Testosterone Replacement. Seacourses Dec 30, 2017 January 6, 2018 Dr. Stacy Elliott

Transcription

1 Testosterone Replacement Seacourses Dec 30, 2017 January 6, 2018 Dr. Stacy Elliott

2 Copyright 2017 by Sea Courses Inc. All rights reserved. No part of this document may be reproduced, copied, stored, or transmitted in any form or by any means graphic, electronic, or mechanical, including photocopying, recording, or information storage and retrieval systems without prior written permission of Sea Courses Inc. except where permitted by law. Sea Courses is not responsible for any speaker or participant s statements, materials, acts or omissions.

3 Orgasmic threshold May be elevated Ejaculation Orgasm lincreased duration plateau phase May be altered Semen volume Arousal (Erection) Refractory period Increased duration

4 Sexual Function Changes with Age spontaneous & a.m. erections rigidity of erection: faster detumescence pre-ejaculatory sensation force/volume of ejaculation need to ejaculate Less orgasmically driven: more intimacy driven

5 Aging and lowered T - Age is not a specific risk factor for hypogonadism (HG) - Age alone is associated with little decline in mean total T levels ( > 40 years) until 70s and 80s - SHBG does increase with age, so bioavailable T (BioT) falls faster than total T (TT) - The lowering of T is more correlated with comorbidites, (DM, hypertension, hyperlipidemia, asthma/copd and/or kidney disease) regardless of age - BMI of 30 kg/m² tripled the risk of symptomatic HG (normal weight men 1:6, BMI > 35 kg/m² 2:3) - Low T likely a marker of poor health

6 Testosterone Biosynthesis

7 Male Reproductive Hypothalamus Hormonal Axis GnRH (-) (-) Pituitary LH FSH Estradiol Leydig cells Testicles Sertoli Cells Aromatase Testosterone Spermatogenesis DHT 5 reductase

8 Bioavailable testosterone ( 40%) (Free T + that loosely bound to Albumin) Total Testosterone (100%) Albuminbound 38% SHBGbound 60% Free 2%

9 Factors that Influence [SHBG] Lower SHBG Obesity Diabetes Hypothyroidism Nephrotic syndrome Glucocorticoid use Progestins Androgenic steroids Increase SHBG Aging Hepatic cirrhosis Hyperthyroidism HIV Estrogens

10 Diagnosis of Hypogonadism (HG) Classical primary HG: testicular failure ( Low T, elevated LH,FSH : hypergonadotrophic HG) Secondary HG: central (low T, low LH,FSH secondary to GNRH or LHRH failure : hypogonadotrophic HG) Adult onset hypogonadism (AOH) is a subgroup of men with signs and symptoms of HG without an adequate pituitary response to low T levels (normal or low levels of LH FSH) i.e. functional hyposecretion at the level of both the pituitary and the testes.

11 Testosterone: Target Organs Post puberty: Homeostasis & Metabolic Agent skin hair growth, balding, sebum production muscle strength, volume, energy reduction in visceral fat male sexual organs penile growth spermatogenesis, erection prostate growth and function brain libido, mood, cognition heart cardiovascular health liver protein synthesis kidney stimulation of erythropoietin production bone strength and density bone marrow stimulation of stem cells

12 Signs and symptoms* associated with testosterone deficiency syndrome Sexual: Decreased libido; erectile dysfunction; decreased frequency of morning erections; delayed ejaculation, reduced seminal volume, anorgasmia Somatic: Increased visceral body fat/obesity; decreased lean muscle mass; decreased strength; fatigue/loss of energy; decreased physical activity/ vitality; low bone mineral density; anemia; flushes; loss of facial, axillary and pubic hair/slow beard growth; decline in general feeling of well-being Psychological: Depression/depressed mood; mood changes; irritability; inability to concentrate; insomnia/sleep disorders * May be subtle

