Testosterone Therapy in Men with Hypogonadism

(Endocrine Society 2018 Guideline)

Ngwe Yin, MD

Assistant Clinical Professor of Medicine, UCSF

Fresno Medical Education Program

Feb 2, 2019

Disclosures

• None

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Objective

• At the end of the talk, you will be able to Diagnose androgen deficiency syndromes in menChoose therapeutic options for patient with diagnosed

androgen deficiencyMonitor during testosterone therapy

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3 Key Questions

• Does the patient have hypogonadism?

• If yes, primary or secondary hypogonadism?

• Any contraindication to start T therapy?

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Case 1

• 44 M was referred for management of hypogonadism

• Fatigue, mood changes x 6mo

• Morning total T 155.7 ng/dL [Immunoassay] (267-870 ng/dL) at a local lab confirmed with 2nd morning sample

• 4 biologic children (wife got pregnant without assistance)

• Exam: BMI 28, no gynecomastia, normal testicular exam

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Case 1

• What is the appropriate next step?

1. Patient has hypogonadism and start testosterone

2. Confirmed that testosterone assay is accurate and reliable

• Total T measured by LC/MS/MS 479 (250-1100 ng/dL), Free T 85 (35-155 pg/ml)

• Take home point – assay does matter!

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2018 Testosterone guidelines: T assays

• Emphasize on use of Accurate and reliable assay - equilibrium dialysis or

LC/MS/MS Lab certified by CDC or another accuracy based certifying

program https://www.cdc.gov/labstandards/pdf/hs/CDC_Certified

_Testosterone_Procedures-508.pdf

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T assays

• 1. Immunoassay: a great deal of variability at lower ranges, measures above 250 ng/dL, automated, simple to perform, faster turnaround time, sensitivity and interference issues.

• 2. LC/MS/MS: good sensitivity, accuracy and precision especially in the low range, can measure as low as low 20 ng/dL, high level of complexity.

• 3. Equilibrium Dialysis: gold standard method for measuring free T, high level of complexity, takes 2 days to perform.

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Immunoassays LC/MS/MS Equilibrium Dialysis

Quest Total T250-827 ng/dL

Total T250-1100 ng/dL

Free T (calculated)18-69 yrs 46.0 – 224.0 pg/mL

>69 yrs 6.0 – 73.0 pg/mL

Free T<70 yrs 35.0 – 155.0 pg/mL>70 yrs 30.0 – 135.0 pg/mL

LabCorpTotal T264 −916 ng/dL

Total T264 −916 ng/dL

Free T (calculated)50-59 yrs 7.2 – 24.0 pg/mL

>59 yrs 6.6 – 18.1 pg/mL

Free T (equilibrium ultrafiltration)5.00−21.00 ng/dL

Free T (equilibrium dialysis) 52.0 – 280.0 pg/mL

St AgnesTotal T 275 – 781 ng/dL Free T – send out to Quest

T assays (large interassay & interlaboratory variability)

Epic order

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Case 2 • 39 M is referred for management of hypogonadism

• No energy, fatigue x 3 years and getting worse recently

• Lab: Hb 16.9, Hct 48.2%, total T 232 LC/MS/MS (250-1100 ng/dL), Prolactin 5.3, SHBG 7 (10-50), free T 48.9 (35-155 pg/ml)

• Normal libido, no decreased erection

• Underwent normal puberty, has 3 biologic children (13, 8, 2 years old – wife got pregnant without assistance)

• ROS: snoring, daytime sleepiness

• Exam: BMI 39, no gynecomastia, well-virilized, normal testicular exam

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Case 2

Which of the following is false?

1. Patient likely has OSA and get sleep study

2. Patient has hypogonadism and start T replacement

3. Patient has low total T and SHBG likely due to obesity

4. Relative low total T likely improve if patient loses weight

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Diagnosis

• 1.1 We recommend diagnosing hypogonadism only in men with symptoms and signs consistent with testosterone deficiency and unequivocally and consistently low serum total T and/or free T concentration (when indicated).

• 1.2 We recommend against routine screening of men in the general population for hypogonadism.

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Diagnosis

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Symptoms and signs consistent with androgen deficiency

2 fasting 8am total TFree T (if suspect altered SHBG)

LH & FSHSemen fluid analysis (if fertility issue)

Low T, low or normal LH & FSHSecondary hypogonadism

Pituitary hormones, Transferrin Saturation, MRIObesity, Opioid, Anabolic steroid use

Low T, high LH & FSHPrimary hypogonadism

Karyotype (Klinefelter syndrome)

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Diagnosis

Specific symptoms and signs Nonspecific symptoms and signs

Incomplete or delayed sexual development Decreased energy, motivation, self-confidence

Loss of axillary and pubic hair Depressed mood

Testes <6 ml Poor concentration and memory

Suggestive symptoms and signs Sleep disturbance

Reduced sexual drive Mild unexplained anemia

Decreased spontaneous erection Reduced muscle bulk and strength

Gynecomastia Increased body fat, BMI

Eunuchoidal body proportions

Inability to father child, low sperm count

Height loss, low trauma fracture, low BMD

Hot flashes, sweats

Testosterone Transport

• Total T = Free T + albumin-bound T + SHBG-bound T

• Bioavailable T = Free T + albumin-bound T

• Free Androgen Index = T (ECLIA) : SHBG ratio

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Measure Free T

• 1. Conditions associated with ↓ SHBG (obesity, DM, glucocorticoid, anabolic steroid use, hypothyroidism, acromegaly, nephrotic syndrome, polymorphisms in SHBG genes)

• 2. Conditions associated with ↑ SHBG (aging, HIV, hepatitis, cirrhosis, hyperthyroidism, estrogen, polymorphisms in SHBG genes)

• 3. Total testosterone in borderline zone of reference range (eg., 200-400 ng/dL)

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Case 3

• 36 M p/w headache, low libido, decreased erection x 4mo, referred for management of hypogonadism

• 1 biologic child

• Exam: BMI 24, normal secondary sexual characteristics and testicular exam

• Morning total T 150 LC/MS/MS (250-1100 ng/dL) x 2

• LH 2.0 (1.0-9.0 mIU/ml)

• FSH 3.0 (1.0-13.0 mIU/ml)

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Case 3

• Which of the following is next best step?

