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Diagnosis and Management of Testosterone Deficiency

24th Annual Pharmacological Conference for Advanced Practice Providers at UNMC

Chris Deibert MD MPHAssistant Professor of Urology – UNMCMen’s Health Program – Nebraska Medicine

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Objectives1. Identify appropriate testing for testosterone deficiency

1. Symptoms2. 2 early AM testosterones, FSH/LH,

prolactin, hemoglobin2. Develop treatment options including testosterone

and non-testosterone therapies1. Testosterone formulations: gel, patch, injection, long

lasting2. Non-testosterone options: clomiphene, anastrazole

3. Comprehensively discuss potential risks1. fertility,2. CV disease, prostate, sleep apnea3. body changes

I have no financial or other disclosures. I will discuss off-label use of some medications and this is marked

What is Testosterone?The picture can't be displayed.

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What is Testosterone?

• The key sex hormone for men

• Develops male sexual traits

• Muscle mass, strength

• Facial and body hair

• Bone density and linear growth

• Maturation of sex organs

• Sperm production

Physiological EffectsPrenatal: Development of male reproductive tract, prostate, seminal vesicles; (via DHT) development of male external genitalia

Infancy:

“brain masculinization”?

Puberty: pushes from

boys to men

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Male reproductive hormonal axis

Brain

Testicles

Symptoms of Low Testosterone (Hypogonadism)

• Non-sexual Symptoms

• Lower energy

• Depressed mood

• Non-sexual Signs

• Increased body fat

• Reduced muscle mass

• Anemia

• Bone density loss

• Sexual Symptoms

• Lower sex drive

• Sexual Signs

• Poorer erections

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What are normal values?

Bullets

AN Junior, IntBrazJUrol 2011

20%

Epidemiology•Crude estimates: Massachusetts Male-Aging Study (2004)

– 12.3/1000 person-years– 481,000 new cases per year in American men

– Longitudinal, population-based studies of aging men have demonstrated that both TT and FT decline with age along with an increase in SHBG levels

– Prevalence of symptomatic androgen deficiency 5.6% (TT<300 and symptoms)

Potential scope of androgen deficiencyBy 2025, approximately 6.5 American men 30-80 years old affected

Prevalence and incidence of androgen deficiency in middle‐aged and older men: estimates from the Massachusetts Male Aging Study.Araujo AB, O'Donnell AB, Brambilla DJ, Simpson WB, Longcope C, Matsumoto AM, McKinlay JB.J Clin Endocrinol Metab. 2004 Dec;89(12):5920‐6.Prevalence of symptomatic androgen deficiency in men.Araujo AB, Esche GR, Kupelian V, O'Donnell AB, Travison TG, Williams RE, Clark RV, McKinlay JB.J Clin Endocrinol Metab. 2007 Nov;92(11):4241‐7. 

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Title

Bullets

R Jain, Drug UtilizationFDA Advisory Committee 9/2014

Guidelines

No Groups Recommend Screening

2018 American Urological Association Guideline

2018 Endocrine Society Guideline

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Causes/Associations

High blood pressure 40%

High cholesterol 40%

Diabetes up to 50%

Overweight up to 50%

HIV 30%

Alcoholism

Chronic opioid use

Sleep apnea

Hypogonadism DiagnosisInitial Screening: A blood testTotal testosterone

– MORNING draw, before 10am– Nadir values ~15% lower than peak morning values– May be up to 50% lower in younger patients– Even at same collection time, individual variability of 10%

No clear consensusUS Food and Drug Administration <300 ng/dLInternational consensus statement

– T >350 does NOT require treatment– T<230 with symptoms does require treatment

Other screening tests may include- PSA for prostate cancer: age 55-69, family history- Red cells (hematocrit) Winters SJ, Laboratory assessment of testicular function. Endotext

Brambilla DJ, Clin Endocrinol 2007, Jarow JP, J Urol 2013Wang C, J Androl 2009

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SHBG50‐60%

Albumin 38‐44%

Free2‐3%

CIRCULATINGTESTOSTERONE 

Hypogonadism Diagnosis

Symptomatic hypogonadism AND

2 morning testosterone level <300ng/dL AND

no other medical or modifiable factors that might contribute to symptoms

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Contraindications/Considerations

History of prostate cancer, breast cancer

Elevated PSA or palpable prostate nodule that have not been evaluated with biopsy

Hct >50%

Severe obstructive sleep apnea

Severe LUTS/BPH

Severe CHF

Desired future fertility

When is treatment not necessary?