13 Signs and Symptoms of TDS Order of Appearance Mild Severe 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

14 Prevalence of Hypogonadism: HIM Study 1 1. Mulligan T, Frick MF et al. Int J Clin Pract. 2006; 60:762-9.

15 Watch for symptoms in high risk groups Metabolic syndrome and diabetes Obesity Untreated sleep apnea Head trauma or radiation Chronic neurological diseases ( SCI, MS,etc) Other chronic disease processes ( CRF, COPD) Refractory depression Anemia and sarcopenia of undetermined origin HIV and weight loss Glucocorticoid or opioid therapy ED with failed trial of PDE5i

16 What to order? Bioavailable T correlates best with symptoms The level of SHBG will dictate how much testosterone can actually get into the cells Practically total T if you are suspicious as Lifelabs will not do the bioavailable T unless total T is under 8.4 nmol/l The key is low T + symptoms = treatment potential Consistency is the key get 2 values Can have transient low T with comorbid illness, medications or malnutrition or variable time of day

17 Serum testosterone (ng/ml) Daily and Weekly Variability in T Examples of different response patterns 1 Up to 50% of young healthy men have temporary T levels below the normal range in a 24-hour Weekly period.( Spratt Variability et al in 1988) T Time (weeks) 1. Morley JE, et al. Metabolism. 2002;51:

18 What does the research say? Remember the spectrum testosterone levels that will demonstrate symptoms use common sense Patients below 10.4 nmol/l have a greater likelihood of symptoms ( 1) Low testosterone levels require confirmation and investigation of: 1 SHBG levels Serum luteinizing hormone (LH) Follicle-stimulating hormone (FSH) Prolactin Distinguish between primary and secondary causes (1) Bhasin et al. J Clin Endocrinol Metab. 2010;95:

19 Diagnosing - Symptomatic by history - Questionnaires can be too non-specific - Take a serum total T sample between 7 11* or within 3 hours of waking for shift workers - Investigate secondary or reversible causes

20 When to do Bioavailable T If your total testosterone comes back borderline or low normal on a symptomatic patient, you can ask for a BioT or SHBG to see how much bioavailable testosterone ( free T and that loosely attached to albumin) is available to the androgen receptor ( i.e. is he truly hypogonadal) But ask why? Canadian recommendation is for 3 month trial of those symptomatic men in the grey area ( nmol/l)

21 If you highly suspect hypogonadism Do appropriate bloodwork to save you and your patient time - baseline total testosterone - FSH, LH, prolactin, CBC ( Hct, Hb) - optional: TSH, IGF-1, ferritin, Fe sat, Vit D Assess prostate before instituting therapy - mandatory DRE and PSA

22 Low testosterone levels have been associated with: Sexual dysfunction Diabetes Metabolic syndrome Decreased max. exercise capacity Osteoporosis and increased fracture risk Decreased muscle mass Lower quality of life Increased cardiovascular risk ALL CAUSE AND CV MORTALITY Maggi et al. J Sex Med. 2007;4: ; Shelton et al. Urol Clin North Am. 2012;39:63-75; Ukkola et al. Ann Med. 2013;45:206-12

23 Lower T levels result in. Prostate Cancer Issues Greater risk of prostate cancer High Gleason scores Worse stage at presentation Worse survival Mental Health Issues Psychological effects, higher rate of depression in men with HG TRT alone may reverse dysthymia ( but not MDD) TRT can improve refractory depression

24 Metabolic Syndrome and T Androgen deficiency contributes to metabolic components of MetS but this is a bidirectional process Obesity men are more likely to be HG Visceral obesity causes inflammatory cytokines If you lose 15% of BW - you will gain T If you gain 10% more BW lose T by affecting cytokine level

25 T and insulin Testosterone maintains insulin sensitivity Men with normal / higher T levels have better insulin sensitivity and lower insulin levels than men with hypogonadism Insulin resistance is higher in men with lower T (hypogonadal)

