Hypogonadism, Male

  • Diagnosis
  • Algorithms
  • Screening
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Indications for Testing

  • Signs and symptoms of hypogonadism
    • Prepubertal
      • Delayed development of secondary sexual characteristics
      • Small testes, genitalia
      • Decrease in height
    • Postpubertal
      • Sexual difficulties
      • Erectile dysfunction
      • Infertility
      • Decreased muscle and/or skeletal mass
      • Decreased body hair
      • Low energy, fatigue
      • Change in mood, sleep, or increased anger
      • Decreased cognitive function

Laboratory Testing

  • Initial testing
    • Total testosterone concentration – adequate for most patients as initial test (Bhasin, Endocrine Society, 2010; Morales, 2015)
      • Early morning (between 7-11 am or within 3 hours after waking) fasting sample recommended due to diurnal variation (Morales, 2015)
      • Repeat measurement on different day to confirm
      • Children – mass spectrometry assay required to detect physiologic levels of testosterone
      • Adult males – electrochemiluminescent assay adequate to detect normal testosterone levels
        • Results – numbers may be lower with aging
          • <200 ng/dL – repeat testing
          • 200-400 ng/dL – repeat testing using free testosterone or sex hormone-binding globulin (SHBG) to calculate free or bioavailable testosterone measurements
          • >400 ng/dL – normal testosterone
    • Follicle-stimulating hormone (FSH)/luteinizing hormone (LH) – not necessary in aging male
      • Use to differentiate between primary and secondary etiologies
      • Elevated LH and FSH, low testosterone – primary hypogonadism
      • Normal or low LH and FSH, low testosterone – secondary or tertiary hypogonadism
    • Prolactin
      • Consider prolactin measurement in secondary hypogonadism
      • Elevated prolactin should prompt evaluation of pituitary gland
  • Associated testing
    • Chromosomal analysis – for prepubertal male
      •  Evaluate karyotype to identify Klinefelter syndrome
    • Semen analysis – for infertility
      • Volume
      • Motility
      • Concentration
      • Morphology

Imaging Studies

  • Magnetic resonance imaging (MRI) – evaluate pituitary in suspected secondary hypogonadism
  • Testicular ultrasound
  • Dual-energy x-ray absorptiometry (DEXA) bone scan – evaluate for changes in bone density due to low testosterone

Differential Diagnosis (also see Etiologies in Clinical Background section)

  • Screening in general population not recommended (Endocrine Society, 2010)
  • Assessment of testosterone levels (morning total testosterone) recommended for men with (Endocrine Society, 2010; Dohle, European Association of Urology [EUA], 2015)
    • History of sellar disease or damage (mass, radiation, other)
    • Medication use associated with low testosterone
      • Glucocorticoid
      • Opioids
    • End-stage renal disease (ESRD) on dialysis
    • Chronic obstructive pulmonary disease (COPD) – moderate to severe
    • Infertility
    • Osteoporosis
    • HIV-associated weight loss
    • Type 2 diabetes mellitus (DM)
    • Obesity
    • Metabolic syndrome

Regular follow-up needed in patients receiving testosterone therapy (Dohle, EAU, 2015)

  • Testosterone – monitor response to testosterone replacement therapy
    • Collect morning total testosterone and SHBG or free testosterone
    • Check at 3, 6, and 12 months, then annually
  • Prostate-specific antigen (PSA) – evaluate in postpubertal males
    • Use total PSA
    • PSA >4.0 is a contraindication to testosterone replacement
  • CBC – evaluate for increased red cell mass
    • Hematocrit >55% is a contraindication to testosterone replacement
    • Check at 3, 6, and 12 months, then annually

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. Hypogonadism can be primary or secondary, congenital or acquired. Common causes of acquired hypogonadism include diabetes mellitus (DM) and long-term use of opioid medications.

Epidemiology

  • Prevalence
    • ~4-5 million men in U.S.
    • 20% of men ≥60 years
    • Frequency increases with obesity, aging, and type 2 DM (T2DM)

Classification

  • Primary
    • Pathology occurs at level of testes; may be congenital or due to trauma or exposures (eg, radiation, drugs, etc; see list in Etiologies section)
  • Secondary
    • Pathology occurs centrally, at level of pituitary or hypothalamus
    • Can be due to trauma – for example traumatic brain injury (TBI), cancer, or exposure (eg, radiation, drugs, etc; see list in Etiologies section)
  • Adult men (age-related or late-onset hypogonadism)
    • Pathology at testes and hypothalamic-pituitary axis
  • Target organ insensitivity/resistance
    • Rare – defects of androgen receptors, 5-alpha reductase deficiency, and others
  • Additional distinctions
    • Congenital – present at birth
      • Klinefelter, congenital testicular defects, congenital adrenal hyperplasia
    • Acquired
      • Due to exposure, trauma, or other disease – common causes include
        • Chronic opioid use
        • T2DM/obesity
        • Prednisone or other glucocorticoid
        • Hypothyroidism