• Do Not Use for

• Body building

• “Normal” T levels

• Fertility

• To treat prostate cancer

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What if I don’t treat?

• Symptoms will continue

• If you have significant heart disease, therapy may actually decrease risk of more heart disease though this remains very controversial

Treatment Options

• Testosterone replacement therapy (TRT)

• Non-Testosterone therapy

Non-T therapies have the advantage of increasing serum T levels without suppressing sperm production

– First choice in men wishing to preserve fertility, or in subfertile men with abnormal semen parameters and low testosterone

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Non-Testosterone Therapy:SERMs

• Off-Label Selective estrogen receptor modulators• Block central Estrogen Receptor, inhibiting central

feedback inhibition and stimulating increased endogenous production of LH, promotes testosterone production

• Clomiphene citrate 25mg 3 times weekly up to 50mg daily• Expect T increase by 150+ points• Side effects: blurred vision, hot flashes,

headache

Non-Testosterone Therapy:SERMs

• Clomiphene citrate 25mg 3 times weekly up to 50mg daily

• Expect T increase by 150+ points

• Side effects: blurred vision, hot flashes, headache

• Follow up: labs in 3-4 weeks. (Total T, FSH or LH, estradiol). symptoms should be improved here too. if not, titrate dose up and repeat labs/symptom check in 3-4 weeks.

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Non-Testosterone Therapy:hCG

Natural LH analog that stimulates testicular production of Testosterone

Prevents testicular atrophy

hCG 500-2000 units IM or SC 2-3x/week

nuimagemedical

Non-Testosterone Therapy:hCG

hCG 500-2000 units IM or SC 2-3x/week

Follow up: labs in 4 weeks. (Total T, LH, estradiol). symptoms should be improved here too. if not, titrate dose up and repeat labs/symptom check in 4 weeks.

nuimagemedical

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Non-Testosterone Therapy Aromatase inhibitors

• T is normally converted to estradiol in peripheral adipose tissues by aromatase at 0.3% daily

• First choice for men with T:Estradiol ratio <10

• Anastrozole 1mg PO every other or daily

• expect Estradiol down and T up 100-200 points

• Side effects: blurred vision, headache

Non-Testosterone Therapy Aromatase inhibitors

• Anastrozole 1mg PO every other or daily

• expect Estradiol down and T up 100-200 points

• Side effects: blurred vision, headache

• Follow up: labs in 4 weeks. (Total T, LH, estradiol). symptoms should be improved here too. if not, titrate dose up and repeat labs/symptom check in 4 weeks.

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TRT – Testosterone Replacement Therapy

Gel Shots Pellets Patches Pills

Skin Gel

Shots

Patches Pellets

Testosterone Replacement Therapy

Mechanism of Non-injectable:

– Transdermal patch q24h (2mg or 4mg)

– Transdermal gel q24h applied to upper arm, axilla

– Buccal tablets q12h 30mg PO BID

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Testosterone Replacement Therapy

IM injection

– T-proprionate q24h

– T-cypionate or T-enanthate start at 200mg every other week

• Generic, less expensive than non-injectables

• Can achieve higher blood levels than non-injectables

• Patients can be taught self-injection

• Peak measured 24h after 1st injection, trough measured immediately prior to 2nd injection

– Target peak 700-1200 ng/dL

– Target trough 400-600 ng/dL

– Adjustments in dose affect peak level, and adjustments in dosing interval affect trough level

Testosterone Replacement Therapy

Subcutaneous pellet– Inserted into buttock or flank via 5min office

procedure– Lasts 3-5 months– Attractive option for men who are unable or

unwilling to learn self-injection– Dose: 6-10 pellets, 450-750mg– Check T level after 1 month andAt 3 months. If <400, replace orconsider increasing dose

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T Undecanoate 750mg

Office administered gluteal injection

Weeks 0, 4, then every 10

No dose adjustment possible as only 1 dose made

Testosterone Replacement Therapy

Dose Adjustment

Goal Range 450-600 with symptom improvement, not "Cure"

Formulation Adjustment Strategy

Patch change to higher dose

Gel increase # of applications

IM increase by 50mg

Pellets reduce frequency (q3month) or increase #

AUA Guideline

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Dose Adjustment

AUA Guideline

Formulation Bioavailability Half Life

Patch 10%

Gel 10%

IM Cypionate or Enanthate 95% 8 days

IM Undecanoate 95% 33 days

Pellet 99%

for most, minimal oral bioavailability

Formulation Adjustment

What if there is no symptom improvement?

