MALE HYPOGONADISM: CHOOSING THE APPROPRIATE THERAPY. Michael S. Irwig, M.D. Director, Center for Andrology Division of Endocrinology & Metabolism

Transcription

1 MALE HYPOGONADISM: CHOOSING THE APPROPRIATE THERAPY Michael S. Irwig, M.D. Director, Center for Andrology Division of Endocrinology & Metabolism

2 Disclosures Aromatase inhibitors & clomiphene citrate are not FDA approved for male hypogonadism

3 The specialty of endocrinology Cardiologists Neurologists Endocrinologists

4 The reference range Don t let the reference range dictate everything.. Clinical judgement is key

5 Clinical judgement For a middle aged man with borderline-low testosterone levels SLEEP APNEA? OBESITY? ADEQUATE SLEEP? DEPRESSION? MEDICATION SIDE EFFECT?

6 Functional Hypogonadism Prevalence is 2-12% of men Grossmann M et al. J Clin Endocrinol Metab 2017

7 Functional Hypogonadism Grossmann M et al. J Clin Endocrinol Metab 2017

8 Pitfall # 1- What s the evidence with testosterone? Endocrine Society s Clinical Practice Guideline EVIDENCE QUALITY RECOMMENDATIONS High 0 Moderate 2 Low 8 Very Low 2 Bhasin S, et al. J Clin Endocrinol Metab 2018

9 Pitfall # 1- What s the evidence with testosterone? Endocrine Society s Clinical Practice Guideline EVIDENCE QUALITY RECOMMENDATIONS High 0 Moderate 2 Low 8 Very Low 2 No cut point for a low testosterone No clear definition of symptomatic Bhasin S, et al. J Clin Endocrinol Metab 2018

10 Pitfall # 1- What s the evidence with testosterone? September the FDA s Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Committee voted 20-1 that the indication should be tightened that testosterone replacement therapy is NOT indicated for age-related declines in testosterone. We don t really know whether aging-associated low testosterone is in fact a disease at all Michael Lincoff, MD, Vice Chairman of cardiovascular medicine, Cleveland Clinic Internal Medicine News 2014

11 Pitfall # 2- How do you define hypogonadism? European Male Aging Study (N=3200 men 40-79) 3 sexual symptoms + total testosterone < 317 ng/dl AM full erections Erections (get and keep) Think about sex Symptomatic 1/past month never or sometimes 3 times/month Wu FC, et al. NEJM 2010

12 Pitfall # 2- How do you define hypogonadism? CONSENSUS STATEMENT ON LATE-ONSET HYPOGONADISM American Society of Andrology (ASA) European Academy of Andrology (EAA) European Association of Urology (EAU) International Society of Andrology (ISA) Intl. Society for the Study of Aging Male (ISSAM) <230 ng/dl >350 ng/dl <8 nmol/l >12 nmol/l Usually benefits? Repeat level No treatment from therapy Wang C, et al. Multiple Andro/Endo/Urology Journals 2008

13 Pitfall # 2- How do you define hypogonadism? LOW NORMAL HIGH Cut points are arbitrary based on statistical percentiles rather than clinical correlations/evidence Different labs establish their own normal ranges Reference range is often based on lean adult men < 40 years and is usually not age adjusted

14 Pitfall # 2- How do you define hypogonadism? Massachusetts Male Aging Study REFERENCE RANGE: Using the 2.5% (roughly below 2 SD) of healthy men, the proposed normal lower limit for total testosterone was: Testosterone Age 251 ng/dl ng/dl ng/dl ng/dl Mohr BA, et al. Clin Endocrinol 2005

15 Pitfall # 2- How do you define hypogonadism? Massachusetts Male Aging Study REFERENCE RANGE: Using the 2.5% (roughly below 2 SD) of healthy men, the proposed normal lower limit for total testosterone was: Testosterone Age 251 ng/dl ng/dl ng/dl ng/dl Mohr BA, et al. Clin Endocrinol 2005

16 Pitfall # 2- How do you define hypogonadism? There is debate whether androgen status is better reflected by TOTAL versus FREE testosterone

17 How does T enter into cells? Goldman A, et al. Endocr Rev 2017

18 Testosterone and BMI European Male Aging Study (N=3200 men 40-79) Wu FC, et al. J Clin Endocrinol Metab 2008

19 Testosterone and BMI European Male Aging Study (N=3200 men 40-79) WEIGHT STATUS TOTAL TESTOSTERONE FREE TESTOSTERONE Overweight -66 ng/dl -5.1 pg/ml Obese -147 ng/dl pg/ml Overweight men are 3.3 ( ) times as likely to have secondary hypogonadism Obese men are 8.7 ( ) times as likely to have secondary hypogonadism Tajar A, et al. J Clin Endocrinol Metab 2010

20 Weight loss causes testosterone to increase bariatric surgery diet 86 ng/dl Grossmann M et al. J Clin Endocrinol Metab 2017

