HCG (Human Chorionic Gonadotropin)

Exogenous testosterone suppresses the pituitary hormones LH and FSH, which switches off the testes' own testosterone and sperm production. That causes testicular shrinkage and, in many men, infertility. HCG mimics LH and stimulates the Leydig cells directly, so it keeps intratesticular testosterone and testicular volume up while a man stays on TRT. Coviello and colleagues (2005) showed that low-dose HCG maintained intratesticular testosterone in the normal range during testosterone-induced gonadotropin suppression.

As a TRT adjunct, research and clinical protocols commonly use 250-500 IU subcutaneously two to three times per week. Fertility induction in hypogonadotropic hypogonadism uses higher doses, often 1,000-2,500 IU two to three times weekly, sometimes combined with FSH. As a female ovulation trigger, a single 5,000-10,000 IU dose is standard. HCG is dosed in international units rather than milligrams because it is a glycoprotein hormone standardized by bioactivity.

In many men, yes. Hsieh and colleagues (2013) gave 500 IU HCG every other day to men on testosterone replacement and found that no patient became azoospermic, with intratesticular testosterone preserved. Depenbusch and colleagues (2002) showed HCG alone can maintain spermatogenesis in hypogonadotropic men. It is not a guarantee for every individual, and men actively trying to conceive are sometimes managed off testosterone entirely, but co-administered HCG is the most common strategy for preserving fertility during TRT.

Gonadorelin is a GnRH analog that acts on the pituitary to release the body's own LH and FSH, so it requires an intact pituitary and has a very short half-life that calls for frequent or pulsatile dosing. HCG skips that step and stimulates the testicular Leydig cells directly as an LH mimic, with a much longer half-life. Gonadorelin keeps both LH and FSH signaling engaged, whereas HCG replaces only the LH-like signal, which is why FSH is sometimes added to HCG for full fertility induction.

Enclomiphene is an oral SERM that blocks estrogen receptors at the hypothalamus and pituitary, which raises the body's own LH and FSH and therefore its own testosterone. It needs a functioning HPG axis to work. HCG is injectable and acts downstream, directly on the testes, so it works even when LH is suppressed by exogenous testosterone. Enclomiphene is convenient and oral, while HCG gives more direct, predictable Leydig cell stimulation.

HCG has a long, biphasic half-life, roughly 24 to 36 hours in the terminal phase, far longer than natural LH. That is why 2-3 subcutaneous injections per week are enough to keep testicular stimulation steady, unlike short-acting GnRH agonists that need frequent dosing.