Hypogonadism, Male

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Content

Indications for Testing

  • Signs and symptoms of hypogonadism

Laboratory Testing

  • Screen using serum testosterone concentration – preferably in the early morning with repeat measurement to confirm
    • Children – mass spectrometry assay
    • Adult males – electrochemiluminescent assay (mass spectrometry not necessary); total testosterone measurement is adequate for most patients as initial test (with or without sex hormone binding globulin)
      • <200 ng/dL – repeat testing
      • 200-400 ng/dL – repeat using free or bioavailable testosterone measurements
      • >400 ng/dL – normal testosterone
    • Biochemical evidence of deficiency is necessary to prescribe treatment (ASCP's Pathology-Related Choosing Wisely Recommendations, 2015; American Urological Society, The Endocrine Society, American Association of Clinical Endocrinologists)
  • FSH/LH – use to differentiate between primary and secondary etiologies after low testosterone established by two measurements
    • Elevated LH and FSH, low testosterone – primary hypogonadism
    • Normal or low LH and FSH, low testosterone – secondary or tertiary hypogonadism
      • Consider prolactin measures in secondary hypogonadism – prolactin often normal but may be elevated
    • Normal LH, elevated FSH, normal testosterone – seminiferous tubule disease
    • Normal LH, FSH, and testosterone – consider other etiologies

Imaging Studies

  • Secondary hypogonadism – consider MRI for pituitary imaging

Differential Diagnosis (also see Etiologies in Clinical Background section)

Hypogonadism Testing Algorithm

Hypogonadism is one of the most common endocrine disorders in men and is characterized by low serum testosterone levels and/or low sperm counts with clinical signs and symptoms of androgen loss.

Epidemiology

  • Prevalence
    • ~4-5 million men in U.S.
    • 20% of men ≥60 years
    • Frequency increases with obesity, aging, and diabetes mellitus type II

Etiologies

Pathophysiology

  • Gonadotropin-releasing hormone (GnRH) is secreted from the hypothalamus
  • GnRH stimulates the release of leuteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary
    • LH promotes secretion of testosterone from Leydig cells
    • FSH stimulates spermatogenesis
      • Inhibin B production from Sertoli cells inhibits FSH
  • 1-3% of circulating testosterone is free – responsible for biologic activity of testosterone
  • 91-98% of circulating testosterone is bound
    • 60% bound to albumin
    • 40% bound to sex hormone binding globulin (SHBG)
      • Substantial alterations in SHBG affect total testosterone level
        • Free testosterone and bioavailable testosterone levels more accurately reflect bioactive testosterone under these circumstances
        • Bioavailable testosterone = free testosterone plus albumin-bound testosterone
      • Alterations in SHBG
        • Increased by aging, hyperthyroidism, liver disease, HIV anticonvulsant drugs
        • Decreased by obesity, diabetes mellitus, hypothyroidism, glucocorticoids, androgens, progestins, nephrotic syndrome

Clinical Presentation

  • Manifestations depend on the following
    • Age of onset
    • Duration of deficiency
    • Profoundness of deficiency
  • Prepubertal/pubertal hypogonadism
    • Eunuchoidal body habitus
    • Gynecomastia
    • Small testes – volume typically <5 cm3
    • Lack of secondary sexual characteristics
    • Most common cause is Klinefelter syndrome
      • Hypogonadism signs and symptoms listed above plus
        • Small testes – 5ml
        • Long length of legs
        • Psychosocial abnormality unrelated to hypogonadism
        • Impaired higher level linguistic competence
        • Inability to sustain attention without impulsivity
        • Predisposition to develop morbidities later in life unrelated to hypogonadism
  • Postpubertal hypogonadism
    • Sexual – decreased libido, impotence, decrease in testicular volume
    • Psychological – depression
    • Constitutional – weakness, fatigue
    • Low bone mineral density
    • Gynecomastia
    • Muscle loss
    • Abdominal adiposity
    • Other signs and symptoms dependent on etiology
      • Pituitary tumor – visual field cuts
      • Prolactinoma and galactorrhea

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations.
Click on number for test-specific information in the ARUP Laboratory Test Directory

Testosterone, Adult Male 0070130
Method: Quantitative Electrochemiluminescent Immunoassay

Limitations

Not recommended for females or children

Luteinizing Hormone and Follicle Stimulating Hormone 0070193
Method: Quantitative Electrochemiluminescent Immunoassay

Testosterone, Bioavailable and Sex Hormone Binding Globulin (Includes Total Testosterone), Adult Male 0070102
Method: Quantitative Electrochemiluminescent Immunoassay
The concentrations of free and bioavailable testosterone are derived from mathematical expressions based on constants for the binding of testosterone to albumin and/or sex hormone binding globulin.

Limitations

Not recommended for females or children

Testosterone Free, Adult Male 0070111
Method: Quantitative Electrochemiluminescent Immunoassay
Total Testosterone and SHBG are measured and free testosterone is estimated from these measurements.

