Hypogonadism, Male

Diagnostic Algorithm

  Hypogonadism Testing Algorithm

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)
  • Autoimmune orchitis
  • Chemotherapy
  • Cryptorchidism
  • Dysgenetic testes
  • Klinefelter syndrome
  • Mumps orchitis
  • Myotonic dystrophy
  • Orchiectomy
  • Radiation
• Secondary (pathology in pituitary)
  • Alcohol abuse
  • Cushing syndrome
  • Drugs (corticosteroids, opiates)
  • Hyperprolactinemia
  • Iron overload
  • Pituitary lesions
  • Severe chronic illness (cancer, chronic liver disease, chronic renal disease, rheumatoid arthritis, diabetes mellitus and obesity)
  • Other genetic mutations
• Tertiary (pathology in hypothalamus)
  • Kallmann syndrome
  • Prader-Willi syndrome
• 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% 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
• Pre-pubertal/pubertal hypogonadism
  • Eunuchoidal body habitus
  • Gynecomastia
  • Small testes
  • Lack of secondary sexual characteristics
• Postpubertal hypogonadism
  • Weakness
  • Decreased libido
  • Depression
  • Impotence
  • Normal penile size
  • Low bone mineral density
  • Gynecomastia
  • Muscle loss
  • Abdominal adiposity

Treatment

• Androgen replacement

Diagnosis

Indications for Testing

• Signs and symptoms of hypogonadism

Laboratory Testing

• Screen serum testosterone concentration (preferably between 8-10 am)
  • For children, use mass spectrometry assay
  • For adult males, use radioimmunoassay (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 to differentiate between primary and secondary etiologies
  • Normal/low LH/FSH and low testosterone – secondary or tertiary hypogonadism
  • Normal LH/FSH and normal testosterone  – consider other etiologies
  • Normal LH, elevated FSH, normal testosterone – seminiferous tubule disease
  • Elevated LH/FSH, low testosterone – primary hypogonadism

Imaging Studies

• Testosterone <150 ng/dL – consider MRI for pituitary imaging
  • If LH is normal to low, prolactin may be increased
  • Expect to see low LH and normal prolactin in these patients

Differential Diagnosis

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

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 & Total (Includes Sex Hormone Binding Globulin), Adult Male 0070109 Method: 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 & Sex Hormone Binding Globulin (Includes Total Testosterone), Females or Children 0081057 Method: 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
Testosterone Free, Females or Children 0081059 Method: High Performance Liquid Chromatography/Tandem Mass Spectrometry/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.
Sex Hormone Binding Globulin 0099375 Method: Electrochemiluminescent Immunoassay
Testosterone, Urine 0070716 Method: Chemiluminescent Immunoassay
Androstenedione 2001638 Method: High Performance Liquid Chromatography/Tandem Mass Spectrometry
5-a-Dihydrotestosterone by Tandem Mass Spectrometry, Serum 2002349 Method: High Performance Liquid Chromatography/Tandem Mass Spectrometry