What is the recommended dosing of Human Chorionic Gonadotropin (HCG) and Clomid (clomiphene citrate) for a patient post long-term Testosterone Replacement Therapy (TRT) to restore natural testosterone production and improve fertility?

HCG and Clomid Dosing Post Long-Term TRT

For men recovering fertility after long-term TRT, initiate HCG at 500 IU subcutaneously 3 times weekly (1,500 IU total per week), and if testosterone remains low after 3 months, add FSH 75-150 IU three times weekly; alternatively, clomiphene citrate 25-50 mg daily can be used to stimulate endogenous gonadotropin production. 1

Initial Recovery Protocol with HCG

The first-line approach uses HCG monotherapy to restore intratesticular testosterone production:

• Start with HCG 500 IU subcutaneously 3 times weekly (total 1,500 IU/week) to maintain intratesticular testosterone in the normal range 1
• The dosing range can extend from 500-2,500 IU per week, with typical administration of 250-500 IU given 2-3 times weekly 1
• For hypogonadotropic hypogonadism specifically, initial treatment uses HCG injections 500-2,500 IU, 2-3 times weekly until testosterone levels normalize 2
• Avoid supraphysiologic HCG doses as they cause Leydig cell desensitization and paradoxically reduce testosterone production 1

Monitoring and Escalation Strategy

Check testosterone levels at 2-3 months to assess testicular response:

• Measure LH and FSH to confirm they remain suppressed initially, then gradually recover 1
• If testosterone remains low after 3 months on HCG alone, add FSH 75-150 IU three times weekly 1
• A recent 2024 study demonstrated optimal recovery using 3,000 IU HCG plus 75 IU FSH three times weekly, with 74% of men showing improved sperm concentrations 3

Clomiphene Citrate as Alternative or Adjunct

Clomiphene citrate stimulates endogenous LH/FSH production rather than replacing it:

• Dose: 25-50 mg daily as an alternative to HCG 1
• Clomiphene 50 mg daily significantly increases FSH, LH, testosterone, and estradiol levels in normogonadotropic men 4
• In men with non-obstructive azoospermia, titrated clomiphene citrate resulted in sperm appearing in ejaculate in 10.9% of cases 5
• For patients showing inadequate FSH response but good testosterone response to clomiphene, continue clomiphene and add HCG 5
• If no hormonal response occurs with clomiphene, discontinue and switch to HCG plus human menopausal gonadotropin (hMG) 5

Combined Therapy Approach

The AUA/ASRM guidelines support combination therapy for infertile men:

• Clinicians may use aromatase inhibitors, HCG, selective estrogen receptor modulators (SERMs), or combinations thereof for infertile men with low serum testosterone 2
• Combined HCG and FSH therapy provides optimal outcomes for fertility preservation 6
• Low-dose HCG (500 IU every other day) maintains semen parameters when given concomitantly with testosterone replacement, with 9 of 26 men achieving pregnancy 7

Critical Timing Considerations

Recovery timelines are prolonged and variable:

• Approximately 67-90% of men eventually recover spermatogenesis after TRT cessation, but this can take 6-24 months 1
• Older age and longer duration of TRT predict slower and less complete recovery 1
• Although most azoospermic males recover sperm after cessation of testosterone therapy, the time course may be months or rarely years 2

Common Pitfalls to Avoid

Critical contraindications and warnings:

• Never prescribe testosterone monotherapy to males interested in current or future fertility - it provides negative feedback causing inhibition of gonadotropin secretion and can result in oligospermia or azoospermia 2
• Exogenous testosterone suppresses intratesticular testosterone production and impairs spermatogenesis, leading to azoospermia in 40% of patients 7
• Do not use excessively high HCG doses that cause receptor desensitization 1
• Patients must be counseled that recovery is not guaranteed and may take up to 2 years 1

Mechanism of Action

Understanding why these medications work:

• HCG mimics LH action directly on testicular Leydig cells, maintaining intratesticular testosterone levels necessary for spermatogenesis 6
• Intratesticular testosterone concentrations are approximately 100-fold higher than serum testosterone (1174 nmol/L vs 14.1 nmol/L), and HCG 500 IU every other day maintains ITT within normal range despite gonadotropin suppression 8
• Clomiphene blocks estrogen receptors at the hypothalamus and pituitary, increasing endogenous FSH and LH secretion 4