Prof Dato Dr TAN Hui Meng University of Malaya, Kuala Lumpur University of Pennsylvania, USA

Prof Dato Dr TAN Hui Meng University of Malaya, Kuala Lumpur University of Pennsylvania, USA

Prevailing context Increase number of men who are potential candidates for Testosterone Replacement Therapy (TRT) Increasing Aging Population - New Cohort BB - affluent, better educated and savouring their golden years. Increase Awareness :Education, Advertisements etc Increase population of chronic opiate and androgenic anabolic users; withdrawal hypogonadism Increase population of non-alcoholic fatty liver :10-25% overall US population :75% of Type 2 Diabetes Mellitus US 500,000 new cases of Testosterone deficiency per year

Benefits of TRT well published Sexual Function Mood Vitality Muscle strength and mass Bone Health Cardiovascular Health

Management of Testosterone Deficiency AUA Guideline 2018

Management of Testosterone Deficiency, AUA Guideline 2018 Guideline 1 - Clinicians should use a total testosterone level below 300 ng/dl (10.4nmol/L) as a reasonable cut-off in support of the diagnosis of low testosterone. (Moderate Recommendation; Evidence Level: Grade B) Guideline 2 - Clinicians should consider measuring total testosterone in patients with a history of unexplained anemia, bone density loss, diabetes, exposure to chemotherapy, exposure to testicular radiation, HIV/AIDS, chronic narcotic use, male infertility, pituitary dysfunction, and chronic corticosteroid use even in the absence of symptoms or signs associated with testosterone deficiency. (Moderate Recommendation; Evidence Level: Grade B)

Guideline 5 - Clinicians should inform testosterone deficient patients that low testosterone is a risk factor for cardiovascular disease. (Strong Recommendation; Evidence Level: Grade B) Guideline 6 - Patients should be informed that testosterone therapy may result in improvements in erectile function, low sex drive, anemia, bone mineral density, lean body mass, and/or depressive symptoms. (Moderate Recommendation; Evidence Level: Grade B)

Guideline 7 - Patients should be informed that the evidence is inconclusive whether testosterone therapy improves cognitive function, measures of diabetes, energy, fatigue, lipid profiles, and quality of life measures. (Moderate Recommendation; Evidence Level: Grade B) Guideline 8 - Patients with testosterone deficiency and a history of prostate cancer should be informed that there is inadequate evidence to quantify the risk-benefit ratio of testosterone therapy. (Expert Opinion)

Guideline 9 - Patients should be informed that there is no definitive evidence linking testosterone therapy to a higher incidence of venothrombolic events. (Moderate Recommendation; Evidence Level: Grade C) Guideline 10 - Prior to initiating treatment, clinicians should counsel patients that, at this time, it cannot be stated definitively whether testosterone therapy increases or decreases the risk of cardiovascular events (e.g., myocardial infarction, stroke, cardiovascular-related death, all-cause mortality). (Moderate Recommendation; Evidence Level: Grade B)

Guideline 11 - All men with testosterone deficiency should be counseled regarding lifestyle modifications as a treatment strategy. (Conditional Recommendation; Evidence Level: Grade B) Guideline 15 -Clinicians may use aromatase inhibitors, human chorionic gonadotropin, selective estrogen receptor modulators, or a combination thereof in men with testosterone deficiency desiring to maintain fertility. (Conditional Recommendation; Evidence Level: Grade C)

Controversies of Testosterone Replacement Therapy!

Effects of TRT on clinical cardiovascular outcomes are conflicting Metaanalysis of clinical trials show no association between TRT and cardiovascular adverse events (None designed to assess adverse effects prospectively!) Basaria S et al NEJM 2010; 363 (2): 109-122 - old frail men Increase Cardiovascular A/E Srinivas-Shankar et al, The Journal of Clinical Endocrinology & Metabolism, 2010;95(2)639 650 - similar population as Basaria Study; No increase in CV A/E

Effects of TRT on clinical cardiovascular outcomes are conflicting Retrospective analyses of electronic medical records to evaluate the possible association of TRT with CV A/E also yield conflicting results Vigen R, et al. JAMA. 2013;310(17):1829-1836 Finkle WD, et al. PLoS One. 2014;9(1):e85805. Baillargeon J, et al. Ann Pharmacother. 2014;48(9):1138-1144.

