Clinical Review & Education

JAMA Diagnostic Test Interpretation

Testosterone Levels for Evaluation of Androgen Deficiency Shehzad Basaria, MD

A 54-year-old man with hypertension and diabetes presented to the endocrinology clinic with a 5-month history of fatigue, weight gain, interrupted sleep, and daytime somnolence. He has normal libido but experiences occasional erectile dysfunction, which is being successfully managed with a phosphodiesterase-5 inhibitor. His other medications include metformin and amlodipine. He is married, has 3 children, and reports a sedentary lifestyle. He recently heard on the radio that his symptoms might be due to “low T.” One month ago, he saw his primary care physician and requested measurement of his testosterone level. His morning total testosterone level (measured by mass spectrometry) was 279 ng/dL (normal reference range for this laboratory, 300-900 ng/dL), prompting his referral. On physical examination, his body mass index was 34.7 (calculated as weight in kilograms divided by height in meters squared).He was not cushingoid and his visual fields were normal. Acanthosis nigricans was noticed on the neck. There was no gynecomastia. His testes were normal in size. His muscle strength was normal. Relevant laboratory tests, including repeat morning total testosterone assessed in an endocrinology clinic, are reported in Table.

Total testosterone at 9 AM, ng/dLb Thyroid-stimulating hormone, mIU/L

Patient’s Value

Reference Rangea

279

300-900

1.9

0.5-4.5

Cortisol, μg/dL

12.7

7.0-25.0

Albumin, g/dL

3.7

3.7-5.1

RESULTS?

A. The patient has androgen deficiency; measure gonadotropins. B. Further evaluation is required; repeat total testosterone measurement using an immunoassay. C. Further evaluation is required; measure free testosterone. D. The patient has androgen deficiency; no further evaluation is required.

Table. Laboratory Values of the Patient Laboratory Test Primary care clinic

HOW DO YOU INTERPRET THESE TEST

Endocrinology clinic Total testosterone at 8 AM, ng/dLb

289

300-900

SI conversions: to convert testosterone to nmol/L, multiply by 0.0347; cortisol to nmol/L, multiply by 27.588. a

Reference ranges are specific to these laboratories.

b

Total testosterone levels were assessed by liquid chromatography tandem mass spectrometry.

Answer C. Further evaluation is required; measure free testosterone.

Test Characteristics Testosterone, a steroid hormone, circulates in plasma mostly bound to plasma proteins, mainly albumin and sex hormone–binding globulin (SHBG). Approximately 1% to 2% of testosterone circulates in free form, which is the fraction that is considered biologically active. The initial test for diagnosing androgen deficiency is serum total testosterone, which should be measured in patients who experience specific (and consistent) signs and symptoms of testosterone deficiency.1,2 These signs and symptoms can be categorized as specific (reduced libido, decreased spontaneous erecQuiz at jama.com tions, gynecomastia, loss of body hair, testicular atrophy, infertility, and hot flushes), or nonspecific (decreased energy, decreased motivation, depressed mood, sleepiness, reduced muscle bulk, increased body fat, increased body mass index, and diminished physical performance).2 Testosterone is secreted in a circadian fashion with peak levels occurring early in the morning; jama.com

therefore, serum testosterone levels should be measured during the morning hours.2 Mass spectrometry is considered the gold standard for measuring total testosterone and is now offered by some commercial laboratories in the United States. If clinicians lack access to a laboratory that offers mass spectrometry, measurement of total testosterone by immunoassays that have been validated against mass spectrometry is appropriate. A single low total testosterone value should always be confirmed by a second measurement because a substantial number of men have normal values on repeat testing.3 Although measurement of serum total testosterone is the first step in the diagnosis of androgen deficiency, total testosterone concentrations may not be reliable in patients with conditions that result in alterations in serum SHBG levels. Conditions associated with an increase in SHBG level include aging, hyperthyroidism, hyperestrogenemia, liver disease, HIV disease, and anticonvulsant use. Conditions associated with a decrease in SHBG level include obesity, insulin resistance and diabetes, hypothyroidism, growth hormone excess, glucocorticoids, androgens, progestins, and nephrotic syndrome.2 In these cases, measurement of free testosterone is helpful. (Reprinted) JAMA May 5, 2015 Volume 313, Number 17

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Clinical Review & Education JAMA Diagnostic Test Interpretation

In 2014, the Medicare midpoint reimbursements were $47.60 for total testosterone, $46.95 for free testosterone, and $40.07 for SHBG.4

sured and free testosterone level was calculated. His SHBG level was low at 7.0 nmol/L (normal reference range for this laboratory, 17-56 nmol/L) and his calculated free testosterone was normal at 12 ng/dL (normal reference range for this laboratory, 9-30 ng/dL).

