When should a male patient with confirmed hypogonadism (low testosterone production) and symptoms of low testosterone start testosterone replacement therapy (TRT) with testosterone injections?

When to Start Testosterone Injections for Hypogonadism

Start testosterone injections only after confirming both biochemical hypogonadism (morning total testosterone <300 ng/dL on two separate occasions) and specific symptoms of testosterone deficiency, particularly diminished libido and erectile dysfunction. 1

Diagnostic Requirements Before Starting Treatment

Biochemical Confirmation

• Measure morning total testosterone (drawn between 8-10 AM) on at least two separate occasions to confirm persistently low levels, as single measurements are insufficient due to assay variability and diurnal fluctuation 1, 2
• Testosterone levels below 300 ng/dL establish hypogonadism, with levels below 230-250 ng/dL representing frank hypogonadism that clearly warrants treatment 3, 1
• For borderline cases (231-346 ng/dL), measure free testosterone by equilibrium dialysis and sex hormone-binding globulin levels, especially in men with obesity 1

Distinguish Primary from Secondary Hypogonadism

• Measure serum LH and FSH after confirming low testosterone to determine the type of hypogonadism 1
• Elevated LH/FSH with low testosterone indicates primary (testicular) hypogonadism, while low or low-normal LH/FSH indicates secondary (hypothalamic-pituitary) hypogonadism 1
• This distinction is critical because men with secondary hypogonadism who desire fertility must receive gonadotropin therapy (hCG plus FSH) instead of testosterone, as testosterone causes azoospermia 1

Required Symptom Assessment

The primary symptoms that justify testosterone therapy are:

• Diminished libido (decreased sexual desire) 1
• Erectile dysfunction 1
• Diminished sense of vitality (though evidence for improvement is weaker) 3

Important caveat: Testosterone therapy produces little to no effect on physical functioning, energy, vitality, or cognition, even in confirmed hypogonadism 1. Do not start testosterone for complaints of fatigue, low energy, or mood symptoms alone, as improvements are minimal (standardized mean difference of only 0.17 for energy) 1.

Absolute Contraindications - Do Not Start If Present

• Active desire for fertility preservation - testosterone suppresses spermatogenesis and causes prolonged azoospermia 1, 4
• Active or treated male breast cancer 1, 4
• Prostate cancer on active surveillance or androgen deprivation therapy 1
• Hematocrit >54% 1, 4
• Untreated severe obstructive sleep apnea 1
• Uncontrolled heart failure 5
• Myocardial infarction or stroke within the last 6 months 5
• Prostate-specific antigen >4 ng/mL (or >3 ng/mL in high-risk men) without urological evaluation 5

When to Start: Clinical Algorithm

Step 1: Confirm Diagnosis

1. Two morning testosterone measurements <300 ng/dL 1, 2
2. Presence of diminished libido and/or erectile dysfunction 1
3. LH/FSH measured to distinguish primary vs. secondary hypogonadism 1

Step 2: Fertility Assessment

• If patient desires fertility now or in near future: Do NOT start testosterone; refer for gonadotropin therapy (hCG plus FSH) 1
• If fertility not desired: Proceed to Step 3

Step 3: Rule Out Contraindications

• Check baseline hematocrit, PSA (if age >40), and prostate examination 1, 4
• Screen for cardiovascular disease, sleep apnea, and breast cancer 1, 5

Step 4: Initiate Treatment

For most patients: Start with intramuscular testosterone cypionate or enanthate 100-200 mg every 2 weeks (or 50-100 mg weekly for more stable levels) 1, 2

Dosing specifics from FDA labeling:

• Testosterone enanthate: 50-400 mg every 2-4 weeks for male hypogonadism 2
• Testosterone cypionate: Similar dosing for replacement therapy 6
• Most patients require 100-200 mg every 2 weeks; doses above 400 mg per month are rarely needed 2

Alternative for elderly or high-risk patients: Consider transdermal gel (40.5 mg daily) for more stable day-to-day levels and lower erythrocytosis risk, though significantly more expensive 1

Special Considerations

Borderline Testosterone (231-346 ng/dL)

• If symptomatic with diminished libido/ED and no contraindications, consider a 4-6 month trial after careful discussion of risks and benefits 3
• Continue beyond 6 months only if clinical benefit is demonstrated 3

Elderly Patients (>70 years) or Chronic Illness

• Prefer easily titratable formulations (gel, spray, or patch) over long-acting injectables to allow for dose adjustment 3
• Target mid-range testosterone levels (350-600 ng/dL) rather than higher normal range 3

Patients with Congestive Heart Failure

• Use caution due to risk of fluid retention 3
• Target mid-range testosterone levels (350-600 ng/dL) 3

Obesity-Associated Secondary Hypogonadism

• First attempt weight loss through low-calorie diets and regular exercise, as this can improve testosterone levels without medication 1
• If lifestyle modifications fail and symptoms persist with confirmed low testosterone, then initiate testosterone therapy 1

Monitoring After Initiation

• Measure testosterone levels 2-3 months after starting or after any dose change 1, 7, 4
• For injectable testosterone, measure levels midway between injections, targeting mid-normal values (500-600 ng/dL) 1, 4
• Monitor hematocrit at 2-3 months and periodically thereafter; withhold treatment if >54% 1, 4
• Check PSA in men over 40 years at baseline and periodically 1, 4
• Reassess symptoms at 12 months - if no improvement in sexual function, discontinue treatment 1, 7

Common Pitfalls to Avoid

• Never start testosterone based on symptoms alone without confirming biochemical hypogonadism on two separate morning measurements 1
• Never start testosterone without asking about fertility desires - this is irreversible and causes prolonged azoospermia 1
• Never diagnose hypogonadism while patient is already on testosterone - must discontinue and allow 2-4 week washout before measuring LH/FSH 1
• Never use testosterone for energy, vitality, or mood complaints alone - evidence shows minimal to no benefit for these symptoms 1
• Never assume age-related decline in young men - investigate for secondary causes of hypogonadism first 1