Who Needs Androgen Replacement?

Transcription

1 Who Needs Androgen Replacement? Carolyn Allan MBBS(Hons), PhD, DRCOG(UK), FRACP Andrologist, Hudson Institute Adj Clin Assoc Prof, Hudson Institute of Medical Research and Dept O&G, Monash University Endocrinologist, Cabrini and Monash Health Advisor, Andrology Australia Men s Health GP Education Seminar, Cabrini Malvern. Saturday August 8 th 2015

2 Black & White...Grey Identifying testosterone deficiency PBS reimbursement criteria Declining testosterone levels as men age Testosterone therapy in the ageing male Cardiovascular risk (Androgen Deprivation in Advanced Prostate Cancer)

3 Identifying Men with Testosterone Deficiency Anyone with a Y chromosome 1 in 200 adult men has testosterone deficiency Commonest hormonal disorder in men 1 in 600 males has Klinefelter s Syndrome Less than 10% of the expected number are diagnosed before puberty Only approximately one fourth of adult males with KS are diagnosed Bojesen A et al. JCEM. 88(2):622-6; NB: Similar data available for Australia. Herlihy AS et al. The prevalence and diagnosis rates of Klinefelter syndrome: an Australian comparison. Med J Aust. 194(1):24-8; 2011.

4 Men at Risk for Testosterone Deficiency Cryptorchidism Testicular trauma or torsion Delayed puberty Genito-urinary infection Infertility Pituitary disease CNS Irradiation Iron overload Haemachromatosis Thalassaemia Major Examination is pivotal 30 ml 4ml

5 RACGP Accredited Online Education Young men s health ALM Androgen deficiency Testicular cancer Male infertility Prostatitis and premature ejaculation Androgen Deficiency Klinefelter s syndrome Available from Andrology Australia by purchase or free if complete an online ALM* * Conditions apply

6 Clinical Features of Testosterone Deficiency Symptoms are non-specific Declining energy levels, easy fatigue, poor concentration, irritability, depression Decreased strength, muscle loss, increasing fat mass Reduced libido, (erectile dysfunction) Osteoporosis Men with longstanding hypoandrogenism may not complain of symptoms 37 47% of men with Te <6.9 nm in MMAS did not have symptoms of AD Araujo et al. JCEM 89: ;2004. Questionnaires are of limited diagnostic use but may have a role in monitoring treatment

7 Approved Indications for Testosterone Rx with Androgen Deficiency Clinical criteria: Patient must have an established pituitary or testicular disorder. Population criteria: Patient must be male. Treatment criteria: Must be treated by a specialist paediatric endocrinologist, specialist urologist, specialist endocrinologist or a registered member of the Australasian Chapter of Sexual Health Medicine; or in consultation with one of these specialists; or have an appointment to be assessed by one of these specialists. The name of the specialist must be included in the authority application.

8 Treatment Regimens Treatment Subcutaneous implants Injections (IM) Sustanon, Primoteston Reandron Transdermal patch Androderm Transdermal gel Testogel Trandermal solution Axiron Transdermal cream AndroForte 2 AndroForte 5 Oral undecanoate Andriol Dosage 3-4 x 200mg pellets every 4-6 months 250mg every 2-3 wks 1000mg every 12 wks (loading dose at 6 wks) 2.5mg applied nightly ; 5mg applied nightly 50mg/5g daily 2 actuations (60mg) daily to axillae 2% (1-2 mls) 5% (1-2 mls) mg in 2-3 divided doses daily

9 Testosterone (nm) Testosterone Levels in the Ageing Male 20 Baltimore Longitudinal Study on Aging 18 (177) 16 (144) (151) (158) (109) (43) Age (Years) Harman. J Clin Endocrinol Metab :

10 Distribution of Mean Testosterone Levels in Men as a Function of Adiposity 50 Obese Non-obese % of subjects BMI 30kg/m 2 ; WC 108cm BMI 26kg/m 2 ; WC 94cm 0 < Total Testosterone (nm) Allan. Med J Aust :

11 Changes in Health Status Account for a Substantial Portion of Longitudinal Te Decline. Travison T G et al. JCEM 2007;92: The estimated difference in T levels between subjects who are obese and those who are not is comparable to the decline observed over 10 yr of aging among subjects whose BMI remained stable.