26 T and Vascular system Men with higher T levels have lower carotid intimal thickness Since the health of endothelial cells depends on androgen ( due to improved eno) men with low levels of T have impaired flow mediated dilatation Men on ADT therapy are at higher risk for diabetes, CAD, MI and sudden death

27 Cardiovascular risk with low T Keating et al (Observational study) 16% increase in the risk of coronary heart disease events (death or myocardial infarction) in patients on androgen deprivation therapy Tsai et al (Observational study) 2-fold increased risk of fatal cardiovascular events over 10-year period in men on androgen deprivation therapy Ruige et al (Meta-analysis) In elderly men, low testosterone predicted increased risk for cardiovascular disease and/or mortality( it is uncertain if low T has a direct negative effect of it it indicates poor general health) 1. Keating et al. J Clin Oncol. 2006;24: ; 2. Tsai et al. J Natl Cancer Inst. 2007;99: ; 3. Ruige et al. Heart. 2011;97:870-5

28 Low T and Mortality Low endogenous testosterone levels are associated with an increased risk in mortality T: testosterone. 1. Shores et al. Arch Intern Med. 2006;166:

29 Bottom Line Rule out potentially reversible causes first sleep apnea, any way he can reduce his weight with lifestyle changes? If the man is low to low normal and symptomatic, it is worth a three month trial of androgen replacement If he is very low he is at risk for heart and bone issues should treat

30 Does T replacement correct ED? T and PDE5i Appears to be a threshold level of TRT ( to low normal range) that will improve ED, beyond that, no further improvement seen in sexual motivation or performance HG states likely down regulate the PDE5 enzyme (which seems to be crucial in determining metabolic and structural imbalance of the CC) = venous leak Men with ED who did not respond to monotherapy may respond to combination therapy (TRT + PDE5i) Majority of studies suggest TRT for PDE5i failures but some state combination doesn t help General consensus is to screen PDE5i failures for low T Aversa 2009, Kalinchenko 2003, Rosenthal 2006, Shabisigh 2006, Bhasin 2001, Buvat 2013

31 Risk associated with TRT When levels are supraphysiological - Erythrocytosis Gynecomastia Lowering of HDL* Others Testicular atrophy and infertility Acne Exacerbate pedal edema in heart failure patients ( esp early on therapy) Worsen untreated sleep apnea Stimulate growth of known prostate cancer ( so far not true) Worsen symptoms of BPH ( so far found to benefit!) Bassil et al. Ther Clin Risk Manag. 2009;5:427-48; Bhasin et al. Best Pract Res Clin Endocrinol Metab. 2011;25:

32 What about the prostate? BPH Testosterone is contraindicated in men with severe BPH-LUTS (IPSS >19) 1 Original consensus: testosterone therapy may worsen symptoms of BPH 1,2 Current view: testosterone therapy improves LUTS in men with low testosterone and mild BPH 3 Prostate Cancer Old view: use of TRT accelerated PCa (throwing fertilizer on a plant) New View: Prostate cancer is largely unaffected by variations in serum testosterone levels within the naturally occurring ranges Androgen Receptors are saturated at 4 nmol/l increasing beyond that will not cause further prostate growth ( providing water to a thirsty plant ) No recurrence of prostate cancer upon testosterone therapy.bhasin et al. J Clin Endocrinol Metab. 2010;95: ; 2. Bassil et al. Ther Clin Risk Manag. 2009;5:427-48; Shigehara et al. Aging Male Mar;14:53-8 Morgentaler. Urol Clin N Am. 2011;38:119-24; 2. Morgentaler Eur Urol. 2006;50:935-9; Kaufman et al. J Urol. 2004;172:920-2; 4. Khera et al. J Sex Med. 2009;6:

33 Saturation model in non-castrate men States that prostatic homeostasis is maintained by a relatively low level of androgenic stimulation Explains the observation that exogenous testosterone administration does not significantly increase intraprostatic androgen levels in hypogonadal men.

