What is the role of human chorionic gonadotropin (hCG) therapy in treating low testosterone in adult males?

Human Chorionic Gonadotropin (hCG) Therapy for Low Testosterone

For men with secondary hypogonadism who desire fertility preservation, hCG therapy (with or without FSH) is mandatory and testosterone replacement is absolutely contraindicated. 1

Primary Clinical Indication

hCG therapy is the first-line treatment for men with secondary (hypogonadotropic) hypogonadism who wish to maintain fertility, as it stimulates endogenous testosterone production without suppressing spermatogenesis, unlike exogenous testosterone which causes azoospermia in 40% of patients. 1, 2

Key Diagnostic Requirements Before Starting hCG

• Confirm secondary hypogonadism by measuring LH and FSH levels—low or inappropriately normal gonadotropins with low testosterone (<300 ng/dL on two morning measurements) indicates secondary hypogonadism. 1, 3
• Document fertility desires explicitly, as this determines whether hCG or testosterone replacement is appropriate. 1
• Verify functioning pituitary gland, as hCG requires intact pituitary-testicular axis to work effectively. 4

Treatment Protocol and Expected Outcomes

Standard hCG Dosing Regimen

• hCG monotherapy: 500 IU intramuscularly every other day, or weekly dosing protocols ranging from 1,000-3,000 IU per week. 5, 2
• Combined therapy for optimal fertility: hCG plus FSH (recombinant or urinary preparations) for 12-24 months promotes testicular growth in nearly all patients, spermatogenesis in approximately 80%, and pregnancy rates around 50%. 1, 3

Testosterone Response

• Mean testosterone improvement of 49.9% from baseline, with levels increasing from approximately 362 ng/dL to 520 ng/dL within 2-3 months. 5
• Similar improvements in sexual function and quality of life compared to testosterone replacement (standardized mean difference 0.35 for sexual function), while preserving fertility. 4, 6

Symptom Improvement Rates

• 86% improvement in erectile dysfunction. 7
• 80% improvement in libido. 7
• 50% overall symptom improvement in men with baseline testosterone >300 ng/dL. 5

Special Clinical Scenario: Men with Testosterone >300 ng/dL

hCG monotherapy can be considered for symptomatic men with testosterone levels >300 ng/dL who do not meet traditional criteria for testosterone replacement, particularly those with low-normal testosterone and hypogonadal symptoms. 7, 5

• This approach appears safe with no changes in hematocrit, PSA, or hemoglobin A1c. 7
• No thromboembolic events reported in clinical series. 7
• Treatment duration typically 6-12 months with ongoing reassessment. 5

Advantages Over Testosterone Replacement

• Preserves fertility: Maintains or improves spermatogenesis rather than suppressing it. 4, 2
• Lower erythrocytosis risk: No significant changes in hematocrit compared to injectable testosterone which carries 44% risk of erythrocytosis. 4, 7
• Maintains testicular volume: Prevents testicular atrophy seen with exogenous testosterone. 3
• Cost-effective: Significantly less expensive than transdermal testosterone formulations ($156 annually vs $2,135). 4, 6

Monitoring Requirements

• Measure testosterone levels at 2-3 months after initiation, then every 6-12 months once stable, targeting mid-normal range (500-600 ng/dL). 1, 4
• Monitor for gynecomastia, the most common side effect due to increased aromatization of testosterone to estradiol. 3
• Reassess symptoms at 12 months—discontinue if no improvement in sexual function despite achieving target testosterone levels. 4, 6
• No routine PSA or hematocrit monitoring changes required compared to baseline, as hCG does not significantly affect these parameters. 7

Predictors of Treatment Success

• Post-pubertal onset of hypogonadism (better response than congenital). 3
• Larger baseline testicular volume (>4 mL predicts better spermatogenic response). 3
• Higher baseline inhibin B levels (marker of Sertoli cell function). 3
• No history of cryptorchidism (undescended testes predict poorer response). 3

Critical Contraindications

• Primary (testicular) hypogonadism: hCG will not work as testes cannot respond to stimulation—check baseline LH/FSH to distinguish from secondary hypogonadism. 4, 3
• Active male breast cancer: Absolute contraindication. 1
• No fertility concerns: If fertility is not desired, testosterone replacement is more straightforward and equally effective for symptom relief. 1, 3

When to Switch to Testosterone Replacement

• Failure to achieve target testosterone levels after 3 months of hCG therapy. 4
• No improvement in sexual function after 12 months despite adequate testosterone levels. 4, 6
• Patient no longer desires fertility preservation. 4
• Development of intolerable side effects (primarily gynecomastia). 3

Combination Therapy for Men Already on Testosterone

For hypogonadal men already on testosterone replacement who wish to restore fertility, add hCG 500 IU intramuscularly every other day to maintain intratesticular testosterone and preserve spermatogenesis. 2

• This approach prevents azoospermia in men on testosterone replacement, with 9 of 26 men achieving pregnancy with partners during treatment. 2
• No deterioration in semen parameters observed during combined therapy. 2
• Works with both injectable and transdermal testosterone formulations. 2

Realistic Expectations

• Sexual function: Small but significant improvements (similar to testosterone replacement). 4, 6
• Energy and vitality: Minimal improvements (SMD 0.17), similar to testosterone replacement. 6
• Physical function and cognition: Little to no benefit, consistent with testosterone replacement outcomes. 1, 6
• Fertility restoration: 80% achieve spermatogenesis with combined hCG/FSH therapy over 12-24 months. 3