What is the role of human chorionic gonadotropin (hCG) in treating secondary hypogonadism in male patients?

hCG as First-Line Treatment for Secondary Hypogonadism with Fertility Preservation

Human chorionic gonadotropin (hCG) is the first-line treatment for men with secondary hypogonadism who need testosterone restoration while preserving fertility potential, as it stimulates endogenous testosterone production without suppressing spermatogenesis. 1, 2

Primary Indication and Mechanism

• hCG is specifically indicated for hypogonadotropic hypogonadism (secondary hypogonadism), where the defect lies in the hypothalamus or pituitary gland, resulting in low or inappropriately normal LH/FSH with low testosterone 3, 2
• The FDA-approved indication includes "selected cases of hypogonadotropic hypogonadism (hypogonadism secondary to a pituitary deficiency) in males" 2
• hCG acts virtually identically to pituitary LH, stimulating Leydig cells to produce testosterone and supporting spermatogenesis 2

When to Use hCG Instead of Testosterone

Never prescribe exogenous testosterone to men desiring current or future fertility—it suppresses FSH and LH through negative feedback, causing azoospermia that can take months to years to recover. 1, 4

• hCG is preferred over testosterone therapy for any man with secondary hypogonadism who wishes to maintain fertility potential 1, 5
• Men with functioning pituitary glands but low testosterone benefit from hCG as it preserves the hypothalamic-pituitary-testicular axis 1
• Recovery of spermatogenesis after testosterone cessation may take months or rarely years, making prevention of suppression critical 1

Standard Dosing Protocol

• Initial dosing: 500-2500 IU administered 2-3 times weekly via subcutaneous or intramuscular injection 1
• Begin with hCG monotherapy to normalize testosterone levels first 1, 3
• If spermatogenesis remains inadequate after testosterone normalization, add FSH injections (hMG, highly purified urinary FSH, or recombinant FSH) 3, 6
• The combination of hCG and FSH for 12-24 months promotes testicular growth in almost all patients, spermatogenesis in approximately 80%, and pregnancy rates around 50% 3

Expected Outcomes and Timeline

• Bilateral testicular volumes typically double within 5-12 months of therapy 7
• Spermatogenesis (appearance of sperm in ejaculate) occurs in approximately 80% of patients, though some men achieve this with hCG alone 3, 6
• Three of 13 men in one study had sperm with hCG treatment alone, while nearly all developed sperm when FSH was added 6
• Larger testicular volume at baseline predicts faster induction of spermatogenesis and better fertility outcomes 8

Advantages Over Testosterone Therapy

• Preservation of fertility through maintained spermatogenesis 4, 1
• No risk of erythrocytosis (elevated red blood cell count) 4
• Maintenance of testicular volume rather than testicular atrophy 4, 8
• Lower cost compared to testosterone formulations 4
• hCG therapy resulted in mean testicular volume of 8.25 mL versus 3.4 mL with testosterone (P < .001) 8

Predictors of Treatment Success

Positive prognostic factors:

• Post-pubertal onset of hypogonadism 3
• Absence of cryptorchidism (undescended testes) history 3, 6
• Higher baseline testicular volume 3
• Higher baseline inhibin B serum concentrations 3
• Repeated cycles of therapy show faster spermatogenesis induction 7

Negative prognostic factors:

• Multiple pituitary deficits 6
• History of bilateral cryptorchidism (though unilateral cryptorchidism does not preclude fertility) 7, 6

Critical Contraindication

Men with primary hypogonadism (elevated LH/FSH with low testosterone) are absolutely contraindicated for hCG therapy—they cannot respond to gonadotropin stimulation and require testosterone replacement. 4

• Primary hypogonadism represents testicular failure where the testes cannot respond to LH/hCG stimulation 9
• These patients have testosterone and sperm counts below normal with serum LH and FSH above normal 9

Common Side Effects

• Gynecomastia is the most common side effect, caused by hCG stimulation of aromatase leading to increased estradiol secretion 3
• This can be managed with aromatase inhibitors if problematic while continuing therapy 3

Special Considerations

• Prior testosterone therapy does not adversely affect response to hCG/FSH treatment—there are no differences in rapidity or degree of response between previously treated and treatment-naïve patients 6
• Even men with Kallmann syndrome as old as 43 years can achieve spermatogenesis with gonadotropin therapy 7
• Reversal of hypogonadism can occur in up to 10% of patients, though the mechanism remains unclear 3
• Some patients who achieve adequate sperm production with combined hCG/FSH therapy can maintain spermatogenesis with hCG monotherapy after FSH withdrawal 6

Alternative to hCG: Clomiphene Citrate

• The European Association of Urology recommends clomiphene citrate (25-50 mg orally three times weekly) as an alternative for stimulating endogenous production in secondary hypogonadism, particularly when fertility preservation is desired 4
• Clomiphene offers advantages including lower cost, oral administration, and no risk of erythrocytosis 4
• However, clomiphene is contraindicated in primary hypogonadism (elevated LH/FSH) as these men cannot respond to gonadotropin stimulation 4