1. Start testosterone therapy

2. Measure prolactin and pituitary panel

3. Order MRI pituitary w/wo contrast

4. Karyotyping

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• Prolactin 4000 (2.0 – 18.0 ng/dL)

Diagnosis

• 1.3 In men who have hypogonadism, we recommend distinguishing between primary (testicular) and secondary (pituitary–hypothalamic) hypogonadism by measuring serum LH and FSH.

• 1.4 In men with hypogonadism, we suggest further evaluation to identify the etiology of hypothalamic, pituitary, and/or testicular dysfunction.

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Diagnosis

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Primary Hypogonadism Secondary Hypogonadism

Organic

Klinefelter syndrome Hypothalamic/Pituitary tumor

Cryptorchidism, Anorchia Iron overload syndromes

Chemotherapy Infiltrative disease of hypothalamus/Pituitary

Testicular irradiation, trauma, torsion, Orchiectomy Idiopathic hypogonadotropic hypogonadism

Advanced age

Functional

Medications (androgen synthesis inhibitors) Hyperprolactinemia

ESRD Opioids, anabolic steroid, glucocorticoid

Alcohol, marijuana abuse

Systemic illness

Severe obesity

Case 4

• 44 M with chronic alcohol use p/w gynecomastia, decreased muscle mass x 1 yr

• Drank heavily until 2 mo ago, currently drink ½ bottle of vodka a week

• 2 children (age 10 and 7)

• Exam: +gynecomastia, normal testicular exam

• Lab: total T 240 (250-1100), free T 32.4 (35-155), LH & FSH normal, hCG <2, E2 30 (<52), prolactin 6.7 (<18), AST 134, ALT 80

• Mammogram was negative

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Case 4

• Next step?

1. Start T therapy

2. Abstinence from EtOH and repeat total T in 3 months

• Alcohol is known to cause functional secondary hypogonadism

• Therefore, to repeat testing after abstinence from alcohol

• Total T improved to 627 ng/dL 6 months of no EtOH

• Gynecomastia also improves

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Treatment

• 2.1 We recommend testosterone therapy in hypogonadal men to induce and maintain secondary sex characteristics and correct symptoms of testosterone deficiency.

• 2.2. We recommend against T therapy in men planning fertility or in men with breast or prostate Ca, a palpable prostate nodule/induration, PSA >4 ng/mL, PSA >3 ng/mL combined with a high risk of prostate Ca, elevated hematocrit, untreated severe OSA, severe LUTS, uncontrolled HF, MI or stroke within the last 6 months, or thrombophilia.

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Older men with age-related decline in T concentration

• 2.4 We suggest against routinely prescribing testosterone therapy to all men 65 years or older with low T.

• In men 65 years who have symptoms consistent with T deficiency and consistently and unequivocally low morning T, we suggest that clinicians offer testosterone therapy on an individualized basis after explicit discussion of the potential risks and benefits.

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Treatment

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Formulation Starting doses Monitoring (measure T)

T enanthate orT cypionate

150-200 mg IM every 2 weeksor 75-100 mg IM weekly

Midway between injection (IM)

T transdermal gel 1%, 1.62%, 2%

50-100 mg of 1%20.25-81 mg of 1.62%

2-8 h following application

T transdermal patch

1 or 2 patches (2-4 mg) daily 3-12 h after application

T undecanoate LA 750 mg IM, at 750 mg at 4 wk, then 750 mg every 10 wk

at the end of dosing interval

T pellets 600-1200 mg implanted SC at the end of dosing interval

2018 Testosterone guidelines: Monitoring

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Assess symptoms respond to treatmentAssess any adverse effects

At 3 months, each visit

Serum T (target mid-normal range) At 3 months, dose change, annually

Hematocrit (stop if Hct >54%, evaluate OSA) Baseline, at 3 months, annually

Bone density if osteoporosis Every 2 years

Prostate monitoring (shared decision making)Age 55-69 and age 40-69 who at increased risk for prostate Ca who choose monitoring

DRE + PSA before initiationAt 3-12 months after initiation, then in accordance with prostate Ca screening guidelines

Monitoring

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Urology consultation if

Increase in serum PSA >1.4 ng/dL within 12 months of initiating T treatment

PSA >4 ng/dL at any time

Abnormal DRE

Substantial worsening of LUTS (lower urinary tract symptoms)

Take home points

• Recommends making a diagnosis of hypogonadism only in men with symptoms and signs consistent with testosterone deficiency and unequivocally and consistently low serum T concentrations.

• Recommends the use of accurate assays for the measurement of total and free testosterone and rigorously derived reference ranges for the interpretation of testosterone levels.

• Recommend confirming the diagnosis by repeating the measurement of morning fasting total T concentrations.

• In men determined to have androgen deficiency, we recommend additional diagnostic evaluation to ascertain the cause of androgen deficiency.

• We recommend against starting T therapy in patients who are planning fertility in the near term or have any of a number of specified conditions.

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References

• https://www.endocrine.org/guidelines-and-clinical-practice/clinical-practice-guidelines/testosterone-therapy

Feb 2, 2019