FDA Caution 4 th March 2015 Biggest impact on controversies of TRT - Headlines, in many news media! - New York Time Overselling T treatment - Lawyers advertisement for cases of CV events - Class lawsuit going on!

TRT controversy continues:- Since, the negatives studies of Vigen and Finkle, a further 16 studies have been published (since 2014) Only one out of 16 studies has shown any increase risk of CV disease in men on Testosterone therapy Many shown benefits particularly in men at risk of CV Disease!

Morgentaler et al review on TRT October 2016 4 flawed studies published showing increasing risk - Over 100 studies shown either benefit or no adverse effect on TRT Low T levels associated with increased CV risk: TRT improves risk factors for CVD - Decrease Fat - Decrease Waist circumference - Increase Glycaemic Control

JAMA Feb 21, 2017 Vol 317, No 7: 708 -Mathew, J Budoff et al. DB Placebo controlled n 170. TT < 275 ng/ml (~ 9.5nmol/L) Symptomatic hypogonadal men, treatment with testosterone gel for 1 year compared with placebo Result: a significantly greater increase in coronary artery noncalcified plaque volume as measured by Coronary Computed Tomography Angiography (CCTA), which is associated with myocardial ischaemia! Effects of TRT- Detrimental?

How Best to deal with current situation Awaiting Prospective Trials on TRT safety and efficacy (another 10 years!) - efficacy to cover all aspects including possibility of improvement in CV profile.

Best Practice Today The Endocrine Society updated clinical practice guidelines on testosterone therapy in men with hypogonadism, 2018 Current Clinical Guidelines- best course of actions- 1)First Do No Harm! - No Routine prescription for those 65 years and older men 2)Diagnosis crucial! - Symptoms- Non-specific - Comorbidities of TDS patients 3) Laboratory accuracy important

Lab Accuracy US: Harmonized Testosterone Reference range (CDC standardization) Age specific normal reference ranges 19 to 39 years 264 to 916 ng/dl 9.15 to 31.75 nmol/l 40 to 49 years 208 to 902 ng/dl 7.21 to 31.22 nmol/l 50 to 59 years 192 to 902 ng/dl 6.66 to 31.27 nmol/l 60 to 69 years 190 to 902 ng/dl 6.5 to 31.27 nmol/l 70 to 79 years 190 to 902 ng/dl 6.5 to 31.27 nmol/l 80 to 99 years 119 to 902 ng/dl 4.1 to 31.27 nmol/l 50 th percentile:531 ng/ml (18.4 nmol/l) Do SHBG: - Try to get Free T or Bio T - Practical purposes : use TT

ISSM Statements : Men with TT of > 346 ng/ml(12nmol/l) are unlikely to have testosterone deficiency and benefit from treatment : Men with TT of < 231 ng/ml(8.0 mnol/l) are most likely to benefit from treatment : TT level between 8-12 nmol/l: Trial of TRT if symptomatic

Lack of long term data - effects on CV events and prostate cancer Select patients for TRT Caution:- CCF Very frail Recent CV events High risk of CV event Recent CaP / Ca Breast Fully treated CaP patients (specialised centers) The Endocrine Society,2018

Informed Consent for TRT Current state of knowledge and understanding Preamble - What's Testosterone Deficiency (TD) - Primary and Secondary TD TRT: Supplementation of Testosterone to replace T normally produce in body Patients declaration:- - Allergy to testosterone, alcohol products or soy - Medication history including supplements and herbal products. - History of breast and prostate cancer- Family History of CaP. - Sleep apnea, enlarged prostate Symptoms of TD are non-specific

Informed Consent Changes in cholesterol levels, PSA levels, liver function enzymes, and other hormone levels can occur, however those labs will be monitored through periodic table. Prostate enlargement which may cause difficulty urinating. This will be motivated via the International Prostate Symptom Score Questionnaire. Potential Adverse events which may be associated with each type of TRT. It has been explained to me, and I fully understand, that occasionally there are complications with TRT such as - Acne - Enlargement of breast - Fluid retention. This could be a minor as some swelling around your ankles but could cause serious problems in persons with liver, kidney or kidney disease. - Sleep apnea can occur or worsen with treatment. If you think you could have sleep apnea, you should discuss with your primary physician or your center for men provider. If you are currently being treated, it is your responsibility to ensure your condition is controlled and you are compliant with your treatment. - TRT may cause your LH and FSH levels to be severely limited, affecting your fertility. Patients should not be on TRT if attempting to father a child. - Red blood cell levels can increase as testosterone stimulates the bone marrow activities. This is called polycythaemia. The increased blood thickness could be risk factor for stroke, heart attack or blood clots, among others. You may be asked to donate blood periodically or your dosage could be adjusted. This will be monitored periodically with blood tests - Testosterone is converted to estrogen in the body so increasing testosterone can also increase estrogen. Levels that are too high may increase risk of blood clots, stroke, or heart attack though this is not clear. Levels will be monitored periodically and medicine to decrease this conversion or TRT dosage adjustment may be used if deemed necessary.

