Testosterone Therapy in Men with Hypogonadism (Endocrine Society 2018 Guideline) Ngwe Yin, MD Assistant Clinical Professor of Medicine, UCSF Fresno Medical Education Program
Disclosures None
Objective At the end of the talk, you will be able to Diagnose androgen deficiency syndromes in men Choose therapeutic options for patient with diagnosed androgen deficiency Monitor during testosterone therapy
3 Key Questions Does the patient have hypogonadism? If yes, primary or secondary hypogonadism? Any contraindication to start T therapy?
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 2 nd morning sample 4 biologic children (wife got pregnant without assistance) Exam: BMI 28, no gynecomastia, normal testicular exam
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!
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
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.
T assays (large interassay & interlaboratory variability) Immunoassays LC/MS/MS Equilibrium Dialysis Quest LabCorp St Agnes Total T 250-827 ng/dl Free T (calculated) 18-69 yrs 46.0 224.0 pg/ml >69 yrs 6.0 73.0 pg/ml Total T 264 916 ng/dl Free T (calculated) 50-59 yrs 7.2 24.0 pg/ml >59 yrs 6.6 18.1 pg/ml Total T 275 781 ng/dl Free T send out to Quest Total T 250-1100 ng/dl Total T 264 916 ng/dl Free T (equilibrium ultrafiltration) 5.00 21.00 ng/dl Free T <70 yrs 35.0 155.0 pg/ml >70 yrs 30.0 135.0 pg/ml Free T (equilibrium dialysis) 52.0 280.0 pg/ml
Epic order
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
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
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.
Diagnosis Symptoms and signs consistent with androgen deficiency 2 fasting 8am total T Free T (if suspect altered SHBG) LH & FSH Semen fluid analysis (if fertility issue) Low T, low or normal LH & FSH Secondary hypogonadism Pituitary hormones, Transferrin Saturation, MRI Obesity, Opioid, Anabolic steroid use Low T, high LH & FSH Primary hypogonadism Karyotype (Klinefelter syndrome)
Diagnosis Specific symptoms and signs Incomplete or delayed sexual development Loss of axillary and pubic hair Testes <6 ml Suggestive symptoms and signs Reduced sexual drive Decreased spontaneous erection Gynecomastia Nonspecific symptoms and signs Decreased energy, motivation, self-confidence Depressed mood Poor concentration and memory Sleep disturbance Mild unexplained anemia Reduced muscle bulk and strength 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
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)
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)
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
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.
Diagnosis 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
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
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.
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.
Treatment Formulation Starting doses Monitoring (measure T) T enanthate or T cypionate T transdermal gel 1%, 1.62%, 2% T transdermal patch T undecanoate LA 150-200 mg IM every 2 weeks or 75-100 mg IM weekly 50-100 mg of 1% 20.25-81 mg of 1.62% Midway between injection (IM) 2-8 h following application 1 or 2 patches (2-4 mg) daily 3-12 h after application 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 Assess symptoms respond to treatment Assess any adverse effects Serum T (target mid-normal range) Hematocrit (stop if Hct >54%, evaluate OSA) Bone density if osteoporosis Prostate monitoring (shared decision making) Age 55-69 and age 40-69 who at increased risk for prostate Ca who choose monitoring At 3 months, each visit At 3 months, dose change, annually Baseline, at 3 months, annually Every 2 years DRE + PSA before initiation At 3-12 months after initiation, then in accordance with prostate Ca screening guidelines
Monitoring 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.
References https://www.endocrine.org/guidelines-and-clinicalpractice/clinical-practice-guidelines/testosterone-therapy