12 Serum testosterone, dihydrotestosterone and estradiol concentrations in older men self-reporting very good health: the healthy man study. Sartorius et al. Clin Endocrinol (5): Men (n = 325) 40 years self-reporting very good or excellent health; 9 samples measured over 3 months. 25 Testosterone Testosterone Serum Testosterone (nmol/l) Serum Testosterone (nmol/l) (67) (101) (100) (46) (11) Age (decile) Age (years)

13 Approved Indications for Testosterone Therapy Population criteria: Patient must be male, AND be aged 40 years or older. Clinical criteria: Patient must not have an established pituitary or testicular disorder, AND the condition must not be due to age, obesity, cardiovascular diseases, infertility or drugs. Treatment criteria: Must be treated by a specialist urologist, specialist endocrinologist or a registered member of the Australasian Chapter of Sexual Health Medicine; or in consultation with one of these specialists; or have an appointment to be assessed by one of these specialists. Androgen deficiency is defined as: (i) testosterone level of less than 6 nmol per litre; OR (ii) testosterone level between 6 and 15 nmol per litre with high luteinising hormone (LH) (greater than 1.5 times the upper limit of the eugonodal reference range for young men, or greater than 14 IU per litre, whichever is higher). Androgen deficiency must be confirmed by at least two morning blood samples taken on different mornings. The dates and levels of the qualifying testosterone and LH measurements must be, or must have been provided in the authority application when treatment with this drug is or was initiated. The name of the specialist must be included in the authority application.

14 Testosterone (nm) Circadian Variation in Serum Testosterone Young Men Old Men Clock Time (Hours) WJ Bremner, et al, J Clin Endocrinol Metab 56:1278, 1983.

15 Variability in Testosterone Levels Allan et al. Int J Androl 2010 e-pub May 19 A single testosterone level is a reliable measure but There is sufficient intrasubject variability to warrant repeat sampling

16 Testosterone and Ageing Similarities between normal ageing and syndrome of hypogonadism in young men: Muscle mass and strength Body composition ( fat, lean mass) BMD, fractures Libido and sexual function Vigor, mood, cognition Testosterone treatment of young hypogonadal men improves level of function therefore Does testosterone treatment of older men improve function and/or extend life & health?

17 Testosterone Treatment of Older Men: Randomized Controlled Trials Short-term (< 3 years) Small numbers (<100) of healthy older men Variable baseline T levels (normal to low) Some beneficial effects: Muscle, fat, bone, libido, cognition (spatial, verbal) Few adverse effects Hematocrit, HDL ± prostate Excess cardiovascular events? No long-term clinical outcomes Bone fracture, frailty, CV events

18 Cardio-Metabolic Effects of Testosterone Therapy 1. Body Composition Reduction in total body fat kg. Increase in muscle mass kg. Snyder. JCEM : Lipid Profiles Allan &McLachlan. Clin Endocrinol : Decrease in total and LDL-cholesterol of 10%. Fall in HDL-levels? Schleich. Eur J Endocrinol : Isidori. Clin Endocrinol : Insulin Resistance Data inconclusive (study design). Liu. Eur J Endo : Direct effect of testosterone vs. indirect result of body composition modification. Schroeder. JCEM : Arterial Function No change in FMD (flow mediated dilatation).

19 Testosterone Therapy and Body Composition Treatment modality Transdermal Intramuscular Treatment duration 3 months 3 years Baseline TT 8.1nmol/L 9.9nmol/L Treatment effect (increase in TT) 30% 70% Baseline BMI Reduction in body fat 29.9kg - 0.2kg (1.2%) 28.7kg - 4.5kg (16%) Prevention of gain in visceral fat after 12 months Allan. J Clin Endocrinol Metab : men aged 62 years (mean) Transdermal testosterone or placebo for 52 weeks. TT nmol/L % change Visceral Fat P=0.001

20 The T4DM Study Can testosterone treatment, in combination with a lifestyle program, reduce the incidence of T2DM in men with pre-diabetes and low testosterone? Double-blind, randomised, placebo-controlled multicentre study 2 yrs treatment Testosterone + Weight Watchers Placebo + Weight Watchers Testosterone undecanoate Reandron 1000mg IMI 3 monthly Total recruitment: 1500 men aged years, overweight or obese, with testosterone 8 13 nmol/l Information and online pre-screening at NSW, Vic, SA and WA sites Local contact:

21 Do Androgens have a Detrimental Effect on the Cardiovascular System? Strong epidemiological association between male sex and premature onset of cardiovascular risk: 26-year follow-up of the Framingham population 5-10 years in advance of women Lerner. Am Heart J : Case reports linking the use of anabolic steroids with cardiac toxicity Sullivan. Prog Cardiovasc Dis :1-15. AAS-induced atherosclerosis Unfavourable influence on serum lipids and lipoproteins Thrombosis Vasospasm or direct injury to vessel walls

22 Adverse Events Associated with Testosterone Administration Basaria NEJM.363: Study cohort 209 (target=252) community-dwelling men aged 65 years (mean 74 years). Limited mobility + Te nmol/l (mean 8.4 nmol/l). 53% pre-existing CVD Intervention Te gel (10gm Testim 1%) for 6/ men completed 6/12 of Rx. Dose titrated after 2 weeks if Te <17.4 or >34.7 nmol/l. Aim: Mobility (leg-press strength) Testosterone and Aging: Clinical Research Directions. Institute of Medicine 2003 CV events were not a pre-specified outcome 23 vs. 5 CV-related adverse events MI=2, stroke=1, angina=1, CCF=2, carotid art occ=1, arrhythmia=6, syncope=3, ETT ECG changes=2, peripheral oedema=4, HPT=3.

23 Adverse Events Associated with Testosterone Administration Basaria NEJM.363: nmol/l 8.9 nmol/l Te Men: Te nmol/L Change in hormone level nmol/L Basaria 2013.J Gerontol A Biol Sci Med Sci. 68:153-60

24 Retrospective Cohort Studies Vigen 2013 JAMA.310(17):1829 n=8,709 (1,223 started Te) Finkle 2014 PLOS.9(1):e85805 n=55,593 (7, yrs) VA Database: Angio and Te<10nmol/L All cause mortality, MI, stroke after 27 months (NB: >80% prior CHD) Cases 67 deaths; 23 MI; 33 CVA Cases 65 Abs risk diff 5.8% (25.7% Te) HR 1.29 (adj for CAD) No effect CAD vs. No CAD Health insurance claims Non-fatal AMI 90 days after initial Te script (cf to 12 months prior) Post/Pre-prescription RR 1.36 (RR yrs) Compared to PDE5i nil effect Limitations: no time to event or pt years exposure data; no adj for baseline Te NB: Raw data 10.1% (Te) vs. 21.2% (non-te); post publication corrections Limitations: no Te levels; no data re Te usage or CV RFs; NB: RR 3.43 only significant 75 yrs; actual cases 8-22/group in men >65 yrs; low event rates overall cf. to pop data

25 Testosterone Treatment and Mortality in Men with Low Testosterone Levels VA clinical database Shores. JCEM : veterans aged >40 yrs with Te <8.7nmol/L (n=1273) 21% CHD; mean BMI 33kg/m 2 Te treatment in 398 (39%); follow-up 40.5 months Mortality 10.3% cf. with 20.7% in untreated men (P<0.0001)

26 Risks of Testosterone Treatment? Safety Announcement [ ] The U.S. Food and Drug Administration (FDA) is investigating the risk of stroke, heart attack, and death in men taking FDA-approved testosterone products. We have been monitoring this risk and decided to reassess this safety issue based on the recent publication of two separate studies that each suggested an increased risk of cardiovascular events among groups of men prescribed testosterone therapy. We are providing this alert while we continue to evaluate the information from these studies and other available data, and will communicate our final conclusions and recommendations when the evaluation is complete. Update [ ]..based on the available evidence from published studies and expert input from an Advisory Committee meeting, FDA has concluded that there is a possible increased cardiovascular risk associated with testosterone use.

27 Androgen Deprivation Therapy in Prostate Cancer ADT: A Model of Hypoandrogenism - castrate levels of serum testosterone. Bone density ( fracture risk). Skeletal mass and Fat mass. Adverse cardio-metabolic profile insulin sensitivity ( metabolic syndrome). Lipid changes - TC, LDL, TG,? HDL. arterial stiffness. Increased CVS morbidity and mortality NB: Changes evident as early as 12 weeks.

28 Education for our Community Available at no charge