What is the diagnostic approach for male hypogonadism?

Diagnostic Approach for Male Hypogonadism

Male hypogonadism requires both biochemical confirmation with two separate morning total testosterone measurements below 300 ng/dL (measured between 8-10 AM) and specific clinical symptoms—particularly diminished libido and erectile dysfunction—to establish the diagnosis. 1

Step 1: Confirm Biochemical Hypogonadism

Obtain two fasting morning testosterone measurements on separate days between 8-10 AM, as diurnal variation is significant and single measurements are unreliable. 2, 3

• Total testosterone < 300 ng/dL (10.5 nmol/L) on both occasions confirms low testosterone 1, 2
• If total testosterone is borderline (200-400 ng/dL), measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG), especially in obese patients where SHBG alterations can affect interpretation 2, 3
• Calculate free testosterone index (total testosterone/SHBG ratio): values <0.3 indicate hypogonadism 2

Critical pitfall: Never measure testosterone during acute illness, as levels are artificially suppressed and unreliable. 2 Do not rely on screening questionnaires alone—they lack specificity for systematic diagnosis. 2

Step 2: Document Specific Clinical Symptoms

Primary symptoms warranting treatment:

• Decreased libido (reduced sexual desire) 1, 2
• Erectile dysfunction 1, 2
• Decreased frequency of spontaneous erections 2

Secondary symptoms with weaker evidence:

• Decreased energy and vitality 2
• Reduced muscle mass 2
• Hot flashes 2
• Gynecomastia 2

Important caveat: Symptoms alone without biochemical confirmation are insufficient for diagnosis—approximately 20-30% of men over 60 have low-normal testosterone but this does not constitute disease requiring treatment. 2

Step 3: Distinguish Primary from Secondary Hypogonadism

Measure LH and FSH levels after confirming low testosterone to definitively classify the type of hypogonadism. 2, 3, 4

• Elevated LH and FSH with low testosterone = Primary (hypergonadotropic) hypogonadism, indicating testicular failure 1, 2, 4
• Low or inappropriately normal LH/FSH with low testosterone = Secondary (hypogonadotropic) hypogonadism, indicating hypothalamic-pituitary dysfunction 1, 2, 4

This distinction is critical because it determines treatment approach and fertility preservation options. 2, 3 Men with secondary hypogonadism can potentially achieve both fertility restoration and normal testosterone with gonadotropin therapy, whereas primary hypogonadism patients can only receive testosterone replacement, which permanently compromises fertility. 2

Critical pitfall: Never attempt to diagnose the type of hypogonadism while the patient is already on testosterone therapy, as exogenous testosterone suppresses LH/FSH and results will be misleading. 3

Step 4: Identify Underlying Causes

For Primary Hypogonadism, evaluate for:

• Klinefelter syndrome (47,XXY) 1
• Cryptorchidism history 1
• Testicular trauma or torsion 1
• Chemotherapy or radiation exposure 1
• Mumps orchitis 1
• Myotonic dystrophy 1

For Secondary Hypogonadism, evaluate for:

• Measure serum prolactin to exclude hyperprolactinemia 2
• Consider pituitary MRI if prolactin elevated or other pituitary dysfunction suspected 2
• Kallmann syndrome (anosmia with hypogonadism) 1
• Pituitary tumors (micro/macroadenomas) 1
• Traumatic brain injury 1
• Hemochromatosis—check iron saturation 2

For Functional Hypogonadism:

• Review medications: glucocorticoids, opioids, anabolic steroids, GnRH agonists 1, 2
• Assess for obesity and metabolic syndrome 2
• Evaluate for chronic illness, sleep apnea, poorly controlled diabetes 2

Step 5: Additional Laboratory Assessment

Screen for comorbid conditions:

• Thyroid function tests (TSH, free T4) to exclude thyroid disorders affecting SHBG and testosterone metabolism 2
• Fasting glucose and HbA1c for diabetes screening 2
• Lipid panel 2
• Complete blood count (baseline hematocrit/hemoglobin) 2

If osteoporosis risk factors present:

• Bone density assessment (DXA scan of lumbar spine and femoral neck) 2
• Corrected serum calcium and phosphate 2
• 25-OH vitamin D levels if housebound, malabsorption, or hypocalcemic 2

Step 6: Assess for Treatment Contraindications

Before initiating testosterone therapy, document:

• Fertility desires: Testosterone therapy is absolutely contraindicated in men seeking fertility—they require gonadotropin therapy instead 2, 3
• Prostate assessment: Digital rectal examination and PSA level in men over 40 years 2
• Cardiovascular history: Recent MI or stroke within 3-6 months is a relative contraindication 2
• Hematocrit: Values >54% are an absolute contraindication 2
• Breast cancer history: Active or treated male breast cancer is an absolute contraindication 2
• Sleep apnea: Untreated severe obstructive sleep apnea is a contraindication 2

Diagnostic Algorithm Summary

1. Two morning testosterone measurements < 300 ng/dL + specific symptoms (especially sexual dysfunction) = Hypogonadism confirmed 1, 2
2. Measure LH/FSH to classify as primary (elevated) vs. secondary (low/normal) 2, 4
3. Investigate underlying causes based on classification 1, 2
4. Screen for comorbidities and contraindications to treatment 2
5. Document fertility desires before any treatment decisions 2, 3

Key pitfall to avoid: Do not initiate testosterone therapy without confirming elevated gonadotropins in primary hypogonadism or documenting that the patient does not desire fertility in secondary hypogonadism, as this would indicate different management approaches. 2, 3