A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial
Abbara A, Jayasena CN, Christopoulos G, Narayanaswamy S, Izzi-Engbeaya C, Nijher GM, Comninos AN, Peters D, +10 more
Human Reproduction (2017) · n=62
A second dose of kisspeptin-54 ten hours after the first lifted the proportion of women achieving ≥60% mature-oocyte yield from 45% to 71% — without an increase in OHSS rates in a high-risk population.
This is the Phase 2 randomized controlled trial conducted by the Imperial College London reproductive endocrinology group that established kisspeptin-54 as an effective ovulation-trigger agent in women at high risk of ovarian hyperstimulation syndrome during in-vitro fertilization. Investigators enrolled 62 women aged 18 to 34 with antral follicle count ≥23 or anti-Müllerian hormone ≥40 pmol/L — the population most vulnerable to OHSS under conventional human chorionic gonadotropin trigger — and randomized them 1:1 to receive kisspeptin-54 at 9.6 nmol/kg as a single subcutaneous injection plus saline 10 hours later, or the same kisspeptin-54 dose followed by a second 9.6 nmol/kg dose at 10 hours. The hypothesis was that extending the luteinizing-hormone-surge exposure via a second pulse would improve oocyte maturation without reintroducing the OHSS risk associated with the long-acting hCG trigger.
The primary endpoint — proportion of patients achieving an oocyte yield of ≥60% — was met. The two-dose arm achieved the threshold in 71% of participants versus 45% in the single-dose arm (absolute difference +26%, 95% CI 2–50%; p = 0.042), corresponding to a nearly three-fold increase in odds. OHSS rates remained low across both arms: one case of moderate early OHSS in the single-dose group and one mild late OHSS in the two-dose group, both well below the rates typically reported with hCG triggers in comparably high-risk populations. Live-birth rates were 19.4% in the single-dose arm and 39% in the two-dose arm; the trial was not powered for live-birth as a primary endpoint, but the directional signal was consistent with the maturation finding.
The paper builds on the same group's earlier 2014 JCI proof-of-concept work establishing that a single kisspeptin-54 injection could trigger oocyte maturation in IVF and the 2015 JCEM dose-finding study, and is the closest the kisspeptin literature has come to a registration-quality design.
The trial is single-center (Hammersmith Hospital, Imperial College London) and modest in size at 62 randomized participants — a Phase 2 design appropriate for proof-of-concept but not powered for definitive efficacy or pregnancy outcomes. The comparator is one versus two doses of kisspeptin-54 rather than kisspeptin versus hCG; the cleanest case for kisspeptin's safety advantage in OHSS-risk populations rests on the historical hCG comparator literature and the absence of severe OHSS in this and the antecedent trials, not on a head-to-head trial in this paper. The 19.4% live-birth rate in the single-dose arm is below typical IVF benchmarks in this age range and reflects the OHSS-risk-enriched population rather than a general-IVF effect estimate. Industry independence is high — the trial was investigator-initiated and funded by the UK NIHR and Medical Research Council — and the kisspeptin-54 peptide was supplied by an academic source rather than a commercial sponsor. Regulatory progression to Phase 3 has not occurred as of 2026, and no kisspeptin product is currently licensed as an IVF trigger in any jurisdiction; the molecule remains an investigational tool in academic reproductive-endocrinology centers. Independent replication outside the Dhillo / Imperial College group is the principal outstanding gap. For broader context on kisspeptin's reproductive-endocrine pharmacology and adjacent indications, see the kisspeptin peptide page.
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