Whether or not goal T is in range

Goal Range 450-600 with symptom improvement, not "Cure"

Switch to any other form. Try and get guys to IM injections because the bioavailability is so good (and it is cheap)

AUA Guideline

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Side Effects of TRT

• Acne

• Breast soreness or swelling (gynecomastia)

• High red cell count (erythrocytosis, polycythemia)

• Swelling of feet/ankles (fluid retention)

• Smaller testicles

• Infertility

• Lightheadedness

• Gels can cause skin irritation/rash

• Gels cannot contact children and pregnant women

Major Safety Concerns

• Men with known breast or prostate cancer• Elevated PSA or abnormal prostate exam require

biopsy first• Kidney, liver disease may have increased water

retention• High red blood cell count >50%• May worsen sleep apnea• Blocks sperm production so avoid if trying to have

children

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Additional Safety Concerns:Prostate Cancer

• Prostate cancer is very testosterone sensitive

• Treatment for men who develop metastatic prostate cancer is total blockage of testosterone

• Testosterone therapy does not cause new Prostate Cancer

• After prostate cancer treatment, surgery or radiation, testosterone therapy is likely safe but no RCT to show this. Follow the PSA closely

Carson CC JUrol 2015

Additional Safety Concerns:Heart Disease

Major concerns that TRT can raise heart risk

Blood clots, stroke, heart attack

Conflicting studies that TRT may actually reduce heart disease risk

FDA continues to study this. Label changed March 2015 to reflect possible increased risk of heart attack and stroke

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Expectations of Treatment

• Improved energy

• Improved sex drive

• Increased muscle mass

• Decrease body fat

• Improved bone density

• Help sleep

• May improve erections in only 50%

Follow up on Treatment

Therapy is often life-long

Repeat blood testing 1-3 months after initiation, and after any adjustments

- Testosterone level

- Red cell count (H/H)

- PSA for prostate cancer if >40 years

Then annually with physical exam

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Summary

General Population Screening: No

Diagnosis: Symptoms AND T<300-350

Treatment Risks: possible CV, worsening OSA and BPH. Infertility

Does not cause prostate cancer.

Treatment options: gels, injections, pellets

Follow Up: 3-6 months. If no benefit, switch doses/modalities but stop after 6 months. Interval labs (PSA, CBC, Testosterone)

ConclusionAdvocating for comprehensive male care

- controlling diabetes and high blood pressure

- Stop smoking and adjust sleep

Consider Testosterone testing only if symptomatic

Not a panacea for all ailments

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References

Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endo Metab. 2007; 92: 4241-7.

Arver S, Lehtihet M. Current guidelines for the diagnosis of testosterone deficiency. Front Horm Res. 2009; 37: 5-20.

Basaria S Coviello AD, Travison TG, et al. Adverse Events Associated with Testosterone Administration. NEJM 2010: 363(2): 109-122.

Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010; 95(6): 2539-59.

Corona G, Rastrelli G, Forti G, Maggi M. Update in testosterone therapy for men. J Sex Med. 2011; 8(3): 639-54.

Dohle GR, Arver S, Bettocchi C, Kliesch S, Punab M, de Ronde W. Guidelines on Male Hypogonadism. EAU, 2012.

Finkle WD, Greenland S, Ridgeway GK, Adams JL, et al. (2014) Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men. PLoS ONE 9(1): e85805. doi:10.1371/journal.pone.0085805

Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endo Metab. 2001;86: 724-31.

Hsieh TC, Pastuszak AW, Hwang K, Lipshultz LI. Concomitant Intramuscular Human Chorionic Gonadotropin Preserves Spermatogenesis in Men Undergoing Testosterone Replacement Therapy. J Urol 2013; 189: 647-50.

Laughlin GA, Barrett E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 2008: 93(1): 68-75.

Morales A, Collier CP, Clark AF. A critical appraisal of accuracy and cost of laboratory methodologies for the diagnosis of hypogonadism: The role of free testosterone assays. Can J Urol. 2012; 19(3): 6314-8.

Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Eng J Med. 2004; 350: 482-92.

Sokol RZ. Endocrinology of male infertility: Evaluation and treatment. Semin Reprod Med. 2009; 27(2): 149-158.

Tanrikut C, Goldstein M, Rosoff JS, Lee RK, Nelson CJ, Mulhall JP. Varicocele as a risk factor for androgen deficiency and effect of repair. BJUI 2011; 108: 1480-4.

http://se.namiclevelandcounty.org/testosterone‐e‐before‐and‐after‐pics.html

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Men’s Health ProgramDr. Chris Deibert402‐559‐4292

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