Limitations

Not recommended for females or children

Testosterone Free, Females or Children 0081059
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry/Electrochemiluminescent Immunoassay
Total Testosterone and SHBG are measured and free testosterone is estimated from these measurements.

Luteinizing Hormone (LH), Pediatric 2007567
Method: Quantitative Electrochemiluminescent Immunoassay

Limitations

For patients ≥7 years, order luteinizing hormone, serum

Additional Tests Available

Testosterone, Free and Total (Includes Sex Hormone Binding Globulin), Adult Male 0070109
Method: Quantitative Electrochemiluminescent Immunoassay
The concentration of free testosterone is derived from a mathematical expression based on the constant for the binding of testosterone to sex hormone binding globulin. 

Comments

Aid in the evaluation of suspected hypogonadism in men with a total testosterone level at the lower limit of the normal range

Not recommended for females or children

Testosterone, Bioavailable and Sex Hormone Binding Globulin (Includes Total Testosterone), Females or Children 0081057
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry/Electrochemiluminescent Immunoassay
The concentrations of free and bioavailable testosterone are derived from mathematical expressions based on constants for the binding of testosterone to albumin and/or sex hormone binding globulin.

Comments

Acceptable test in the evaluation of suspected hyperandrogenemia in women and children

Acceptable test for evaluating androgen deficiency in men

Sex Hormone Binding Globulin 0099375
Method: Quantitative Electrochemiluminescent Immunoassay

Androstenedione 2001638
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Comments

Aid in the investigation of virilizing endocrinopathies and in managing congenital adrenal hyperplasia in conjunction with other sex steroids

5-a-Dihydrotestosterone by Tandem Mass Spectrometry, Serum 2002349
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Testosterone Free and Total by ED/LC-MS/MS (Free) and LC-MS/MS (Total), Adult Males 2004246
Method: Quantitative Equilibrium Dialysis/High Performance Liquid Chromatography-Tandem Mass Spectrometry

Comments

Laboratory reference method for determining free and total testosterone in men

Total or free testosterone is generally adequate for most evaluations of suspected hypogonadism

Testosterone, Free, Adult Males by ED/LC-MS/MS 2003246
Method: Quantitative Equilibrium Dialysis/High Performance Liquid Chromatography-Tandem Mass Spectrometry

Comments

Laboratory reference method for determining free testosterone in men

Free testosterone is generally adequate for most evaluations of suspected hypogonadism

Guidelines

American Society for Clinical Pathology. Choosing Wisely - Pathology-Related Choosing Wisely Recommendations. An initiative of the ABIM Foundation. [Initial posting Feb 2015; Accessed: Nov 2015]

Bhasin S, Basaria S. Diagnosis and treatment of hypogonadism in men. Best Pract Res Clin Endocrinol Metab. 2011; 25(2): 251-70. PubMed

Bhasin S, Cunningham G, Hayes F, Matsumoto A, Snyder P, Swerdloff R, Montori V, 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): 2536-59. PubMed

Kushnir M, Blamires T, Rockwood A, Roberts W, Yue B, Erdogan E, Bunker A, Meikle W. Liquid chromatography-tandem mass spectrometry assay for androstenedione, dehydroepiandrosterone, and testosterone with pediatric and adult reference intervals. Clin Chem. 2010; 56(7): 1138-47. PubMed

Paduch D, Brannigan R, Fuchs E, Kim E, Marmar J, Sandlow J. The laboratory diagnosis of testosterone deficiency. Urology. 2014; 83(5): 980-8. PubMed

General References

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

Basaria S. Male hypogonadism. Lancet. 2014; 383(9924): 1250-63. PubMed

Ho C, Beckett G. Late-onset male hypogonadism: clinical and laboratory evaluation. J Clin Pathol. 2011; 64(6): 459-65. PubMed

Morales A, Collier C, Clark A. 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. PubMed

Palmert M, Dunkel L. Clinical practice. Delayed puberty. N Engl J Med. 2012; 366(5): 443-53. PubMed

Pantalone K, Faiman C. Male hypogonadism: more than just a low testosterone. Cleve Clin J Med. 2012; 79(10): 717-25. PubMed

Traish A, Miner M, Morgentaler A, Zitzmann M. Testosterone deficiency. Am J Med. 2011; 124(7): 578-87. PubMed

Viswanathan V, Eugster E. Etiology and treatment of hypogonadism in adolescents. Pediatr Clin North Am. 2011; 58(5): 1181-200, x. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Hammoud A, Meikle W, Peterson M, Stanford J, Gibson M, Carrell D. Association of 25-hydroxy-vitamin D levels with semen and hormonal parameters. Asian J Androl. 2012; 14(6): 855-9. PubMed

Kushnir M, Rockwood A, Roberts W, Pattison E, Bunker A, Fitzgerald R, Meikle W. Performance characteristics of a novel tandem mass spectrometry assay for serum testosterone. Clin Chem. 2006; 52(1): 120-8. PubMed

Medical Reviewers

Last Update: December 2015