What are the common causes of low testosterone (hypogonadism) in adult men and how should it be evaluated?

Root Causes of Low Testosterone (Hypogonadism)

Low testosterone results from either testicular failure (primary hypogonadism) or dysfunction of the hypothalamic-pituitary axis (secondary hypogonadism), with the distinction determined by measuring LH and FSH levels alongside testosterone. 1

Classification by Pathophysiology

Primary Hypogonadism (Hypergonadotropic)

Primary hypogonadism occurs when the testes themselves fail to produce adequate testosterone despite maximal pituitary stimulation, resulting in elevated LH and FSH levels. 1, 2

Common Acquired Causes

• Prior chemotherapy or radiation exposure is one of the most frequent acquired causes of testicular failure in adult men 2
• Cryptorchidism history, even if surgically corrected, frequently results in permanent testicular dysfunction 1
• Varicocele can cause progressive testicular damage over time 1
• Bilateral orchitis (mumps, trauma) destroys Leydig cell function 1
• Testicular torsion or surgical removal reduces testosterone production capacity 1

Genetic/Congenital Causes

• Klinefelter syndrome (47,XXY) is the most common genetic cause, often diagnosed during fertility evaluation 1, 2
• Y chromosome microdeletions (particularly AZF region) affect spermatogenesis and testosterone production 1, 2
• Myotonic dystrophy (types I and II) causes progressive testicular failure 1
• Uncorrected cryptorchidism with INSL3 and LGR8 mutations leads to permanent dysfunction 1

Uncommon Primary Causes

• Sickle cell disease, hemochromatosis, and adrenoleukodystrophy can infiltrate or damage testicular tissue 1
• Congenital anorchia and disorders of sex development (gonadal dysgenesis) eliminate testosterone production 1
• Defects in testosterone biosynthesis enzymes prevent hormone synthesis despite intact testicular tissue 1

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Secondary Hypogonadism (Hypogonadotropic)

Secondary hypogonadism results from impaired hypothalamic-pituitary signaling, characterized by low testosterone with inappropriately low or normal LH and FSH levels. 1, 3

Functional Hypogonadism (Most Common in Adults)

Functional hypogonadism—the most prevalent form in adult men—occurs when comorbidities suppress the HPG axis without structural damage, and is potentially reversible by treating underlying conditions. 1

• Obesity causes increased aromatization of testosterone to estradiol in adipose tissue, with subsequent estradiol-mediated negative feedback suppressing pituitary LH secretion 1, 3
• Type 2 diabetes and metabolic syndrome disrupt HPG axis function through insulin resistance and inflammatory pathways 1
• Chronic systemic diseases (chronic organ failure, HIV infection, chronic inflammatory arthritis) suppress gonadotropin secretion 1
• Opioid medications directly suppress GnRH pulsatility and are a leading iatrogenic cause 1
• Glucocorticoid excess (Cushing syndrome or exogenous steroids) inhibits the HPG axis 1
• Acute and critical illness temporarily suppresses testosterone production 1
• Aging gradually reduces GnRH pulsatility and Leydig cell responsiveness 1, 4

Drug-Induced Secondary Hypogonadism

• Anabolic steroids and exogenous testosterone suppress endogenous production via negative feedback 1
• GnRH agonists or antagonists (used for prostate cancer) directly block gonadotropin release 1
• Opiates are among the most potent suppressors of the HPG axis 1
• Progestogens (including cyproterone acetate) and estrogens inhibit LH secretion 1
• Hyperprolactinemia-inducing drugs (antipsychotics, metoclopramide) suppress gonadotropin release 1

Structural/Organic Secondary Causes

• Pituitary adenomas (micro or macroadenomas) compress normal pituitary tissue or cause hyperprolactinemia 1
• Traumatic brain injury damages the hypothalamus or pituitary stalk 1
• Pituitary surgery or cranial irradiation destroys gonadotroph cells 1
• Inflammatory diseases (lymphocytic hypophysitis, sarcoidosis, Wegener's granulomatosis) infiltrate the pituitary 1
• Hypothalamic tumors disrupt GnRH secretion 1

Congenital Secondary Hypogonadism

• Idiopathic hypogonadotropic hypogonadism (IHH) includes normosmic IHH and Kallmann syndrome (with anosmia) 1
• Prader-Willi syndrome causes hypothalamic dysfunction 1
• Combined pituitary hormone deficiency affects multiple pituitary axes 1

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Androgen Resistance (Rare)

In rare cases, hypogonadism results from reduced testosterone-androgen receptor interaction despite normal testosterone levels. 1

• Partial or complete androgen insensitivity prevents testosterone action at target tissues 1
• Kennedy disease (spinal and bulbar muscular atrophy) involves CAG repeat expansions in the androgen receptor gene 1
• 5α-reductase type II deficiency impairs conversion of testosterone to the more potent dihydrotestosterone 1

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Diagnostic Evaluation Algorithm

Step 1: Confirm Biochemical Hypogonadism

• Measure morning total testosterone (8-10 AM) on two separate occasions—single measurements are insufficient due to diurnal variation and assay variability 1
• Diagnosis requires both measurements <300 ng/dL (10.5 nmol/L) AND specific symptoms (diminished libido, erectile dysfunction) 1
• Avoid testing during acute illness, as this transiently suppresses testosterone 1

Step 2: Distinguish Primary from Secondary Hypogonadism

• Measure LH and FSH after confirming low testosterone 2, 3
• Elevated LH/FSH with low testosterone = primary (testicular) hypogonadism 1, 2, 3
• Low or low-normal LH/FSH with low testosterone = secondary (hypothalamic-pituitary) hypogonadism 1, 3

Step 3: Identify Reversible Causes

• Evaluate for obesity, metabolic syndrome, and diabetes—weight loss can reverse functional hypogonadism 1, 3
• Review all medications, particularly opioids, glucocorticoids, and anabolic steroids 1
• Measure prolactin if secondary hypogonadism is present, as hyperprolactinemia is treatable 1, 2
• Consider pituitary MRI if prolactin is elevated, LH/FSH are disproportionately low, or other pituitary hormone deficiencies are suspected 1

Step 4: Workup for Primary Hypogonadism

• Karyotype analysis to rule out Klinefelter syndrome (47,XXY) in men with small testes or infertility 1, 2
• Y chromosome microdeletion testing if severe oligospermia or azoospermia is present 1, 2
• Semen analysis to assess fertility potential 2
• Iron studies to exclude hemochromatosis as a cause of testicular damage 2

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Critical Clinical Pitfalls

• Never diagnose hypogonadism on symptoms alone—approximately 20-30% of men receiving testosterone in the U.S. lack documented low testosterone before treatment initiation 1
• Never skip LH/FSH measurement—the distinction between primary and secondary hypogonadism determines whether fertility can be preserved with gonadotropin therapy 1, 2, 3
• Never start testosterone without confirming the patient does not desire fertility—exogenous testosterone suppresses spermatogenesis and causes prolonged, potentially irreversible azoospermia 1, 3
• Always address reversible causes first (obesity, medications, metabolic disease) before initiating testosterone therapy, as functional hypogonadism may resolve with lifestyle modification 1, 3
• Measure free testosterone by equilibrium dialysis in obese men or those with borderline total testosterone, as low SHBG can artificially lower total testosterone while free testosterone remains normal 1, 3