What is the appropriate workup for secondary (central) hypogonadism?

Workup for Secondary Hypogonadism

The workup for secondary hypogonadism requires two separate morning testosterone measurements (8–10 AM) showing levels <300 ng/dL, followed by measurement of LH and FSH to confirm inappropriately low or normal gonadotropins, and then systematic evaluation for reversible causes and pituitary pathology. 1, 2, 3

Initial Diagnostic Confirmation

Testosterone Measurement

• Obtain two fasting morning total testosterone levels between 8:00–10:00 AM on separate days, as diurnal variation causes lower afternoon values that risk false-positive diagnoses 2, 4
• Both measurements must be <300 ng/dL to establish biochemical hypogonadism 1, 2, 3
• In obese men or those with borderline values (231–346 ng/dL), measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG), as low total testosterone may reflect reduced SHBG with normal free testosterone 2, 3, 4
• Single measurements are insufficient due to significant intra-individual variability and assay differences 2, 4

Gonadotropin Assessment

• Measure serum LH and FSH after confirming low testosterone to differentiate primary from secondary hypogonadism 2, 3, 4, 5
• Secondary hypogonadism is characterized by low or inappropriately normal LH/FSH with low testosterone, whereas primary hypogonadism shows elevated gonadotropins 1, 3, 6, 5
• This distinction has critical treatment implications, particularly for fertility preservation 2, 3

Evaluation for Pituitary Pathology

Prolactin Measurement

• Measure serum prolactin in all men with confirmed secondary hypogonadism, as hyperprolactinemia is a common reversible cause 2, 5
• If prolactin exceeds 1.5 times the upper limit of normal, order pituitary MRI to exclude prolactinoma 2, 5

Pituitary Imaging Indications

Order pituitary MRI when any of the following are present: 2, 5

• Total testosterone <150 ng/dL with LH <1.5 IU/L and FSH <1.5 IU/L (regardless of prolactin level)
• Prolactin >1.5 times the upper limit of normal
• Visual field defects (e.g., bitemporal hemianopsia) or anosmia
• Symptoms suggesting mass effect (headaches, visual changes)

Assessment for Reversible Causes

Functional Hypogonadism Screening

Evaluate for common reversible causes that transiently suppress the hypothalamic-pituitary axis: 3, 6, 4

• Obesity and metabolic syndrome: Weight loss through low-calorie diets can reverse obesity-associated secondary hypogonadism 3
• Medications: Opioids, glucocorticoids, anabolic steroids
• Acute or critical illness: Defer diagnosis until recovery
• Chronic systemic diseases: Type 2 diabetes, HIV, chronic organ failure, inflammatory conditions 1
• Sleep disorders: Obstructive sleep apnea
• Nutritional deficiencies: Eating disorders, excessive exercise

Additional Baseline Laboratory Tests

Obtain the following to identify underlying conditions and establish pre-treatment baselines: 2, 3

• Fasting glucose and HbA1c to exclude diabetes
• Thyroid-stimulating hormone (TSH) to rule out thyroid dysfunction mimicking hypogonadal symptoms
• Complete blood count to document baseline hematocrit/hemoglobin (testosterone therapy risk)
• Lipid profile for metabolic assessment
• Prostate-specific antigen (PSA) in men >40 years before considering treatment
• Iron studies if hemochromatosis is suspected (a cause of secondary hypogonadism) 1

Symptom Assessment

Qualifying Symptoms for Treatment

Document the presence of specific symptoms that justify treatment: 2, 3

• Diminished libido (most specific symptom)
• Erectile dysfunction (particularly when PDE5 inhibitors fail)
• Decreased spontaneous/morning erections

Symptoms with Minimal Evidence for Benefit

Recognize that testosterone therapy provides little to no benefit for: 2, 3

• Fatigue or low energy
• Physical functioning or muscle strength
• Depressive symptoms
• Cognitive complaints

Fertility Assessment

Before any treatment decision, explicitly document whether the patient desires future fertility, as testosterone therapy causes azoospermia that may take months to years to reverse 2, 3

Common Pitfalls to Avoid

• Never diagnose hypogonadism on a single testosterone measurement; two separate morning values are mandatory 2, 4
• Never test testosterone outside the 8–10 AM window, as this increases false-positive rates 2
• Never omit LH/FSH testing after confirming low testosterone; this distinction directs treatment choice and fertility counseling 2, 5
• Never rely solely on symptoms without biochemical confirmation, as symptoms are nonspecific and overlap with many conditions 2, 4
• Never skip evaluation for reversible causes, particularly medications, obesity, and systemic illness 3, 6, 4
• Never assume age-related decline in young men; investigate for secondary causes 2
• Approximately 25–30% of men receiving testosterone therapy do not meet formal diagnostic criteria, highlighting the need for strict adherence to testing protocols 2

Diagnostic Algorithm Summary

1. Obtain two separate morning (8–10 AM) total testosterone measurements 2, 3, 4
2. If both <300 ng/dL, measure LH and FSH to confirm secondary hypogonadism (low/normal gonadotropins) 2, 3, 5
3. In obese men or borderline values, add free testosterone by equilibrium dialysis and SHBG 2, 3, 4
4. Measure prolactin in all cases of secondary hypogonadism 2, 5
5. Order pituitary MRI if prolactin >1.5× ULN or testosterone <150 ng/dL with LH/FSH <1.5 IU/L 2, 5
6. Screen for reversible causes: medications, obesity, systemic illness, sleep apnea 3, 6, 4
7. Obtain baseline labs: glucose, HbA1c, TSH, CBC, lipids, PSA (if >40 years) 2, 3
8. Document specific symptoms (libido, erectile function) and fertility desires 2, 3
9. Address reversible causes first (weight loss, medication adjustment) before considering testosterone therapy 3, 4