34 Giving men TRT with PCa Vancouver : treated 82 HG men with TRT - no biochem recurrence on 22 RP (PSA velocity per year) - 3/50 ( 6%) recurrence on radiation patients ( PSA velocity: 0.12 per year) - N=8 Active Surveillance (PSA velocity 1.1 ug/l per year increase), but no higher grade Gleason on subsequent biopsy Ory et al: J of Urology 196: Oct 2016

35 TAKE HOME MESSAGES for the prostate! Risks are associated with testosterone therapy and should be discussed and monitored in patients Prostate cancer is largely unaffected by variations in serum testosterone levels within the naturally occurring ranges Testosterone therapy may be considered on an individualized basis in patients who have had definitive local treatment for PCa with undetectable PSA levels PSA: prostate specific antigen.

36 Who gets TRT/who doesn t Yes Symptomatic men with low T who have been appropriately worked up Men with equivocal levels of T who are symptomatic can undergo a three month trial But TRT may worsen: erythrocytosis ( >50%), untreated obstructive sleep apnea, severe congestive heart failure No Men who have breast cancer or metastatic ( or high grade) prostate cancer Men with suspicious prostate nodule or PSA > 3 Men wanting fertility within the next 1-2 years Men with class III or IV heart failure

37 Giving men TRT with Advanced PCa SMSNA November 2017 Initial experience with TRT in 7 ( average age 69) selected HG men with advanced PCa wishing TRT despite recognizing potential risks of rapid PCa progression ( ). Gleason 7 (n=4), 8 ( n=1), 9 ( n=2) 6/7 had had ADT and discontinued :1/7 refused ADT despite bone metastases Median PSA at initiation of TRT = 2.1 ng/ml 4/7 had asymptomatic bone mets at initiation of TRT All reported improved energy, cognition, libido, sexual function and sense of well being No cases of disease flare, acute pain, or vertebral collapse 3 patients continue TRT, 2 DC with PSA> 20 ng/ml, 2 deceased Krawowsky Y, Morgentaler A : SMSNA Abstract 132 San Antonio 2017

38 Does TRT increase CV risk? Testosterone therapy does not increase cardiovascular risk and has been reported to have beneficial effects on patients with angina and heart failure (1-3) 1.Toma et al. Circ Heart Fail. 2012;5:315-21; 2. Malkin et al. Heart. 2004;90:871-6; 3. Carson et al. J Sex Med. 2012;9: THREE SCIENTIFALLY FLAWED BUT HIGH PROFILE STUDIES Tom trial of 2010 Vigen et al 2013 Finkle et al 2014

39 Event Rate per 1,000 Patient Years CARDIOVASCULAR EVENTS ARE NOT AFFECTED BY TESTOSTERONE TREATMENT * Placebo Testosterone *Odds ratio significantly different from placebo. CABG: coronary artery bypass graft. 1. Calof et al. J Gerontol A Biol Sci Med Sci. 2005;60:1451-7; 2. Carson et al. J Sex Med. 2012;9:54-67.

40 Testosterone Replacement Therapy (TRT) Goals: Symptom improvement Achievement of physiological T levels Several safe and effective formulations available Use ASTEP acronym to choose formulation: Availability Safety Tolerability Efficacy Preference s & solutions Invasiveness

41 Canadian Testosterone Formulations Testosterone Formulation Oral Testosterone undecanoate Intramuscular injections Testosterone cypionate Testosterone enanthate Brand Name Andriol pms-testosterone Depo-testosterone Delatestryl Testosterone patch Androderm Testosterone topical solution Axiron ( discontinued Dec 2017) Testosterone gel Tube Sachet/pump Testim AndroGel