Application of Test Result to This Patient The patient described in this case is obese and has insulin resistance, conditions that are associated with reduced serum SHBG levels, thereby leading to decreased total testosterone levels (while levels of free testosterone are generally preserved).2,5-7 The low SHBG levels lead to low serum total testosterone levels in the absence of hypothalamic, pituitary, or testicular disease. Measurement of free testosterone levels in obese patients aids in making an accurate diagnosis of androgen deficiency. This patient’s 2 serum total testosterone levels were measured using mass spectrometry, the standard method2; therefore, repeat measurement with an immunoassay is unlikely to be helpful. Serum gonadotropins are measured to distinguish primary from secondary hypogonadism. However, gonadotropins should be measured once the diagnosis of androgen deficiency is confirmed, which is not the case in this patient. The next step in this patient's evaluation is measurement of free testosterone. Although equilibrium dialysis is considered the gold standard for measuring free testosterone,2 it is not widely available to clinicians. Calculation of free testosterone by mass action equation using values of SHBG, albumin, and total testosterone (measured by a reliable assay) provides a reasonable alternative.8,9 Algorithms for calculating free testosterone concentrations are available on the Internet (http://www.issam.ch/freetesto.htm). The tracer analog displacement assays for free testosterone that are offered by many hospital and private laboratories are inaccurate and their use is not recommended. In this patient, total testosterone level is only moderately reduced, which in the presence of obesity and insulin resistance and absence of specific symptoms of androgen deficiency, is likely because of low SHBG levels.6,7 The patient’s SHBG level was meaARTICLE INFORMATION Author Affiliation: Section on Men's Health, Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Corresponding Author: Shehzad Basaria, MD, Section on Men's Health, Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 ([email protected]). Section Editor: Mary McGrae McDermott, MD, Senior Editor. Conflict of Interest Disclosures: Dr Basaria has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reports having previously received investigatorinitiated research grants from Abbvie Pharmaceuticals (previously Solvay Pharmaceuticals) and consulting for Eli Lilly. Additional Contribution: We thank the patient for sharing his experience and for granting permission to publish it. REFERENCES 1. Basaria S. Male hypogonadism. Lancet. 2014;383 (9924):1250-1263.

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What Are Alternative Diagnostic Testing Approaches? Measurement of bioavailable testosterone (free testosterone + albumin-bound testosterone) could be considered; however, it is not widely available. The algorithms that calculate free testosterone also provide concentrations for bioavailable testosterone. The Endocrine Society guidelines recommend against population-level screening for androgen deficiency because its cost-effectiveness and effect on public health remains unclear.

Patient Outcome This patient’s symptoms of interrupted sleep and daytime somnolence suggested underlying sleep apnea, commonly encountered in obesity, which was likely contributing to his fatigue. The patient was counseled regarding weight loss10 and was referred for a sleep study, which confirmed sleep apnea. Treatment with continuous positive airway pressure significantly improved his symptoms.

Clinical Bottom Line • The diagnosis of androgen deficiency should be based on at least 2 morning testosterone measurements (collected on separate days; using a reliable assay) in a symptomatic patient. • Obesity is associated with reduced levels of SHBG, which results in low total testosterone levels. Therefore, free testosterone should be measured in the evaluation of androgen deficiency in obese men. • In obese men presenting with nonspecific symptoms of androgen deficiency, underlying conditions responsible for such symptoms should be excluded.

2. Bhasin S, Cunningham GR, Hayes FJ, et al; Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559.

7. Plymate SR, Matej LA, Jones RE, Friedl KE. Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin. J Clin Endocrinol Metab. 1988;67(3):460-464.

3. Brambilla DJ, O’Donnell AB, Matsumoto AM, McKinlay JB. Intraindividual variation in levels of serum testosterone and other reproductive and adrenal hormones in men. Clin Endocrinol (Oxf). 2007;67(6):853-862.

8. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84(10):3666-3672.

4. Centers for Medicare & Medicaid Services. Clinical laboratory fee schedule. http://www.cms .gov/Medicare/Medicare-Fee-for-Service-Payment /ClinicalLabFeeSched/clinlab.html. Accessed November 30, 2014. 5. Camacho EM, Huhtaniemi IT, O’Neill TWF, et al; EMAS Group. Age-associated changes in hypothalamic-pituitary-testicular function in middle-aged and older men are modified by weight change and lifestyle factors: longitudinal results from the European Male Ageing Study. Eur J Endocrinol. 2013;168(3):445-455.

9. Mazer NA. A novel spreadsheet method for calculating the free serum concentrations of testosterone, dihydrotestosterone, estradiol, estrone and cortisol: with illustrative examples from male and female populations. Steroids. 2009;74 (6):512-519. 10. Hammoud A, Gibson M, Hunt SC, et al. Effect of Roux-en-Y gastric bypass surgery on the sex steroids and quality of life in obese men. J Clin Endocrinol Metab. 2009;94(4):1329-1332.

6. Glass AR, Swerdloff RS, Bray GA, Dahms WT, Atkinson RL. Low serum testosterone and sex-hormone-binding-globulin in massively obese men. J Clin Endocrinol Metab. 1977;45(6):1211-1219.

JAMA May 5, 2015 Volume 313, Number 17 (Reprinted)

Copyright 2015 American Medical Association. All rights reserved.

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