Can a male patient with a history of hypogonadism (low testosterone levels) use Human Chorionic Gonadotropin (HCG) as monotherapy to restore testosterone levels and fertility after Testosterone Replacement Therapy (TRT)?

HCG Monotherapy for Testosterone and Fertility Restoration Post-TRT

Yes, HCG monotherapy can effectively restore both testosterone levels and fertility in men after stopping TRT, and represents the guideline-recommended approach for men with secondary hypogonadism who desire fertility preservation. 1, 2

Why HCG Works After TRT

HCG directly stimulates testicular Leydig cells to produce testosterone and supports spermatogenesis by mimicking luteinizing hormone (LH), bypassing the suppressed hypothalamic-pituitary axis that occurs during TRT. 3 This is critical because exogenous testosterone suppresses the body's natural production system, causing azoospermia (zero sperm count) in most men. 1, 2

• TRT shuts down the hypothalamic-pituitary-gonadal axis, suppressing LH and FSH secretion, which leads to testicular atrophy and loss of sperm production 1, 2
• HCG bypasses this suppressed axis by directly stimulating the testes, independent of pituitary function 3
• This makes HCG the logical choice for men transitioning off TRT who want to restore both testosterone and fertility 1, 2

Evidence for HCG Monotherapy Effectiveness

Testosterone Restoration

HCG monotherapy increases testosterone levels by approximately 50% in men with previous TRT use, with mean levels rising from 307 ng/dL to 422 ng/dL. 4

• A 2022 study of 28 men transitioning from TRT to HCG showed statistically significant testosterone increases without adverse effects 4
• Another 2022 study demonstrated 86% improvement in erectile dysfunction and 80% improvement in libido with HCG monotherapy 5
• HCG produces testosterone increases of 223% in hypogonadal men, comparable to clomiphene citrate 6

Fertility Restoration

Combination therapy with HCG plus FSH promotes spermatogenesis in approximately 80% of men with hypogonadotropic hypogonadism and achieves pregnancy rates around 50% after 12-24 months of treatment. 3

• HCG alone can restore testosterone but may require addition of FSH for optimal sperm production 1, 3
• Men with post-pubertal onset hypogonadism, larger baseline testicular volume, and no history of cryptorchidism have better outcomes 3
• The AUA/ASRM guidelines explicitly state that HCG (with or without FSH) should be used for infertile men with hypogonadotropic hypogonadism 1

Recommended HCG Protocol

FDA-Approved Dosing for Hypogonadism

For hypogonadotropic hypogonadism in males, the FDA label recommends either 500-1,000 units three times weekly for 3 weeks followed by the same dose twice weekly for 3 weeks, OR 4,000 units three times weekly for 6-9 months. 7

Practical Clinical Protocols

• Initial monotherapy: 2,000-3,000 units subcutaneously 2-3 times per week 4, 5, 8
• If fertility is the primary goal: Add recombinant FSH 75-150 units subcutaneously 2-3 times per week after 3-6 months if sperm counts remain low 1, 3
• Duration: Expect 12-24 months of therapy for optimal spermatogenesis and fertility outcomes 3

Monitoring Requirements

Initial Assessment (Before Starting HCG)

• Measure morning total testosterone (8-10 AM) on two separate occasions to confirm hypogonadism 2
• Measure LH and FSH to confirm secondary (not primary) hypogonadism—HCG only works if the testes can respond 2
• Obtain baseline semen analysis to document starting fertility status 9
• Check hematocrit, PSA (if age >40), and prolactin 2

Follow-Up Monitoring

• Testosterone levels: Check at 1 month, 3 months, then every 3-6 months 4, 8
• Semen analysis: Repeat at 3-6 month intervals to assess sperm production 9, 3
• Hematocrit: Monitor periodically—HCG causes less erythrocytosis than injectable testosterone 4
• Symptom assessment: Evaluate libido, erectile function, and energy at each visit 5, 8

Safety Profile and Advantages Over TRT

HCG monotherapy demonstrates a favorable safety profile with significantly lower risk of erythrocytosis compared to testosterone injections. 4

• One study showed statistically significant decrease in hematocrit from 45.3% to 44.2% after switching from TRT to HCG 4
• No thromboembolic events reported in clinical studies 4, 5
• PSA levels either remain stable or decrease slightly 4
• Gynecomastia is the most common side effect, occurring due to HCG-stimulated aromatase activity increasing estradiol 3

When to Add FSH to HCG

If sperm counts remain zero or very low after 6 months of HCG monotherapy, add recombinant FSH to optimize spermatogenesis. 1, 3

• FSH directly stimulates Sertoli cells and supports sperm maturation 3
• Combined HCG + FSH therapy produces better fertility outcomes than HCG alone in men with secondary hypogonadism 1, 3
• Different FSH preparations (recombinant FSH, highly purified urinary FSH, human menopausal gonadotropins) show similar efficacy 3

Critical Pitfalls to Avoid

• Never restart testosterone if fertility is desired—this will immediately suppress spermatogenesis again 1, 2
• Don't use HCG in men with primary testicular failure (elevated LH/FSH with low testosterone)—their testes cannot respond to HCG stimulation 2, 3
• Don't expect immediate results—testosterone recovery occurs within 1-3 months, but sperm production requires 12-24 months of therapy 3, 4
• Don't skip the washout period—allow 2-4 weeks after stopping TRT before starting HCG to permit accurate diagnostic testing 2
• Don't ignore baseline testicular volume—men with very small testes (<4 mL) from prolonged TRT may have limited recovery potential 3

Alternative: Clomiphene Citrate

Clomiphene citrate 25-50 mg daily or every other day represents an oral alternative to HCG that produces similar testosterone increases (223% from baseline) and may be preferred for cost and convenience. 9, 6

• Clomiphene works by blocking estrogen receptors in the hypothalamus, increasing GnRH and subsequently LH/FSH secretion 9
• A 2018 randomized study showed equivalent testosterone restoration between clomiphene and HCG 6
• However, guidelines still recommend HCG (with or without FSH) as first-line for fertility restoration in secondary hypogonadism 1, 2
• Clomiphene may be considered when HCG is not feasible due to cost or injection aversion 9

Expected Timeline and Outcomes

• Testosterone normalization: 1-3 months 4, 6, 8
• Symptom improvement: 50-86% of men report improvement in libido and erectile function within 1-3 months 5, 8
• Sperm appearance in ejaculate: 6-12 months 3
• Optimal sperm counts and pregnancy potential: 12-24 months 3
• Overall success rate for spermatogenesis: Approximately 80% in men with secondary hypogonadism 3