Hypogonadism, Male

Diagnosis

Indications for Testing

• Signs and symptoms of hypogonadism

Laboratory Testing

• Screen serum testosterone concentration – preferably between 8-10 am
  • Children – mass spectrometry assay
  • Adult males – electrochemiluminescent assay (mass spectrometry not necessary)
    • <200 ng/dL – repeat testing
    • 200-400 ng/dL – measure free or bioavailable testosterone
    • >400 ng/dL – normal testosterone
• FSH/LH – 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
    • 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

• Testosterone <150 ng/dL – consider MRI for pituitary imaging

Differential Diagnosis (also see Etiologies)

• Pituitary lesions
• Dementia
• Hypothyroidism
• Adrenal tumor
• Depression
• Diabetes mellitus
• Hemochromatosis
• Cystic fibrosis

Clinical Background

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

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

• Primary – pathology in testes
  • Trauma
    • Orchiectomy
    • Testicular torsion
  • Drugs
    • Chemotherapy
    • Spironolactone
    • Ketoconazole
  • Radiation
  • Klinefelter syndrome (47,XXY)
  • Congenital testicular defects
    • Cryptorchidism
    • Dysgenetic testes
  • Infectious
    • Mumps
    • HIV
    • Mycobacterium leprae
  • Inflammatory
    • Autoimmune
  • Myotonic dystrophy
• Secondary
  • Pituitary pathology
    • Drugs (corticosteroids, opiates)
    • Hyperprolactinemia
    • Pituitary lesions
  • Iron overload
    • Hemochromatosis
    • Thalassemias
    • Other
  • Hepatic defects
    • Alcohol abuse
    • Exogenous estrogen
  • Severe chronic illness (cancer, chronic liver disease, chronic renal disease, rheumatoid arthritis, diabetes mellitus, obesity)
    • Endocrine diseases
    • Cushing syndrome
    • Diabetes mellitus
    • Metabolic syndrome
    • Congenital adrenal hyperplasia
• Tertiary – pathology in hypothalamus
  • Kallmann syndrome
  • Prader-Willi syndrome
  • Neoplastic
    • Craniopharyngioma
    • Germ cell tumors
    • Histocytosis X
  • Inflammatory
    • Wegener granulomatosis
    • Sarcoidosis
  • Infectious – Mycobacterium tuberculosis
• Age-related hypogonadism – pathology in testes and hypothalamus

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
• 2% of circulating testosterone is free
• 98% of circulating testosterone is bound 
  • 60% bound to albumin   
  • 40% bound to sex hormone binding globulin
    • Substantial alterations in sex hormone binding globulin 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

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
  • Lack of secondary sexual characteristics
• Postpubertal hypogonadism
  • Sexual – decreased libido, impotence
  • Psychological – depression
  • Constitutional – weakness, fatigue
  • Low bone mineral density
  • Gynecomastia
  • Muscle loss
  • Abdominal adiposity

Treatment

• Androgen replacement

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
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.	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.	Suggested for children due to an improved sensitivity of testosterone by LC-MS/MS
Sex Hormone Binding Globulin 0099375 Method: Quantitative Electrochemiluminescent Immunoassay
Testosterone, Urine 2004772 Method: Quantitative Gas Chromatography-Mass Spectrometry
Androstenedione 2001638 Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
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
Testosterone, Free, Adult Males by ED/LC-MS/MS 2003246 Method: Quantitative Equilibrium Dialysis/High Performance Liquid Chromatography-Tandem Mass Spectrometry

Diagnostic Algorithm

  Hypogonadism Testing Algorithm