Male Hypogonadism

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.

Quick Answers for Clinicians

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Diagnosis

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, 2018; Morales, 2015)
      • Early morning (between 7 and 11 am or within 3 hours after waking) fasting sample recommended due to diurnal variation (Morales, 2015)
      • Repeat measurement on different day to confirm
      • In children – mass spectrometry assay required to detect physiologic levels of testosterone
      • In men – electrochemiluminescent assay adequate to detect normal testosterone levels
        • Results – concentrations may decrease 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
      • Measure 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  – Endocrine Society recommends investigating causes/etiology of hypothalamic, pituitary, and/or testicular dysfunction (Bhasin, 2018)
    • 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

Screening

  • Screening in general population not recommended (Bhasin, Endocrine Society, 2018)
  • Assessment of testosterone levels (morning total testosterone) recommended for men with the following (Bhasin, Endocrine Society, 2018; 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 DM
    • Obesity
    • Metabolic syndrome

Monitoring

  • 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
  • Endocrine Society suggests discussing options for prostate cancer monitoring in men 40-69 years (Bhasin, 2018)
  • Refer patient to urologist if changes in prostate-specific antigen (PSA) or prostate by digital rectal exam
  • PSA – evaluate in postpubertal males
    • Use total PSA
    • PSA >4.0 is a contraindication to testosterone replacement (Bhasin, Endocrine Society, 2018)
  • CBC – evaluate for increased red cell mass
    • Hematocrit >55% is a contraindication to testosterone replacement
    • Check at 3, 6, and 12 months, then annually

Background

Epidemiology

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

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)
  • Secondary
    • Pathology occurs centrally, at level of pituitary or hypothalamus
    • Can be due to trauma, eg, traumatic brain injury (TBI), cancer, or exposure (eg, radiation, drugs, etc.; see list in Etiologies)
  • 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
        • Type 2 DM/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 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
    • Severity 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

ARUP Laboratory Tests

Aid in evaluation of suspected hypogonadism in men

Use to monitor testosterone replacement therapy

Not recommended for females or children

Differentiate between primary and secondary etiologies of hypogonadism

Acceptable test for evaluation of suspected hypogonadism in men

Not recommended for females or children

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

Not recommended for females or children

Most sensitive test for detection of hyperandrogenemia in women and children

Acceptable test for androgen deficiency in men

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.

Test intended for patients 2 weeks-6 years

For patients ≥7 years, order serum luteinizing hormone

Differentiate between primary and secondary etiologies of hypogonadism

Screening for anterior pituitary tumor

Related Tests

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

Not recommended for females or children

Acceptable test in evaluation of suspected hyperandrogenemia in women and children

Acceptable test for evaluating androgen deficiency in men

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

Not generally clinically indicated

Laboratory reference method for determining free and total testosterone in men

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

Not generally clinically indicated

Laboratory reference method for determining free testosterone in men

Free testosterone is generally adequate for most evaluations of suspected hypogonadism

Medical Experts

Contributor
Contributor

Young

Brittany A. Young, MD, PhD
Assistant Professor of Clinical Pathology at University of Utah
Co-Director of Clinical Laboratories at University Hospital, ARUP Laboratories

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®