Efficacy of Kisspeptin-54 to Trigger Oocyte Maturation in Women at High Risk of Ovarian Hyperstimulation Syndrome (OHSS) During In Vitro Fertilization (IVF) Therapy

Abstract

Context: In vitro fertilization (IVF) treatment is an effective therapy for infertility, but can result in the potentially life-threatening complication, ovarian hyperstimulation syndrome (OHSS).

Objective: This study aimed to investigate whether kisspeptin-54 can be used to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS.

Setting and design: This was a phase 2, multi-dose, open-label, randomized clinical trial of 60 women at high risk of developing OHSS carried out during 2013-2014 at Hammersmith Hospital IVF unit, London, United Kingdom.

Intervention: Following a standard recombinant FSH/GnRH antagonist protocol, patients were randomly assigned to receive a single injection of kisspeptin-54 to trigger oocyte maturation using an adaptive design for dose allocation (3.2 nmol/kg, n = 5; 6.4 nmol/kg, n = 20; 9.6 nmol/kg, n = 15; 12.8 nmol/kg, n = 20). Oocytes were retrieved 36 h after kisspeptin-54 administration, assessed for maturation, and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos. Women were routinely screened for the development of OHSS.

Main outcome measure: Oocyte maturation was measured by oocyte yield (percentage of mature oocytes retrieved from follicles ≥ 14 mm on ultrasound). Secondary outcomes include rates of OHSS and pregnancy.

Results: Oocyte maturation occurred in 95% of women. Highest oocyte yield (121%) was observed following 12.8 nmol/kg kisspeptin-54, which was +69% (confidence interval, -16-153%) greater than following 3.2 nmol/kg. At all doses of kisspeptin-54, biochemical pregnancy, clinical pregnancy, and live birth rates per transfer (n = 51) were 63, 53, and 45%, respectively. Highest pregnancy rates were observed following 9.6 nmol/kg kisspeptin-54 (85, 77, and 62%, respectively). No woman developed moderate, severe, or critical OHSS.

Conclusion: Kisspeptin-54 is a promising approach to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS.

Trial registration: ClinicalTrials.gov NCT01667406.

Figure 1.

Patient flow diagram showing the number of patients assessed for eligibility, study enrolment, and kisspeptin-54 dose allocation. The study had a prospective adaptive design whereby the first 15 patients were randomly assigned 1:1:1 to receive kisspeptin-54 at doses of 3.2, 6.4, or 12.8 nmol/kg (n = 5 per group) to trigger oocyte maturation during IVF treatment. After interim analysis of oocyte maturation, subsequent patients were randomly assigned 1:1:1 to receive 6.4, 9.6, or 12.8 nmol/kg (n = 15 per group). No patients were lost to followup and no patients discontinued the intervention.

Figure 2.

IVF study protocol using kisspeptin-54 to trigger oocyte maturation. The timeline shows the day of menstrual cycle for a typical patient. On day 2 or 3 of the menstrual cycle, daily sc recombinant FSH (Gonal F, 112.5 IU) was commenced. Daily GnRH antagonist injections (cetrotide, 0.25 mg) were commenced after 5 d of recombinant FSH injections. If serum LH was undetectable (< 0.5 IU/L) on day 7 of recombinant FSH injections, the dose of cetrotide was halved to 0.125 mg daily. When at least three ovarian follicles ≥18 mm diameters were visible on ultrasound, a sc bolus injection of kisspeptin-54 (3.2, 6.4, 9.6, or 12.8 nmol/kg) was administered to trigger oocyte maturation (between 2030 and 2300 h). Injections of GnRH antagonist and FSH were stopped 24 and 12 h prior to kisspeptin administration, respectively. Transvaginal ultrasound-directed oocyte retrieval (TVOR) was carried out 36 h following kisspeptin-54 injection, and ICSI was performed using fresh sperm from the male partner. One or two embryos were transferred to the uterine cavity 3–5 d following oocyte retrieval. If pregnancy was confirmed, progesterone and estradiol supplementation were provided for luteal phase support until 12 weeks' gestation. Progesterone 100 mg daily im injections (Gestone, Nordic Pharma) were used from the morning following oocyte retrieval until 6 weeks' gestation, then 400 mg twice daily progesterone suppository/pessary (Cyclogest; Actavis) was continued until 12 weeks' gestation. Estradiol valerate 2 mg orally three times daily (Progynova; Bayer) was commenced from the evening of TVOR until 12 weeks' gestation. All women recruited to the study were regarded as being at high risk of OHSS and were routinely screened for the development of early OHSS (assessed on day of embryo transfer 3–5 d after TVOR) and late OHSS (assessed 11 d after embryo transfer). Biochemical pregnancy (serum βHCG > 10 miU/mL) was assessed 11 d following embryo transfer and clinical pregnancy was assessed by ultrasonography at 6 weeks' gestation.