) Caused by an increased erythropoietin (EPO) Results in increased viscosity At risk for thromboembolic events Managed with phlebotomy/ altering T dosing with goal of hct Bachman; 2009 McMullen; 2010 ESG

43 Thrombotic Events 2015 Retrospective study 153 men on TRT (475 ng/dl) 64 men not on TRT (236 ng/dl) Follow-up of >3 years Ramasamy 2015 Urology 86:283

44 Thrombotic Events On TRT Group Deaths: 0 Thrombotic events: 4 MI 1 / CVA 2 / PE 1 Off TRT Group Deaths: 5* Metastatic lung cancer 3 / Metastatic prostate cancer 1 / COPD 1 Thrombotic events: 0** *Statistically significant **Not statistically significant Ramasamy 2015 Urology 86: 283

45 TRT & Hematocrit 2015 Pastusnak

46 Does T Increase CV Events? JAMA 2013 A dataset of 8709 VA men s/p coronary angiography with prior T <300 ng/dl were retrospectively assessed for rates of death, MI & CVA. Risk increased by 5.8% from 19.9% in Non-T group vs. 25.7% in T group.

47 Study Shortcomings Retrospective Flawed inclusion criteria: All T men contributed to non-t group before starting T Flawed exclusion criteria: A large set of men with MI/CVA were excluded from non-t group (n=1132). Flawed data analysis: Statistics contradicted raw data analysis Non-matched groups for T: 207 ng/dl Non-T group vs. 175 ng/dl T group (p<0.001) Suboptimal mean T conc in treated group was only 332 ng/dl. Traish 2014

48 Raw Data Non-T Grp T Grp CV Events & TRT 50% reduction in CV Events % of Events Death MI CVA

49 2014 Meta-analysis Meta-analysis of placebo-controlled randomized clinical trials 75 articles evaluated 3016 men on TRT & 2448 men on placebo Mean duration of 34 weeks Testosterone was not related to any increase in CV risk Corona 2014 Expert Opin Drug Saf 13:1327

50

51 FDA March 3, 2015 We are requiring labeling changes...to reflect the possible increased risk of heart attacks and strokes associated with testosterone use. We are also requiring manufacturers...to conduct a welldesigned clinical trial to more clearly address the question of whether an increased risk of heart attack or stroke exists among users of these products.

52 T is Associated with Decreased Mortality Non-T Grp T Grp The relationship of TRT with mortality was investigated in VA men with T <250 mg/dl. Mortality was significantly less in the T-group 10.3% as compared to 20.7% in the Non-T group (p<0.0001). 0.22% 0.165% 0.11% 0.055% 0% 20.7% Mortality 10.3% Shores 2012

53 T Reduces Mortality Rate Normal T Low T Low T -Treated Diabetic men with low T (<300 ng/dl) have a higher mortality rate. 20% 15% 10% TRT can reduce that risk from 5% from 19.2% to 8.4% (p=0.002) 0% 9% 19.2% Mortality 8.4% Muraleedharan 2013

54 Future Studies

55 Therapy

56 Perfect TRT Formulation Produce "physiologic" levels of T for a prolonged period Reasonably safe Convenient dosing & administration method Affordable

57 Therapy Injections Gels Pellets Every 1-2 wks Daily Every 3-4 mos Supraphysiologic Low-Mid Normal Mid-High Normal Polycythemia Highs & Lows Poor Absorption Transference Bruising Soreness $ $-$$ $$$

58 TRT & Total T 2015 Pastusnak

59 IM Injection Gluteus Medius (upper outer quadrant of buttock) Avoid Superior Gluteal Artery & Sciatic Nerve Alternate sides

60 IM Injections 1300 Total Testosterone Dobs 1999 Days

61 Daily Gels 1300 Total T (ng/dl) Hours Steidle

62 Daily Gels 100% Percent who achieve tt ng/dL 149 men Patients (%) 84% 68% 52% 79.1% 79.5% 73.8% 36% 20% <= >32.4 BMI Dobs 2014 JSM 11:857

63 Pellets

64 Pellets 1300 Total T (ng/dl) Months McCullough 2012

65 Depot IM Injection Testosterone undecanoate solution in mixture of benzyl benzoate/refined castor oil 3mL (750mg) injection over seconds 0 week, 4 weeks then every 10 weeks thereafter 6x first year then 5x /yr Cleavage of undecanoic acid side chain by tissue esterases to release testosterone

66 Depot IM Injection Pulmonary Oil Microembolism Occurred with 4cc/1000mg Outside USA 9 events in 8 men of 3556 men Urge to cough, sob, throat tightening, chest pain, dizziness, syncope, Anaphylaxis 2 events in 3556 men Observation x 30 minutes Mandated Risk Evaluation & Mitigation Strategy program

67 Depot IM T Total Testosterone ng/dl Days After Injection Aveed

68 Monitoring for TRT Pre-TRT: two blood draws (tt then LH, FSH, hct) & psa/dre/ipss* Post-TRT titration: 2-4 hrs after transdermal application D2 and D5 after weekly IM T injection then D2 thereafter Post-TRT maintenance: q6mos: tt hct & psa/dre/ipss*

69 Other Therapies Fertility Preserving Selective Estrogen-Receptor Modulators (block E2-Rc at hypothalamus) HCG Injections Aromatase inhibitors Blocking conversion of T to E2

70 Cutting Edge TRT 2014 FDA approves first nasal T spray (minimizes risk of transference to women/kids) - Natesto 2 pumps TID = 33mg

71 !!! Thank you!!! Wayne Kuang MD (505) cell (505) mdformen.com

72 Bibliography Vigen 2013 JAMA 310:1829 Traish 2014 JSM 11: 624 Shores 2012 JCEM 97: 2050 Muraleedharan 2013 Eur J Endo 169: 725 Wang 2009 Aging Male 12(1): 5 Bhasin 2010 J Clin Endo Metab 95(6): 2536 Carter 2013 AUA Guideline McCullough 2012 J Sex Med 9: 594 Mulligan 2006 Int J Clin Pract 60: 762 NOF Clinician Guide to Prevention & Rx of Osteroporosis 2010 Osteo in Men 2008 NEJM 358: 1474 Carruthers 2009 Aging Male 12(1):21 Morales 2006 Eur Urol 50: 407 Harman 2001 J Clin Endo Metab 86(2): 784 Sharlip 2012 J Urol Steidle 2003 J Clin Endo Metab 88(6): 2673 Dobs 1999 J Clin Endo Metab (84(10): 3469