Enclomiphene works with topical and oral TRT but is less effective with injectable TRT due to differences in suppressive effects. Topical and oral TRT are less suppressive to the hypothalamic-pituitary-testicular axis (HPTA), allowing enclomiphene to override estrogen-mediated negative feedback by selectively blocking estrogen receptors. This increases LH (and FSH) levels, signaling the testes to produce testosterone. However, injectable TRT causes sustained elevations in testosterone, which suppress LH and FSH production, limiting enclomiphene's ability to increase LH and FSH. While enclomiphene may help maintain some testicular volume in these cases, it is less effective in supporting spermatogenesis.

In contrast, hCG, an LH mimetic, directly stimulates the testes to produce intratesticular testosterone, critical for spermatogenesis. This makes hCG more suitable for injectable TRT users, as it compensates for the suppressed LH. However, hCG only mimics LH and does not restore FSH signaling, which is also essential for fertility. Enclomiphene is cost-effective and increases both LH and FSH, essential for optimal fertility, whereas hCG is expensive and requires multiple subcutaneous injections weekly.