Treatment of Low Testosterone (Hypogonadism)
Primary Treatment Decision: Testosterone Therapy vs. Alternatives
For men with confirmed hypogonadism and sexual dysfunction who desire improved sexual function, initiate testosterone replacement therapy after discussing benefits, harms, and costs; however, if fertility preservation is a concern, use clomiphene citrate, selective estrogen receptor modulators (SERMs), or gonadotropins instead. 1, 2
Diagnostic Confirmation Required Before Treatment
Before initiating any treatment, confirm the diagnosis with:
- Morning total testosterone levels measured on at least two separate days, both showing levels below the normal range 1
- Presence of hypogonadism-consistent symptoms: reduced sexual function, decreased libido, erectile dysfunction, hot flushes, decreased energy, reduced physical strength, or concentration difficulties 1
- Avoid testing during acute illness, as this can falsely lower testosterone levels 1
- Measure free testosterone or androgen index to prevent unnecessary endocrine investigation in up to 50% of men with low total testosterone 1
- Check LH and prolactin only if testosterone is low to differentiate primary from secondary hypogonadism 1
Treatment Algorithm Based on Clinical Scenario
For Men NOT Desiring Fertility (Primary or Secondary Hypogonadism)
Testosterone replacement therapy is the treatment of choice 3, 4, 5
Formulation Selection:
- Intramuscular testosterone is preferred over transdermal formulations due to significantly lower cost with similar efficacy and safety 1
- FDA-approved formulations include:
Monitoring Requirements:
- Re-evaluate symptoms at 12 months and periodically thereafter 1
- Discontinue testosterone if no improvement in sexual function occurs 1
- Monitor for adverse effects including polycythemia, prostate issues, and cardiovascular events 4, 6
For Men Desiring Current or Future Fertility (Secondary Hypogonadism Only)
Testosterone monotherapy should NOT be prescribed as it suppresses spermatogenesis 1, 2, 7
First-Line Fertility-Preserving Options:
Clomiphene citrate is the preferred alternative for men with secondary hypogonadism who wish to preserve fertility, as it stimulates endogenous testosterone production without suppressing spermatogenesis 2
- Best candidates: Men with secondary (hypogonadotropic) hypogonadism with functioning pituitary glands 2
- Particularly effective in obesity-related hypogonadism where increased aromatization suppresses LH 2
- Advantages: Preserves/improves spermatogenesis and has lower risk of polycythemia compared to testosterone 2
- Limitation: Not FDA-approved for male hypogonadism; less effective for primary hypogonadism 2
Alternative Fertility-Preserving Options:
Aromatase inhibitors, hCG, or SERMs (or combinations) may be used for infertile men with low testosterone 1
Gonadotropin therapy (hCG + FSH) for 12-24 months:
- Promotes testicular growth in nearly all patients 8
- Achieves spermatogenesis in approximately 80% 8
- Pregnancy rates around 50% 8
- Requires frequent subcutaneous or intramuscular injections 8, 9
- Most effective in post-pubertal onset hypogonadism and higher baseline testicular volume 8
For Primary Hypogonadism with Fertility Desires
Surgical sperm retrieval with assisted reproductive technology (ART) is the only option, as these men cannot respond to gonadotropins or SERMs 1, 5
Specific Indications and Contraindications
FDA-Approved Indications for Testosterone:
- Primary hypogonadism: Testicular failure from cryptorchidism, bilateral torsion, orchitis, Klinefelter's syndrome, chemotherapy, or toxic damage 3
- Hypogonadotropic hypogonadism: Gonadotropin/LHRH deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation 3
Absolute Contraindications to Testosterone:
- Prostate or breast cancer 4, 6, 5
- Erythrocytosis or hyperviscosity 4, 6
- Untreated obstructive sleep apnea 6
- Severe heart failure 4, 6
- Desire for fertility (testosterone suppresses spermatogenesis) 1, 2
What NOT to Treat with Testosterone
Do NOT initiate testosterone for age-related low testosterone to improve energy, vitality, physical function, or cognition, as evidence shows no benefit for these outcomes 1
- The FDA has not established safety/efficacy for "age-related hypogonadism" or "late-onset hypogonadism" 3
- Only treat if sexual dysfunction is present and the patient desires improvement 1
Critical Safety Warnings
Secondary Exposure Risk:
- Children must avoid contact with unwashed or unclothed application sites in men using testosterone gel due to virilization risk 3
- Patients must strictly adhere to application instructions 3
Cardiovascular and Thromboembolic Risks:
- Venous thromboembolic events (DVT, PE) have been reported with testosterone products 4
- Evaluate patients with leg pain/swelling for DVT and shortness of breath for PE; discontinue if suspected 4
- Long-term cardiovascular safety is uncertain; some studies report increased MACE risk 4
Other Serious Risks:
- Abuse potential at higher doses, leading to serious cardiovascular/psychiatric events 4
- Gynecomastia is common, especially with gonadotropin therapy due to increased estradiol 8
- Sodium/water retention may cause edema or heart failure in predisposed patients 4
Ineffective or Questionable Treatments
Supplements (antioxidants, vitamins) have questionable clinical utility with inadequate data to recommend specific agents 1
SERMs for idiopathic infertility have limited benefits relative to ART results 1
FSH analogues may be considered for idiopathic infertility to improve sperm concentration and pregnancy rates, but evidence is limited 1