How hCG Increases Testosterone in Men with Secondary Hypogonadism
Human chorionic gonadotropin (hCG) mimics luteinizing hormone (LH) and directly stimulates the Leydig cells in the testes to produce endogenous testosterone, making it the preferred first-line treatment for men with secondary hypogonadism who wish to preserve fertility. 1, 2
Mechanism of Action
hCG is structurally homologous to LH and binds to the same testicular LH receptors, triggering the biochemical cascade that converts cholesterol to testosterone within Leydig cells. 3 Unlike exogenous testosterone replacement, which suppresses the hypothalamic-pituitary-gonadal axis and causes azoospermia, hCG preserves the natural feedback loop while restoring testosterone production. 1, 2
In men with secondary (hypogonadotropic) hypogonadism—characterized by low testosterone with low or low-normal LH and FSH—the testes retain their capacity to respond to gonadotropin stimulation. 4 hCG exploits this preserved testicular function by bypassing the deficient pituitary signaling and directly activating testosterone synthesis. 2
Clinical Efficacy
All 13 men with hypogonadotropic hypogonadism treated with hCG achieved normal male testosterone levels, with 12 of 13 showing marked and continuous increases in testicular volume. 5 This demonstrates that hCG monotherapy is sufficient to normalize testosterone in the majority of men with secondary hypogonadism. 5
In a more recent cohort of 28 men with previous exogenous testosterone use who were switched to hCG monotherapy, mean testosterone levels increased significantly from 307.36 ±148.74 to 422.11 ±268.15 ng/dL when baseline labs were drawn outside the therapeutic window of prior testosterone therapy. 6 This confirms that hCG can restore physiologic testosterone levels even after prolonged suppression from exogenous testosterone. 6
A randomized trial of 282 hypogonadal men comparing clomiphene citrate (CC), hCG, and combination therapy found that testosterone levels increased 223% across all groups (from baseline 2.31 ±0.66 nmol/L to final 5.17 ±1.77 nmol/L), with no statistically significant difference between hCG monotherapy and the other regimens. 7 This demonstrates that hCG alone is as effective as combination approaches for testosterone restoration. 7
Recommended Dosing Regimen
The standard hCG dosing is 500-2500 IU administered 2-3 times weekly via subcutaneous or intramuscular injection. 2 Most protocols use 5000 IU twice weekly, which was the regimen employed in the randomized trial showing equivalent efficacy to clomiphene. 7
In clinical practice, one study reported an average dose of 5579 ±1773.7 IU when hCG was combined with clomiphene citrate 25 mg daily, with treatment continued until normal testosterone levels were achieved and maintained until spermatozoa appeared. 8 However, the randomized data suggest that hCG monotherapy at 5000 IU twice weekly is sufficient without requiring clomiphene co-administration. 7
Treatment Algorithm
Confirm secondary hypogonadism: Two morning testosterone measurements <300 ng/dL with low or low-normal LH and FSH. 4
Initiate hCG monotherapy: 5000 IU subcutaneous or intramuscular injection twice weekly (every 3-4 days). 2, 7
Monitor testosterone at 1 and 3 months: Target mid-normal range (500-600 ng/dL). 7
Assess testicular volume and symptom response: Expect increases in testicular size and improvements in libido, erectile function, and secondary sexual characteristics. 5, 8
Consider adding FSH if fertility is the goal: If sperm do not appear after 3-6 months of hCG monotherapy, add recombinant FSH 75-150 units subcutaneously 2-3 times weekly. 4, 5
Advantages Over Testosterone Replacement
hCG preserves fertility by maintaining spermatogenesis, avoids the risk of erythrocytosis seen with testosterone injections, and prevents testicular atrophy. 1 In the cohort of men switched from testosterone to hCG, there was a statistically significant decrease in hematocrit from 45.27 ±4.06% to 44.16 ±3.48%, with no thromboembolic events reported. 6 This contrasts sharply with injectable testosterone, which causes erythrocytosis in approximately 44% of users. 4
Prior exogenous testosterone use does not adversely affect response to hCG therapy—there were no differences in rapidity or degree of testosterone rise, testicular volume increase, or maximal sperm density achieved between men who had received previous testosterone and those who had not. 5 This is critical because it means men can safely transition from testosterone replacement to hCG without compromising efficacy. 5, 6
Fertility Outcomes
Three of 13 men achieved sperm in the ejaculate with hCG monotherapy alone, and all but one developed sperm during combined hCG and FSH therapy. 5 In a more recent study using hCG plus clomiphene, 47.4% of patients had sperm in semen after 12 months, though most sperm were completely deformed with progressive motility below 8%. 8
The key clinical point is that hCG alone can initiate spermatogenesis in some men with secondary hypogonadism, but adding FSH optimizes sperm production for those actively pursuing fertility. 4, 5 Four of five men who achieved sperm densities greater than 1 million/mL during combined hCG/FSH therapy maintained or increased sperm production when FSH was withdrawn and hCG monotherapy continued. 5
Critical Contraindication
Men with primary hypogonadism (elevated LH and FSH with low testosterone) cannot respond to hCG because their testes are intrinsically dysfunctional. 1 These patients require testosterone replacement therapy, as gonadotropin stimulation will not restore testosterone production when the Leydig cells themselves are damaged. 4, 1
Alternative: Clomiphene Citrate
Clomiphene citrate 25-50 mg three times weekly is an oral alternative that stimulates endogenous testosterone production by blocking estrogen receptors in the hypothalamus, thereby increasing GnRH pulsatility and LH secretion. 4 The randomized trial showed clomiphene was equally effective as hCG in raising testosterone levels (223% increase from baseline), with the advantage of oral administration and lower cost. 7
However, clomiphene is only effective in secondary hypogonadism with low or low-normal LH/FSH, and is ineffective in primary hypogonadism where LH/FSH are already elevated. 4 For men who prefer to avoid injections and are not immediately pursuing fertility, clomiphene represents a reasonable first-line option. 1, 7
Common Pitfalls
Never use hCG in men with primary hypogonadism—check LH and FSH before initiating therapy to confirm secondary hypogonadism. 4, 1
Do not assume hCG monotherapy will optimize sperm production—if fertility is the primary goal, plan to add FSH after 3-6 months if sperm counts remain low. 4, 5
Do not restart testosterone if fertility is desired—this will immediately suppress spermatogenesis again and negate the benefits of hCG therapy. 4
Monitor for inadequate testosterone response—if testosterone remains <300 ng/dL after 3 months of hCG at 5000 IU twice weekly, consider increasing the dose or adding clomiphene rather than switching to testosterone replacement. 8, 7