When is treatment for hypogonadism (low testosterone levels) recommended?

When to Treat Testosterone (Hypogonadism)

Diagnostic Criteria Required Before Treatment

Testosterone replacement therapy should only be initiated when BOTH biochemical AND clinical criteria are met: total testosterone <300 ng/dL on two separate early morning measurements AND the presence of specific symptoms/signs of androgen deficiency. 1

Biochemical Requirements

• Measure total testosterone on two separate occasions, both drawn in early morning (8-10 AM) in a fasting state 1, 2
• Use a threshold of <300 ng/dL (or <320 ng/dL per some guidelines) as the cutoff for low testosterone 1
• Measure free testosterone by equilibrium dialysis and sex hormone-binding globulin, especially in men with obesity where binding proteins may be altered 2
• Measure LH and FSH to distinguish primary (testicular) from secondary (pituitary-hypothalamic) hypogonadism 2

Clinical Symptoms Required for Treatment

Treatment requires documented symptoms—biochemical evidence alone is insufficient. 1 Look specifically for:

• Sexual dysfunction: reduced libido, erectile dysfunction, decreased ejaculate volume 1, 2
• Physical changes: reduced energy, diminished endurance, fatigue, decreased muscle mass 1
• Cognitive/mood symptoms: depression, poor concentration, impaired memory, irritability 1
• Physical exam findings: gynecomastia, reduced body hair, small/soft testes, increased body mass index 1

High-Risk Populations Who Should Be Screened Even Without Symptoms

Consider measuring testosterone in asymptomatic men with these conditions, as they are at high risk for hypogonadism: 1

• Unexplained anemia 1
• Bone density loss or osteoporosis 1
• Type 2 diabetes 1, 2
• HIV/AIDS 1
• History of chemotherapy or testicular radiation 1
• Chronic narcotic use 1
• Male infertility 1
• Pituitary dysfunction 1
• Chronic corticosteroid use 1

When Treatment Is Indicated vs. Not Indicated

Primary Indication: Sexual Dysfunction

For men with age-related low testosterone and sexual dysfunction who desire improvement in sexual function, discuss initiating testosterone therapy after shared decision-making about benefits, harms, and costs. 1

• This is the ONLY indication with demonstrated benefit in age-related hypogonadism 1
• Reevaluate symptoms at 12 months and discontinue if no improvement in sexual function 1

NOT Indicated for These Symptoms Alone

Do NOT initiate testosterone therapy in men with age-related low testosterone solely to improve energy, vitality, physical function, or cognition—evidence shows little to no benefit for these outcomes. 1, 2

This represents a critical divergence between guidelines: while the AUA (2018) supports treatment for broader symptoms 1, the more recent ACP guideline (2020) specifically recommends AGAINST treatment for non-sexual symptoms in age-related hypogonadism 1. Given the priority on morbidity/mortality outcomes and the higher quality/more recent ACP evidence, treatment should focus primarily on sexual dysfunction.

Absolute Contraindications to Treatment

Never initiate testosterone therapy in men with: 3, 4

• Breast cancer or prostate cancer 3, 4
• Men actively seeking fertility (testosterone suppresses spermatogenesis; use gonadotropins instead) 2
• Erythrocytosis (hematocrit >50-54%) 2, 4
• Severe untreated obstructive sleep apnea 4
• Uncontrolled congestive heart failure (Class III-IV) 4
• Severe lower urinary tract symptoms (IPSS >19) without urologic evaluation 4
• Recent major adverse cardiovascular event 5

Treatment Algorithm

Step 1: Confirm Diagnosis

• Two morning testosterone levels <300 ng/dL 1
• Presence of symptoms (primarily sexual dysfunction for age-related hypogonadism) 1
• Measure LH/FSH to classify type 2

Step 2: Screen for Contraindications

• Prostate exam and PSA (if age >40) 2
• Hematocrit 2
• Cardiovascular risk assessment 5

Step 3: Choose Formulation Based on Clinical Context

For age-related hypogonadism with sexual dysfunction: Consider intramuscular testosterone over transdermal formulations due to significantly lower cost ($156/year vs. $2,135/year) with similar efficacy and safety. 1, 2

• Intramuscular (cypionate/enanthate): 200 mg every 2 weeks or 300 mg every 3 weeks 2, 6
• Transdermal gel: 40.5 mg daily to shoulders/upper arms 2, 3
• Transdermal provides more stable levels but costs 13-fold more 1, 2

Step 4: Monitor Response

• Check testosterone levels at 14 days and 28 days after initiation, then every 6-12 months 2, 3
• For injectable testosterone: measure midway between injections, targeting 500-600 ng/dL 2
• Reassess sexual function at 12 months—discontinue if no improvement 1
• Monitor hematocrit periodically; withhold if >54% 2
• Monitor PSA in men >40 years 2

Critical Pitfalls to Avoid

• Do not treat based on testosterone levels alone without symptoms 1—up to 25% of men receiving testosterone do not meet diagnostic criteria 1
• Do not use validated questionnaires to determine treatment candidacy—they are not recommended for this purpose 1
• Do not expect improvements in energy, cognition, or physical function in age-related hypogonadism—evidence does not support these benefits 1, 2
• Do not use testosterone in men seeking fertility—it will worsen fertility by suppressing gonadotropins; use clomiphene citrate or gonadotropins instead 2, 7
• Warn patients about secondary exposure risk—children and women must avoid contact with unwashed application sites 3

Special Consideration: Fertility Preservation

For men with secondary hypogonadism who desire fertility preservation, use clomiphene citrate or gonadotropin therapy instead of testosterone replacement. 2, 7

• Clomiphene stimulates endogenous testosterone production without suppressing spermatogenesis 7
• Testosterone replacement is absolutely contraindicated in men actively seeking fertility 2