21 Testosterone formulations IM Patch Gels Buccal Pellets Nasal spray

22 IM Testosterone undecanoate T enanthate (TE) T undecanoate (TU) BACKGROUND TU has a longer half life due to a longer hydrophobic side chain In the United States it is only available through a REMS program TU (750 mg) is administered in 3 ml by a nurse in a clinic with a certified provider The patient needs to wait for 30 minutes after the injection to see if he develops anaphylaxis or a pulmonary oil microembolism (POME) reaction which typically presents with a cough Dosing in United States is time 0, 4 weeks, every 10 weeks thereafter Number of IM injections/year: 26 with T esters (TE) versus 4-5 with TU Schubert M, et al. J Clin Endocrinol Metab 2004

23 IM Testosterone undecanoate Schubert M, et al. J Clin Endocrinol Metab 2004

24 Testosterone pellets Dosing Technique 9 mm

25 Testosterone nasal spray BID dosing TID dosing CONSIDERATIONS 73% of subjects achieving target levels of total T ( ng/dl) at 90 days Compliance as frequent dosing (BID, TID) is needed 11% had nasal symptoms (discomfort, dryness, congestion, epistaxis, rhinorrhea) Rogol A, et al. Andrology 2016

26 How to monitor T levels FORMULATION Esters Transdermal gels Transdermal patches Buccal bioadhesive Pellets IM undecanoate WHEN TO CHECK T LEVEL Midcycle 2-8 hours after application 3-12 hours after application Immediately before or after application End of dosing interval End of dosing interval (nadir) Bhasin S, et al. J Clin Endocrinol Metab 2018

27 Monitoring testosterone therapy IM Testosterone esters Serum testosterone (ng/dl) Weeks

28 Testosterone formulations ROUTE INVASIVE FREQ. COST OTHER CONSIDERATIONS Esters IM Little 2 weeks $ Peaks and troughs Pain at injection sites More erythrocytosis Undecanoate IM Little 10 weeks $$$ In clinic; 30 minute wait Gel Skin 0 Daily $$$ Transference Stickiness Patch Skin 0 Daily $$$ Skin irritation Buccal Mouth 0 BID $$$ Gum/mouth irritation or pain Bitter taste Falls off Pellets Subcut Very 3-6 months $$$ Infection Pellet extrusion Bleeding Nasal spray Nose 0 BID- TID $$$ Rhinorrhea, epistaxis

29 Insurance Rules TIER = $ SilverScript SoMD Formulary

30 Pitfall # 3- Monitoring men on T gels N= 47 men aged 65 years old from T Trials with average total T < 275 ng/dl Randomized to T or placebo gel for 16 weeks Starting T dose was 5 g/d; target range for T was ng/dl which was changed to ng/dl Testosterone was sampled 2 hours after application on 3 occasions Visits A & B ambulatory visits; gel applied under supervision Visit C inpatient visit; T was sampled at 1,2,4,8,12,16 & 24 hours after supervised application at 8 AM Swerdloff RS et al. J Clin Endocrinol Metab 2015

31 Pitfall # 3- Monitoring men on T gels Wide variability of T readings despite same dose, same time after application & same T assay Swerdloff RS et al. J Clin Endocrinol Metab 2015

32 Pitfall # 3- Monitoring men on T gels Lack of correlation between T levels at ambulatory and inpatient visits Swerdloff RS et al. J Clin Endocrinol Metab 2015

33 Pitfall # 3- Monitoring men on T gels Visit C inpatient visit; T was sampled at 1,2,4,8,12,16 & 24 hours after supervised application at 8 AM During this 24 hour period after applying T 33% had all total T levels between ng/dl 0% had all total T levels between ng/dl Study conclusions: 63% of the total variance was due to within-subject variability Limitations with using ambulatory T measurements for monitoring Swerdloff RS et al. J Clin Endocrinol Metab 2015

34 Screening & monitoring for prostate cancer There is a lot of controversy about the use of PSA for screening for prostate cancer Testosterone therapy is associated with an increase in PSA of ng/ml Sharing decision model of whether to screen: men years old men years old if black or first degree relative with prostate cancer men 70 years old monitoring is not warranted Urological consultation if: PSA > 4.0 ng/ml or rises > 1.4 ng/ml within 1 year (confirm) Bhasin S et al. J Clin Endocrinol Metab 2018

35 What about clomiphene or hcg or AI?

36 Fertility & Androgens TESTOSTERONE & FERTILITY Exogenous testosterone may be an effective male contraceptive and should be avoided in men trying to father a child Exogenous testosterone decreases FSH and LH which decreases intratesticular testosterone which is needed for spermatogenesis It may take months for the axis to normalize after stopping exogenous testosterone TO ASSIST HYPOGONADAL MEN TO PRESERVE OR GAIN FERTILITY Pre-pubertal both FSH and LH (hcg) are needed Post-pubertal LH (hcg) alone may be needed

37 Fertility medications GnRH (pulsatile) hcg (LH analog) hmg (LH & FSH) FEMALE MALE OFF LABEL Ovulation induction Ovulation induction Hypogonadotropic hypogonadism Ovulation induction Follicle development FSH Ovulation induction Follicle development Clomiphene Ovulation induction spermatogenesis spermatogenesis Aromatase inhibitor Breast cancer Fertility Lexicomp 2018