Consent for Testosterone Replacement Therapy (TRT) I understand the risk and benefits of TRT, and agree to proceed with the treatment. I also understand that not every possible complications can be listed in the counselling consultation, and additional risks are possible although unlikely I also understand I will need periodic monitoring of various blood parameters and regular clinical follow up evaluation.

- I was given the opportunity to ask and clarify questions, and I aware that there an alternative methods of treatment which have been explained. - This will be on file and a copy was given to patient... Clinician Signature Date.. Patients Signature Date

Conclusion Surge on demand for TRT Men s Health movement accelerating worldwide TRT benefits well documented-many good studies Gratifying clinical outcome - promotion of men s health and sexual medicine Good Clinical Guidelines and Guidance Proper detailed informed consent Awaiting well conducted long term studies specifically designed to answer efficacy and adverse events of TRT in adult hypogonadism

Future Research on Testosterone Deficiency and Testosterone Replacement Therapy

Research - Epidemiology Are there age-specific reference ranges for testosterone? This question should be answered for both total and free testosterone and should likely be focused on two assays, LC-MS for total testosterone and equilibrium dialysis for free testosterone. What is the impact of changes in testosterone levels over the life-span of an individual patient? Specifically, in a man who has high-normal testosterone levels in his younger years, does a drop in testosterone as he ages (with resultant testosterone levels remaining in the normal range) put him at risk for symptoms and deleterious effects of low testosterone levels?

Is there a threshold testosterone level that is linked to specific symptoms (e.g., fatigue, low sex drive, ED, depression, reduced physical function, cognitive effects) or signs (e.g., bone density loss, elevation of HbA1C, MACE)? Does exposure to chemotherapy put a man at increased risk for development of testosterone deficiency later in life?

Research - Diagnosis What is the role of androgen receptor sensitivity (CAG repeat analysis) in the diagnosis of testosterone deficiency? There is a great need for the development of robust and reliable patient-reported outcome tools (e.g. questionnaires) in the screening and follow-up of response to therapy in men with testosterone deficiency.

Research - Treatment Long-term analysis is needed on the impact of weight loss and exercise on testosterone levels and reversal of testosterone deficiency. Further analysis of the role of subcutaneously administered testosterone. Trials are currently ongoing in using pellets.

Long-term study is needed of the recovery of endogenous testosterone production after short, medium and long-term exogenous testosterone therapy. Study of long-term effects of testosterone therapy on MACE is needed.

Does TRT improves cognitive function, energy, fatigue, diabetic control Does TRT improves quality of life measures Efficacy and Adverse Effects associated with compounded testosterone gel TRT normalisation of T level but no improvement in symptoms

Randomised Double-Blind Placebo-Controlled Trial using I/M 1000 mg Testosterone Undecanoate (Nebido) over 1 year The Nebido treated group showed significant improvement in SF-12 Domain p-value Vitality 0.022 General health 0.002 Role functioning 0.021 Social functioning 0.048 Physical health composite 0.027 Mental health composite 0.018 HM Tan 2010 Nebido Study Tong SF et al. Asian Journal of Andrology 2012;14: 604-11

Randomised Double-Blind Placebo-Controlled Trial using I/M 1000 mg Testosterone Undecanoate (Nebido) over 1 year The Nebido treated group showed significant improvement in AMS scales p-value Total AMS scale 0.017 Psychological subscale 0.030 Somatovegetative subscale 0.016 HM Tan 2010 Nebido Study Chris Ho et al.bjui 2012; 110(2):260-5

Greater study is needed on the prevalence of adverse events (e.g., polycythemia, VTE, gynecomastia, MACE). Further exploration of the impact of long-term testosterone therapy in prostate cancer patients is a great need. In which sub-populations is testosterone therapy safe? Longer-term studies are needed on spermatogenesis recovery strategies in men who have been on testosterone therapy.

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