Re-assessment of the therapeutic LH window in normogonadotropic IVF patients

Previous research has proposed a luteinizing hormone (LH) threshold and ceiling level, below which oestradiol production is not adequate and above which LH may be detrimental to follicular development. This therapeutic LH window was mainly supported by clinical research in anovulatory patients but observations in normogonadotropic women were controversial.

A literature narrative review from 1985 through 2025. Studies evaluated included i) preclinical studies using in vivo superovulation models in rodents and ii) clinical studies in normogonadotropic IVF patients undergoing OS with recombinant FSH (r-FSH) supplemented with r-LH, urinary human chorionic gonadotropin (u-hCG) or r-hCG or with human menopausal gonadotropin (hMG).

In rodents, small amounts of LH/hCG support FSH-induced multiple follicular development in absence of endogenous gonadotropins, while too high LH/hCG exposure consistently induced follicular atresia. In women treatment with too high doses of GnRH agonist or antagonist resulted in undetectable serum LH (well below 1 IU/L), impaired follicular growth, low rises of serum oestradiol, early miscarriage and reduced chance of pregnancy. Too profound suppression was observed in patients treated with a long GnRH agonist protocol, but the incidence depends on the specific agonist, dose and route of administration. Most women treated with the GnRH antagonist protocol, without other pituitary-suppression, remain within the therapeutic LH window (endogenous LH 1-10 IU/L) during the whole stimulation period. In contrast, too much LH/hCG supplementation can compromise clinical outcome, as confirmed in IVF patients treated with r-FSH and a potent r-hCG in a long GnRH agonist protocol. This r-hCG in daily doses of 1 µg or more inhibited the growth of medium-sized follicles which phenomenon has previously also observed in IVF patients treated with u-hCG and in PCOS patients treated with r-LH during ovulation induction.

Whether commercial combination gonadotropins have inhibitory effects on multiple follicular development is difficult to judge and may depend on the protocol, dose of FSH, dose of LH/hCG, number of treatment days and the potency of the specific LH/hCG preparation. It is concluded that normogonadotropic IVF patients undergoing OS have a clearly defined therapeutic LH window below and above which clinical outcome is compromised.