Diagnostic Criteria for Hypogonadism
Hypogonadism is diagnosed by confirming low morning total testosterone levels (<300 ng/dL or <10.5 nmol/L) on two separate occasions, combined with specific clinical symptoms and measurement of gonadotropins (LH/FSH) to classify the type. 1, 2
Biochemical Confirmation Requirements
Testosterone Measurement Protocol
- Obtain two fasting morning testosterone measurements between 8-10 AM on separate days, as single measurements are unreliable due to significant diurnal variation 2, 3, 4
- Total testosterone <300 ng/dL (<10.5 nmol/L) on both occasions confirms biochemical hypogonadism 2, 5
- Testosterone levels <200 ng/dL definitively indicate hypogonadism, while levels between 200-400 ng/dL fall in a grey zone requiring additional testing 6
Free Testosterone Assessment
- Measure free testosterone by equilibrium dialysis if total testosterone is borderline (200-400 ng/dL) or if the patient is obese, as SHBG alterations can make total testosterone misleading 2, 5
- Calculate free testosterone index (total testosterone/SHBG ratio <0.3 indicates hypogonadism) 2
- SHBG levels decrease with obesity, insulin resistance, metabolic syndrome, hypothyroidism, and certain medications (growth hormone, glucocorticoids, anabolic steroids), while they increase with aging, hyperthyroidism, hepatic disease, and estrogen use 1
Classification by Gonadotropin Levels
Primary (Hypergonadotropic) Hypogonadism
- Elevated LH and FSH with low testosterone confirms primary hypogonadism, indicating testicular failure 2, 5, 7
- Causes include chromosomal abnormalities (Klinefelter syndrome), testicular trauma, radiation damage, chemotherapy, and autoimmune orchitis 1, 7
Secondary (Hypogonadotropic) Hypogonadism
- Low or inappropriately normal LH/FSH with low testosterone indicates secondary hypogonadism, reflecting hypothalamic-pituitary-gonadal axis dysfunction 5, 7
- Common causes include obesity (increased aromatization of testosterone to estradiol causing negative feedback), medications (opiates, GnRH agonists/antagonists, glucocorticoids), pituitary tumors, and traumatic brain injury 1, 5, 7
Functional Hypogonadism
- Low testosterone occurs without organic HPG axis alterations, often secondary to comorbidities such as metabolic syndrome, type 2 diabetes, chronic infections, inflammatory disease, COPD, or cardiovascular disease 7, 8
Required Clinical Symptoms
Sexual Symptoms (More Specific)
- Reduced libido, erectile dysfunction, and decreased spontaneous/morning erections are the most specific symptoms for hypogonadism 1, 2, 7
- Less specific sexual symptoms include reduced frequency of sexual intercourse, decreased masturbation, and delayed ejaculation 1, 5
Physical Symptoms
- Decreased vigorous activity, difficulty walking >1 km, decreased bending, hot flushes, and reduced physical strength/function 1, 2
- Reduced muscle mass and strength, increased body fat, diminished bone density, and anemia 7
Psychological Symptoms
- Low mood/mood deflection, decreased motivation, fatigue, concentration or memory difficulties, and sleep disturbances 1, 5, 7
Critical Diagnostic Pitfalls to Avoid
- Never measure testosterone during acute illness, as levels are artificially suppressed and unreliable 2
- Do not rely on screening questionnaires alone for diagnosis, as they lack specificity 2, 6
- Do not initiate testosterone therapy without confirming gonadotropin levels, as this determines whether the patient has primary versus secondary hypogonadism and guides treatment selection 2, 5
- Exclude classical organic causes before diagnosing functional or late-onset hypogonadism 1, 7
Additional Diagnostic Workup
Medication Review
- Check for drugs that interfere with testosterone production or action: glucocorticoids, opioids, antiandrogens (cyproterone acetate, spironolactone, flutamide, bicalutamide), 5α-reductase inhibitors (finasteride, dutasteride), and anabolic steroids 1, 2, 5
Comorbidity Screening
- Thyroid function tests (TSH, free T4) to exclude thyroid disorders affecting SHBG and testosterone metabolism 2
- BMI, waist circumference, and screening for metabolic syndrome and diabetes 2
- Bone density assessment (DXA scan) if osteoporosis risk factors present 2