Etiologies

Pathophysiology

  • Gonadotropin-releasing hormone (GnRH) is secreted from the hypothalamus
  • GnRH stimulates release of LH and 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 equals free testosterone plus albumin-bound testosterone
      • Alterations in SHBG
        • Increased by aging, hyperthyroidism, liver disease, HIV anticonvulsant drugs
        • Decreased by obesity, DM, hypothyroidism, glucocorticoids, androgens, progestins, nephrotic syndrome

Clinical Presentation

  • Manifestations depend on
    • 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
  • Postpubertal hypogonadism
    • Sexual – decreased libido, erectile dysfunction, decrease in testicular volume
    • Change in secondary sexual characteristics – decreased body hair and muscle mass
    • Psychological – depression, anger, sleep disturbances
    • Constitutional – weakness, fatigue
    • Low bone mineral density
    • Gynecomastia
    • Abdominal adiposity, metabolic syndrome, insulin resistance
    • Impairment in cognitive  functioning
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

Prolactin 0070115
Method: Quantitative Chemiluminescent Immunoassay

Guidelines

Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM, 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

Choosing Wisely. An initiative of the ABIM Foundation. [Accessed: Sep 2017]

Dean JD, McMahon CG, Guay AT, Morgentaler A, Althof SE, Becher EF, Bivalacqua TJ, Burnett AL, Buvat J, Meliegy AE, Hellstrom WJ, Jannini EA, Maggi M, McCullough A, Torres LO, Zitzmann M. The International Society for Sexual Medicine's Process of Care for the Assessment and Management of Testosterone Deficiency in Adult Men. J Sex Med. 2015; 12(8): 1660-86. PubMed

Dohle G, Arver S, Bettocchi C, et al. Guidelines on male hypogonadism. European Association of Urology. Arnhem (the Netherlands) [Accessed: Jun 2017]

Kushnir MM, Blamires T, Rockwood AL, Roberts WL, Yue B, Erdogan E, Bunker AM, 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

Morales A, Bebb RA, Manjoo P, Assimakopoulos P, Axler J, Collier C, Elliott S, Goldenberg L, Gottesman I, Grober ED, Guyatt GH, Holmes DT, Lee JC, Canadian Men’s Health Foundation Multidisciplinary Guidelines Task Force on Testosterone Deficiency. Diagnosis and management of testosterone deficiency syndrome in men: clinical practice guideline. CMAJ. 2015; 187(18): 1369-77. PubMed

Paduch DA, Brannigan RE, Fuchs EF, Kim ED, Marmar JL, Sandlow JI. The laboratory diagnosis of testosterone deficiency. Urology. 2014; 83(5): 980-8. PubMed

Seftel AD, Kathrins M, Niederberger C. Critical Update of the 2010 Endocrine Society Clinical Practice Guidelines for Male Hypogonadism: A Systematic Analysis. Mayo Clin Proc. 2015; 90(8): 1104-15. 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

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

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

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. PubMed

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

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

Tournaye H, Krausz C, Oates RD. Concepts in diagnosis and therapy for male reproductive impairment. Lancet Diabetes Endocrinol. 2017; 5(7): 554-564. PubMed

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

Viswanathan V, Eugster EA. 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®

Büttler RM, Martens F, Fanelli F, Pham HT, Kushnir MM, Janssen MJ, Owen L, Taylor AE, Soeborg T, Blankenstein MA, Heijboer AC. Comparison of 7 Published LC-MS/MS Methods for the Simultaneous Measurement of Testosterone, Androstenedione, and Dehydroepiandrosterone in Serum. Clin Chem. 2015; 61(12): 1475-83. PubMed

Büttler RM, Martens F, Kushnir MM, Ackermans MT, Blankenstein MA, Heijboer AC. Simultaneous measurement of testosterone, androstenedione and dehydroepiandrosterone (DHEA) in serum and plasma using Isotope-Dilution 2-Dimension Ultra High Performance Liquid-Chromatography Tandem Mass Spectrometry (ID-LC-MS/MS). Clin Chim Acta. 2015; 438: 157-9. PubMed

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

Kushnir MM, Rockwood AL, Roberts WL, Pattison EG, Bunker AM, Fitzgerald RL, Meikle W. Performance characteristics of a novel tandem mass spectrometry assay for serum testosterone. Clin Chem. 2006; 52(1): 120-8. PubMed

Tran TS, Center JR, Seibel MJ, Eisman JA, Kushnir MM, Rockwood AL, Nguyen TV. Relationship between Serum Testosterone and Fracture Risk in Men: A Comparison of RIA and LC-MS/MS. Clin Chem. 2015; 61(9): 1182-90. PubMed

Medical Reviewers

Content Reviewed: 
July 2017

Last Update: September 2017