42 TT: total testosteone. 1. Nehra et al. Mayo Clin Proc Aug;87(8): Recommendations for TRT Men with TT levels <8.0 nmol/l usually benefit from testosterone therapy Symptomatic men with TT between 8.0 to 12 nmol/l can be considered for a 4 to 6 month trial Continue testosterone therapy beyond 6 months, only in cases where clinical benefit is demonstrated Caution is warranted in men with history of congestive heart failure Easily titratable formulations (gel, topical solution or patch) should be considered for men >70 years, and those with chronic illness

43 Oral Medication Generic Name Dosage Testosterone undecanoate 1,2 ( Andriol) mg daily divided in 2 doses a a This dose should be taken for 2-3 weeks. Subsequent dosages may be reduced to mg daily. 1. Product Monograph: Andriol (testosterone undecanoate capsules) 40 mg. Kirkland, Quebec: Schering-Plough Canada Inc.; Product Monograph: pms-testosterone (testosterone undecanoate capsules) 40 mg. Montreal, Quebec: Pharmascience Inc.; 2009.

44 Mean T Concentration (ng/ml) The Effect of Food on Absorption of Testosterone Undecanoate mg Fed 80 mg Fasted Time (h) T undecanoate should be taken with a normal meal or breakfast to achieve proper T levels 1. Product Monograph: Andriol (testosterone undecanoate capsules) 40 mg. Kirkland, Quebec: Schering-Plough Canada Inc.; 2008.

45 Intramuscular (IM) Injectables Generic Name Testosterone cypionate 1 Depo-testosterone Testosterone enanthate 2 Delatestryl Dosage 200 mg every 2 weeks (Max. dose 400 mg per month) mg every 1-4 weeks 1. Prescribing Information: Depo-Testosterone (testosterone cypionate injection USP, Sterile Solution) 100 mg/ml. Kirkland, Quebec: Pfizer Canada Inc.; Prescribing Information: Delatestryl (testosterone enanthate, Solution for Injection) 200 mg/ml. Mississauga, Ontario: Theramed Corporation; 2007.

46 Transdermal Patch Testosterone Transdermal Delivery System (Testosterone 1 ) Dosage: 2.5 or 5 mg patch applied daily Mid-normal range 4 12 hours after application May require 2 x 5 mg patches in some men Main issue erythema 65.8% Vs % with Gels 1. Product Monograph: Androderm (testosterone, Transdermal Delivery System) 12.2 mg and 24.3 mg. Montreal, Quebec: Paladin Labs Inc.; 2007.

47 Transdermal T Gels Testosterone 1% Gel (Testosterone USP 1 ) Testosterone 1% Gel (Testosterone, Ph.Eur 2 ) Dosage: 5-10 g daily, to deliver mg of testosterone Easy to apply ( daily) 1. Product Monograph: AndroGel (testosterone gel) 1%. Markham, Ontario: Abbott Products Inc.; Product Monograph: Testim (testosterone gel) 1%. Malvern, Pennsylvania: Auxilium Pharmaceuticals Inc.; 2009.

48 Transdermal Topical Solution Product Concentration Dose Axiron 2% testosterone 2-4 actuations daily ( mg daily) Application Site Axilla Steady-state serum concentrations are attained within approximately 1 week of daily dosing BEING DISCONTINUED!! Ease of application (applied to axilla with applicator) Minimal side effects Flexible dosing ( 1 pump = 30 mg gel in 1.5 ml of solution) Low transference potential 1. Axiron Product Monograph. Eli Lilly Canada Inc.

49 Natesto Ease of administration, low dose, and no risk of secondary transference two or three daily doses (5.5 mg per nostril, 11.0 mg single dose). Total daily doses were 22 mg or 33 mg. Lower incidence of LH and FSH suppression Natesto( ) 11 mg b.i.d. or 11 mg t.i.d. restores normal serum total testosterone levels in most hypogonadal men. Erectile function, mood, body composition, and bone mineral density improved from baseline. Adverse event discontinuation rates were 2.1% (b.i.d.) and 3.7% (t.i.d.) Furthermore, DHT, DHT/T, and PSA levels produced by the nasal gel are among the lowest levels observed with a commercial formulation of testosterone Intranasal gel testosterone is detectable using conventional anti-doping tests Rogol et al Androlgoy Volume 5, Issue 4, 844, Article first published online: 17 July 2017

