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 to differentiate between primary and secondary etiologies
  • Normal/low LH/FSH and low testosterone – secondary or tertiary hypogonadism
    • Prolactin may also be elevated
  • 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
• Consider prolactin measures in secondary 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 (also see Etiologies)

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

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 the 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
    • M. 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 – M. 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% 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
• Post-pubertal hypogonadism
  • Sexual – decreased libido, impotence
  • Psychological – depression
  • Constitutional – weakness/fatigue
  • Low bone mineral density
  • Gynecomastia
  • Muscle loss
  • Abdominal adiposity

Treatment

• Androgen replacement

Tests generally appear in the order most useful for common clinical situations

Guidelines

• American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients--2002 update. Endocr Pract. 2002; 8 (6) :440-456.PubMed
• Kushnir MM, Blamires T, Rockwood AL, Roberts WL, Yue B, Erdogan E, Bunker AM, Meikle AW. Liquid chromatography-tandem mass spectrometry assay for androstenedione, dehydroepiandrosterone, and testosterone with pediatric and adult reference intervals. Clin Chem. 2010; 56 (7) :1138-1147.PubMed

General

• Arver S, Lehtihet M. Current guidelines for the diagnosis of testosterone deficiency. Front Horm Res. 2009; 37 :5-20.PubMed
• Belchetz PE, Barth JH, Kaufman JM. Biochemical endocrinology of the hypogonadal male. Ann Clin Biochem. 2010; 47 (Pt 6) :503-515.PubMed
• Gooren LJ. Late-onset hypogonadism. Front Horm Res. 2009; 37 :62-73.PubMed
• Seftel A. Male hypogonadism. Part II: etiology, pathophysiology, and diagnosis. Int J Impot Res. 2006; 18 (3) :223-228.PubMed
• Seftel AD. Male hypogonadism. Part I: Epidemiology of hypogonadism. Int J Impot Res. 2006; 18 (2) :115-120.PubMed
• Sussman EM, Chudnovsky A, Niederberger CS. Hormonal evaluation of the infertile male: has it evolved?. Urol Clin North Am. 2008; 35 (2) :147-55, vii.PubMed
• Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, O'Neill TW, Bartfai G, Casanueva FF, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Boonen S, Vanderschueren D, Labrie F, Huhtaniemi IT. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010; 363 (2) :123-135.PubMed

ARUP Institute for Clinical and Experimental Pathology®

• Kushnir MM, Rockwood AL, Roberts WL, Pattison EG, Bunker AM, Fitzgerald RL, Meikle AW. Performance characteristics of a novel tandem mass spectrometry assay for serum testosterone. Clin Chem. 2006; 52 (1) :120-128.PubMed

Growth Hormone Deficiency
Hemochromatosis
Hypopituitarism
Infertility
Osteoporosis