38 Clomiphene citrate INFORMATION Selective estrogen receptor modulator (SERM) Two isoforms (Enclomiphene is cis isomer and Zuclomiphene is trans isomer) Inhibits estrogen receptors at the hypothalamus Starting dose is 25 mg daily or every other day

39 Clomiphene citrate Randomized Controlled Trial N= 85 overweight men years old with total T < 300 ng/dl and LH < 9.4 IU/L Randomized to Enclomiphene 12.5 or 25 mg/day or placebo LH FSH 66% achieved total T 300 ng/dl Kim ED et al. BJU Int 2016

40 Clomiphene citrate Randomized Controlled Trial N= 24 obese men with total T < 300 ng/dl and new T2DM or IGT Randomized to clomiphene 25 mg/d or placebo (+metformin in both) PRE POST TOTAL TESTOSTERONE (ng/dl) FREE TESTOSTERONE (pg/ml) DHT (ng/ml) ESTRADIOL (pg/ml) LH (mu/ml) FSH (mu/ml) X 2 Pelusi C et al. PLoS ONE 2017

41 rhcg Randomized Controlled Trial N= 40 men >60 years old with total T < 433 ng/dl on 2 occasions Randomized to r-hcg 5000 IU twice weekly or placebo for 3 months Liu PY et al. J Clin Endocrinol Metab 2002

42 rhcg Randomized Controlled Trial 95% had elevated estradiol levels 15% developed nipple tenderness Liu PY et al. J Clin Endocrinol Metab 2002

43 Aromatase Inhibitors Testosterone aromatase Estradiol (E2) NON-STEROIDAL STEROIDAL Anastrozole (1 mg/day) Testolactone Letrozole (2.5-5 mg/day) Formestane Exemestane

44 Aromatase inhibitor Randomized Controlled Trial N= 69 men aged > 60 years old with total T < 350 ng/dl Randomized to anastrozole 1 mg/day or placebo Burnett-Bowie SA, et al. J Clin Endocrinol Metab 2009

45 Clomiphene citrate versus aromatase inhibitor (RCT) N= 26 men with inability to conceive for 1 year; total T < 350 ng/dl and LH miu/ml Randomized to CC 25 mg/day or anastrozole 1 mg/day PERCENT ACHIEVING TOTAL T > 350 ng/dl clomiphene citrate 92% (11/12) anastrozole 67% (8/12) Helo S et al. J Sex Med 2015

46 Fertility medications GnRH (pulsatile) hcg (LH analog) hmg (LH & FSH) FEMALE MALE OFF LABEL Ovulation induction LH FSH E2 Ovulation induction Hypogonadotropic hypogonadism Ovulation induction Follicle development FSH Ovulation induction Follicle development Clomiphene Ovulation induction Aromatase inhibitor spermatogenesis spermatogenesis Breast cancer Fertility Lexicomp 2018

47 Endocrine Society Guidelines Clomiphene citrate has been used empirically in men with hypogonadotropic hypogonadism; however, neither its efficacy nor its safety has been demonstrated in randomized trials. Bhasin S, et al. J Clin Endocrinol Metab 2018

48 Safety of aromatase inhibitors TRIAL DATA Decrease in bone mineral density Pulmonary embolus within 2 days of last dose in a man with a h/o DVT (1 in 12) Joint and tendon pain, limb swelling (2 in 86) Depression and breast tenderness (1 in 86) Helo S et al. J Sex Med 2015 Shoshany O et al. Fertil Steril 2017

49 Safety of clomiphene citrate ONE TRIAL (N=85) Psoriatic arthropathy (1 in 85) Depression (1 in 85) Erthyrocytosis (1 in 85) Ischemic stroke in a 59 yo obese man with T2DM and a h/o atrial fibrillation CASE REPORTS Suicidal behavior Acute mania in a man with known bipolar Pulmonary embolus Central retinal vein occlusion in a carrier of Factor V Leiden Chamberlain RA et al. Int J Fertil 1986 Kim ED et al. BJU Int 2016 Knight JC et al. Psychosomatics 2015 Politou M et al. Genet Test Mol Biomarkers 2009 Sinha P et al. Gen Hosp Psychiatry 2014

50 Estrogen in men Randomized controlled trial of men years old that lasted 4 months Subjects were rendered hypogonadal with goserelin (GnRH agonist) Randomized to: Cohort 1 (N=198) testosterone gel (4 strengths) or placebo Cohort 2 (N=202) testosterone gel (4 strengths) or placebo; plus anastrozole 1 mg/day Finkelstein J et al. N Engl J Med 2013

51 Estrogen in men Finkelstein J et al. N Engl J Med 2013

52 Estrogen in men Finkelstein J et al. N Engl J Med 2013

53 Summary Using clinical judgement when interpreting the reference range How to define hypogonadism The relationship between testosterone, obesity and weight loss Six formulations of testosterone therapy Monitoring testosterone levels and pitfalls Clomiphene hcg Aromatase inhibitors The important role of estrogen in men

54 Questions