What is the most appropriate treatment approach for a patient with fatigue, low libido, and low mood, with testosterone and free testosterone levels at the lower end of normal?

Management of Low-Normal Testosterone with Hypogonadal Symptoms

Do not initiate testosterone replacement therapy in this patient with testosterone levels at the lower end of normal, as guidelines explicitly recommend against treatment in men with normal testosterone levels, even when symptomatic. 1

Diagnostic Confirmation Required

Before any treatment consideration, you must confirm true biochemical hypogonadism:

• Repeat morning testosterone measurements (8-10 AM) on at least two separate occasions to establish persistent hypogonadism, as single measurements are insufficient due to assay variability and diurnal fluctuation 2, 1
• Measure free testosterone by equilibrium dialysis in addition to total testosterone, as this is essential when total testosterone is borderline 2
• Obtain sex hormone-binding globulin (SHBG) levels to distinguish true hypogonadism from low SHBG-related decreases in total testosterone 2
• Biochemical hypogonadism requires total testosterone <300 ng/dL (some guidelines use 275-350 ng/dL threshold) on two separate morning measurements 1

Critical pitfall: The European Association of Urology explicitly warns against using symptoms or screening questionnaires without confirmed biochemical hypogonadism, as approximately 20-30% of men over 60 have testosterone in the low-normal range, but this does not constitute disease requiring treatment 1

If Testosterone Remains Low-Normal After Repeat Testing

Weight loss and lifestyle modification should be the primary intervention if the patient has obesity, as obesity-related decreases in testosterone are frequently reversible 2, 1:

• Low-calorie diets can improve testosterone levels in men with obesity-associated secondary hypogonadism 1
• Increased aromatization of testosterone to estradiol in adipose tissue causes estradiol-mediated negative feedback suppressing pituitary LH secretion 2
• Regular physical activity and exercise should be implemented 1

If True Biochemical Hypogonadism is Confirmed (<300 ng/dL)

Step 1: Distinguish Primary from Secondary Hypogonadism

• Measure serum LH and FSH to differentiate primary (testicular) from secondary (hypothalamic-pituitary) hypogonadism 2, 1
• Elevated LH/FSH with low testosterone indicates primary hypogonadism 1
• Low or low-normal LH/FSH with low testosterone indicates secondary hypogonadism 1

This distinction has critical treatment implications, particularly for fertility preservation 1

Step 2: Complete Hypogonadism Workup for Secondary Hypogonadism

If secondary hypogonadism is identified:

• Measure serum prolactin and iron saturation 2
• Consider pituitary function testing 2
• Consider MRI of the sella turcica to identify etiology of hypothalamic/pituitary dysfunction 2

Step 3: Treatment Selection Based on Fertility Desires

For men desiring fertility preservation:

• Gonadotropin therapy (hCG plus FSH) is mandatory as first-line treatment 1, 3
• Testosterone replacement therapy is absolutely contraindicated in men seeking fertility, as it suppresses spermatogenesis and causes azoospermia 1
• Clomiphene citrate is an effective alternative for secondary hypogonadism, as it stimulates endogenous testosterone production without suppressing spermatogenesis 3

For men not concerned with fertility:

• Transdermal testosterone gel 1.62% at 40.5 mg daily is the preferred first-line formulation due to more stable day-to-day testosterone levels 1, 4
• Intramuscular testosterone cypionate 50-400 mg every 2-4 weeks is a more economical alternative (annual cost $156 vs $2,135 for transdermal) 1, 3

Expected Treatment Outcomes - Setting Realistic Expectations

The primary indication for testosterone therapy is sexual dysfunction and diminished libido 1:

• Small but significant improvements in sexual function (standardized mean difference 0.35) 1
• Small improvements in quality of life, particularly vitality, social functioning, and mental health domains 1

Testosterone therapy provides little to no benefit for:

• Physical functioning 1
• Energy and vitality 1
• Depressive symptoms 1
• Cognition 1

Critical caveat: The American College of Physicians explicitly states that testosterone therapy produces little to no effect on physical functioning, energy, vitality, or cognition, even in confirmed hypogonadism 1. Your patient's primary complaints of fatigue and low mood are unlikely to improve significantly with testosterone therapy.

Monitoring During Treatment

• Check testosterone levels 2-3 months after treatment initiation and after any dose change 1
• For injectable testosterone, measure levels midway between injections, targeting mid-normal value (500-600 ng/dL) 1
• Monitor hematocrit periodically and withhold treatment if >54% 1
• Monitor PSA in men over 40 years 1
• Reevaluate symptoms at 12 months and discontinue testosterone if no improvement in sexual function 1

Absolute Contraindications to Testosterone Therapy

• Active male breast cancer 1
• Prostate cancer (though evidence is evolving) 1
• Active desire for fertility preservation 1
• Untreated severe obstructive sleep apnea 1

Alternative Approach: Address Underlying Causes

Given that your patient's testosterone is at the lower end of normal (not frankly low), consider evaluating and treating other causes of fatigue, low libido, and low mood:

• Screen for depression and consider antidepressant therapy if appropriate
• Evaluate for sleep disorders, thyroid dysfunction, anemia, vitamin D deficiency
• Assess for metabolic syndrome and cardiovascular risk factors
• Consider weight loss and exercise programs if obesity is present 2, 1

Bottom line: Guidelines are clear that testosterone therapy should not be initiated in men with normal testosterone levels, even at the lower end of normal, regardless of symptoms 1. The evidence shows minimal benefit for the patient's primary complaints of fatigue and low mood, even in confirmed hypogonadism 1.