What is the best course of treatment for a 38-year-old male with declining testosterone levels, from a historic high of 495 nanograms per deciliter (ng/dL) at age 32 to 372 ng/dL at age 38, with associated symptoms and comorbidities such as osteopenia?

Treatment Approach for Declining Testosterone with Osteopenia

You should initiate testosterone replacement therapy immediately, as your testosterone levels are now borderline low (372 ng/dL approaches the 350 ng/dL threshold), you have osteopenia requiring treatment, and testosterone therapy has proven bone-protective effects in hypogonadal men. 1, 2, 3

Diagnostic Confirmation Required Before Starting Treatment

Your testosterone trajectory shows a concerning decline from 495 to 372 ng/dL over 6 years, but formal diagnosis requires:

• Repeat morning testosterone measurements (8-10 AM) on two separate occasions to confirm persistent low testosterone, as single measurements are insufficient due to assay variability 1, 4
• Measure free testosterone by equilibrium dialysis in addition to total testosterone, as this is essential when total testosterone is borderline 1
• Obtain LH and FSH levels to distinguish primary (testicular) from secondary (pituitary-hypothalamic) hypogonadism, which has critical treatment implications including fertility preservation 1, 2
• Document baseline hematocrit/hemoglobin before initiating therapy to monitor for erythrocytosis 1
• Measure baseline PSA if you are over 40 years old 1

The distinction between primary and secondary hypogonadism is crucial: elevated LH/FSH with low testosterone indicates primary hypogonadism, while low or low-normal LH/FSH indicates secondary hypogonadism 1. If you have secondary hypogonadism and desire fertility preservation in the future, testosterone therapy is absolutely contraindicated and you must use gonadotropin therapy (hCG plus FSH) instead 5, 1.

Why Testosterone Therapy is Indicated in Your Case

The presence of osteopenia fundamentally changes the risk-benefit calculation. While the American College of Physicians recommends against testosterone therapy for energy/vitality complaints in age-related low testosterone 5, your situation differs critically:

• More than one-third of men under 50 with testosterone deficiency have decreased bone mineral density 2
• Testosterone treatment significantly increases spine bone mineral density (p <0.001) in hypogonadal men 2
• Hypogonadism is a crucial risk factor for male osteopenia and osteoporosis, contributing to fracture-related morbidity and mortality 3, 6
• Your testosterone level of 372 ng/dL is approaching the diagnostic threshold of <350 ng/dL used in major studies, and your declining trend suggests you will soon meet formal diagnostic criteria 2

The European Association of Urology guidelines note that testosterone therapy produces only small improvements in sexual function and quality of life, with little to no effect on physical functioning, energy, or cognition 1. However, bone health represents a distinct indication with stronger evidence 2, 3.

Recommended Treatment Regimen

First-Line: Transdermal Testosterone Gel

Start with transdermal testosterone gel 1.62% at 40.5 mg daily (2 pump actuations) applied to clean, dry, intact skin of shoulders and upper arms 1, 4. The European guidelines favor transdermal preparations over intramuscular injections due to more stable day-to-day testosterone levels 1.

Application instructions:

• Apply once daily in the morning to shoulders and upper arms only—never to abdomen, genitals, chest, armpits, or knees 4
• Wash hands immediately with soap and water after application 4
• Cover application sites with clothing after gel dries 4
• Wash application site thoroughly with soap and water before any skin-to-skin contact with others 4

Alternative: Intramuscular Testosterone (If Cost is Prohibitive)

If the annual cost of transdermal testosterone ($2,135.32) is prohibitive, intramuscular testosterone cypionate or enanthate 100-200 mg every 2 weeks is significantly more economical ($156.24 annually) with similar clinical effectiveness 5, 1. However, injectable testosterone carries higher risk of erythrocytosis compared to transdermal preparations 1.

Monitoring Protocol

• Check testosterone levels at 14 days and 28 days after starting treatment or after any dose adjustment 1, 4
• Target mid-normal testosterone levels (500-600 ng/dL) 1
• For injectable testosterone, measure levels midway between injections (days 5-7) 1
• Once stable, monitor every 6-12 months 1
• Monitor hematocrit periodically and withhold treatment if >54% 1, 4
• Monitor PSA levels if over 40 years, with urologic referral if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter 1

Dose Adjustment Algorithm

Based on pre-dose morning testosterone levels 4:

• >750 ng/dL: Decrease by 20.25 mg (1 pump actuation)
• 350-750 ng/dL: Continue current dose
• <350 ng/dL: Increase by 20.25 mg (1 pump actuation)

Maximum dose is 81 mg (4 pump actuations) 4.

Alternative Consideration: Clomiphene Citrate (If Secondary Hypogonadism and Fertility Concerns)

If you have secondary hypogonadism (low LH/FSH with low testosterone) and any future fertility concerns, clomiphene citrate is the preferred alternative 7. Clomiphene stimulates endogenous testosterone production without suppressing spermatogenesis, preserves fertility, and has lower risk of polycythemia 7. However, clomiphene citrate decreases spine bone mineral density (p = 0.003), making it less suitable for your osteopenia 2.

Concurrent Osteopenia Management

Testosterone therapy alone may not fully eliminate hypogonadal osteopenia 8. Despite long-term testosterone replacement normalizing serum androgen levels, 57.7% of hypogonadal men still had trabecular bone mineral content below -1 SD (osteopenia) 8.

Therefore, you should also:

• Supplement with calcium carbonate 9
• Consider anti-osteoporotic agents if bone density is severely compromised (T-score <-2.5) 3
• Repeat DXA scanning after 12-24 months of testosterone therapy to assess response 8, 3

Absolute Contraindications to Verify

Before starting testosterone, confirm you do NOT have 1, 4:

• Active desire for fertility preservation (use gonadotropins instead)
• Active or treated male breast cancer
• Prostate cancer
• Hematocrit >54%
• Untreated severe obstructive sleep apnea

Expected Outcomes and Realistic Expectations

Set realistic expectations: Testosterone therapy provides small but significant improvements in sexual function and libido (standardized mean difference 0.35), with little to no effect on physical functioning, energy, vitality, or cognition 5, 1. The primary benefit in your case is bone protection and potential improvement in bone mineral density 2, 3.

Reevaluate at 12 months: If no improvement in symptoms or bone density after adequate trial, consider discontinuing testosterone to prevent unnecessary long-term exposure to potential risks without benefit 1.

Critical Pitfalls to Avoid

• Never start testosterone without confirming you do not desire fertility, as exogenous testosterone suppresses spermatogenesis and causes prolonged azoospermia 1
• Never diagnose hypogonadism based on symptoms alone—biochemical confirmation with two morning testosterone measurements is mandatory 1, 4
• Never skip the investigation for secondary causes of hypogonadism in a young man—reversible conditions must be addressed first 1
• Never assume the declining testosterone is simply "age-related" at age 38—investigate for underlying pathology including hyperprolactinemia, hemochromatosis, or pituitary dysfunction 1, 9