50 FORMULATION-SPECIFIC FOLLOW-UP Testosterone Therapy When To Measure Serum Testosterone: Evaluate Patient For: Oral (Andriol, 3-5 hours after ingestion Compliance Pms-Testosterone) 1,2 Taken with fat, split doses Testosterone patch 2-12 hours after application Skin reactions (Androderm) 1,2 Testosterone topical solution (Axiron) 3 Testosterone gel (Testim, AndroGel) 1,2 Intramuscular injections (Delatestryl, Depo-testosterone,) 1,2 Any time >1 week after initiation of topical solution Any time >1 week after initiation of gel use ideally 3-4 hours after application Midway between injections, or at trough Adherence to protocols which minimize transfer and maximize absorbance Adherence to protocols which minimize transfer and maximize absorbance Fluctuations in mood/libido Cough after injections Adjust dose (and/or frequency) to obtain testosterone levels in the mid-normal range 1. Bhasin et al. J Clin Endocrinol Metab. 2010;95: ; 2. Bebb. BCMJ. 2011;53:474-79; 3. Axiron Product Monograph. Eli Lilly Canada.

51 Monitoring At each appointment monitor: Symptom response (clinic) Changes in blood parameters T Hemoglobin Hematocrit PSA/DRE Refer if abnormal Frequency Every 3 6 months Year 1 Annually

52 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 Duration of Treatment (months) MetS = Metabolic Syndrome 1. Morales A, et al. CUAJ. 2010;4:

53 Non-response Non-response may be indicative of: Compliance issues Malabsorption Insufficient dose Unsatisfactory formulation Symptoms unrelated to TDS Long-term lack of response Consider referral to a specialist (endocrinologist/urologist) ED patients who fail T or PDE5i alone: Consider T plus PDE5i

54 Differences between men and women Objective arousal ( erections) is linked to subjective arousal/desire in men Physical changes of arousal ( vaginal lubrication, pelvic vasocongestion ) and the subjective experience can be two distinct entities in women correlation between subjective and objective arousal is poor in women Sexual behavior in aging women ( and men) not solely dependant on androgen levels Depression, relationship changes, partner loss, religious issues, anxiety about future, estrogen levels in women ( vasomotor symptoms sleep disturbances, vaginal effects) Increased prevalence of HSDD and low desire is not direct result of endogenous levels

55 Don t order serum testosterone in women looking for low levels ( Basson 2011) Clinical available assays are not accurate at the low levels found in women Intracellar testosterone is not measured by serum levels of testosterone until recently There is no evidence that low testosterone is linked to low desire when accurate testosterone assessment ( including intracrine peripheral cells levels) is used Hormone imbalance often not the reason ( mood changes, sexual self-image, partner feelings or sexual dysfunction more likely the cause) Basson, Rosemary : This Changed My Practice, UBC CPD 2011

56 Long term risks of T in women Not known Breast and uterine data so far good CVD data controversial Opinions and changes to post menopausal women s use of estrogen following the Women s Health Initiative study serves as a warning in use of systemic sex hormone supplementation for a chronic disorder Long-term RCT s are needed ( > 4 years, randomized, placebo controlled)

57 Lessons from Transgendered Men Quick escalation to male physiological ranges with T Goal is virilisation and masculinisation, but cannot reverse previous feminization if started post pubertal (subcut fat distribution, broader hips, etc) Within 3 months: amenorrhea, increased facial and body hair, skin changes and increased acne, changes in fat distribution, increases in muscle mass, increased libido & may have male pattern hair loss Later effects: deepening of the voice, atrophy of vaginal epithelium, increased clitoral size Unger C. Hormone Therapy I transgender patients Trans Androl & Urol 2016;5:

58 Cases