Georgios Christopoulos

Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization

BACKGROUND Patients with mutations that inactivate kisspeptin signaling are infertile. Kisspeptin-54, the major circulating isoform of kisspeptin in humans, potently stimulates reproductive hormone secretion in humans. Animal studies suggest that kisspeptin is involved in generation of the luteinizing hormone surge, which is required for ovulation; therefore, we hypothesized that kisspeptin-54 could be used to trigger egg maturation in women undergoing in vitro fertilization therapy. METHODS Following superovulation with recombinant follicle-stimulating hormone and administration of gonadotropin-releasing hormone antagonist to prevent premature ovulation, 53 women were administered a single subcutaneous injection of kisspeptin-54 (1.6 nmol/kg, n = 2; 3.2 nmol/kg, n = 3; 6.4 nmol/kg, n = 24; 12.8 nmol/kg, n = 24) to induce a luteinizing hormone surge and egg maturation. Eggs were retrieved transvaginally 36 hours after kisspeptin injection, assessed for maturation (primary outcome), and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos. RESULTS Egg maturation was observed in response to each tested dose of kisspeptin-54, and the mean number of mature eggs per patient generally increased in a dose-dependent manner. Fertilization of eggs and transfer of embryos to the uterus occurred in 92% (49/53) of kisspeptin-54-treated patients. Biochemical and clinical pregnancy rates were 40% (21/53) and 23% (12/53), respectively. CONCLUSION This study demonstrates that a single injection of kisspeptin-54 can induce egg maturation in women with subfertility undergoing in vitro fertilization therapy. Subsequent fertilization of eggs matured following kisspeptin-54 administration and transfer of resulting embryos can lead to successful human pregnancy. TRIAL REGISTRATION ClinicalTrials.gov NCT01667406.

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

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.

Kisspeptin: a novel physiological trigger for oocyte maturation in in-vitro fertilisation treatment

Abstract Background Although in-vitro fertilisation (IVF) treatment allows infertile couples to conceive, it can result in a potentially life-threatening condition termed the ovarian hyperstimulation syndrome (OHSS). The major cause of OHSS is use of human chorionic gonadotropin (hCG) in current IVF protocols for initiating oocyte maturation. The development of a more physiological stimulus for oocyte maturation would avoid this dangerous side-effect and thus improve safety of IVF treatment. Kisspeptin is a recently identified hypothalamic hormone that acutely and potently increases endogenous secretion of luteinising hormone in a gonadotropin-releasing hormone (GnRH)-dependent manner. We aimed to investigate whether kisspeptin can induce oocyte maturation in IVF treatment. Methods In this single-centre prospective clinical trial at Hammersmith Hospital, London, women were recruited with the following inclusion criteria: age 18–35 years, body mass index less than 30 kg/m 2 , serum anti-Mullerian hormone 10–40 pmol/L, and no more than one previous IVF cycle. They underwent a recombinant follicle stimulating hormone plus GnRH antagonist IVF protocol with a single subcutaneous injection of kisspeptin. A control group was not recruited for ethical reasons. Primary outcome was production of mature oocytes (metaphase II oocytes) after egg collection. Participants and doctors giving IVF treatment were masked to the dose of kisspeptin administered. Women were independently randomised by the study statistician, initially to the lowest tier of kisspeptin doses (1·6 or 3·2 nmol/kg, n=2–3 per dose) and then as per protocol to a higher tier of doses (6·4 or 12·8 nmol/kg, n=21 per dose). Oocyte retrieval was done 36 h after kisspeptin injection. After intracytoplasmic sperm injection (ICSI) one or two embryos were transferred to the woman and pregnancy testing done 12 days later. Clinical pregnancy was confirmed on ultrasound scan at 6 weeks of gestation. Multiple means were compared by use of one-way ANOVA with post-hoc Bonferroni correction. Proportions were compared by χ 2 test. All data were analysed on an intention-to-treat basis. Women gave written informed consent. The study received approval from the Hammersmith and Queen Charlottes Research Ethics Committee (application number 10/H0707/2) and the Medicines and Healthcare Products Regulatory Agency. The trial is registered with ClinicalTrials.gov, number NCT01667406. Findings Up to Sept 1, 2013, 47 women completed the study protocol. All doses of kisspeptin resulted in a mean 9·0-fold (SD 7·5) increase in luteinising hormone release 12 h after injection. Oocyte maturation was observed at all doses of kisspeptin. 45 women (96%) had oocyte maturation (mean number of metaphase II oocytes 7·9, SD 4·1). Embryogenesis occurred in 43 women (91%) after treatment with kisspeptin (mean number of zygotes 5·7, SD 3·5). Complete pregnancy data are awaited, but up to Sept 1, 2013, 16 (36%) of 44 women had a positive pregnancy test at 12 days post embryo transfer and ten (23%) had clinical pregnancy confirmed on ultrasound examination at 6 weeks of gestation. Clinical follow-up during pregnancy is continuing, but already the first participant to have received kisspeptin to induce oocyte maturation gave birth to a healthy baby boy in May, 2013. No adverse events were noted at any time during the study. Interpretation The results of this study suggest, for the first time, to our knowledge, that kisspeptin induces oocyte maturation in women undergoing IVF treatment. Kisspeptin might therefore offer a novel therapeutic option for fertility treatment. This small pilot study provides proof of concept that kisspeptin can stimulate oocyte maturation in women undergoing IVF treatment. Further work is now underway in a larger number of patients to determine the optimum protocol for kisspeptin administration to induce oocyte maturation in a population at high risk of OHSS. Funding UK Medical Research Council, National Institute for Health Research.

Acute renal failure and multiple fistulae formation related to an unusual vaginal foreign body

A 52-year-old patient presented with suprapubic pain, mild vaginal bleeding and continuous urinary incontinence. The patient was nulliparous with a history of cerebral palsy and mild learning difficulties. A bimanual examination revealed a hard and calcified vaginal mass, which appeared to be in direct continuation with her cervix. Investigations revealed leucocytosis (white blood cell count: 26.7×106/ml), raised …

Clinical parameters of ovarian hyperstimulation syndrome (OHSS) following different hormonal triggers of oocyte maturation in IVF treatment

Ovarian hyperstimulation syndrome (OHSS) is a serious iatrogenic condition, predominantly related to the hormone used to induce oocyte maturation during IVF treatment. Kisspeptin is a hypothalamic neuropeptide that has recently been demonstrated to safely trigger final oocyte maturation during IVF treatment even in women at high risk of OHSS. However, to date, the safety of kisspeptin has not been compared to current hormonal triggers of oocyte maturation.

GnRH agonist trigger with intensive luteal phase support vs. human chorionic gonadotropin trigger in high responders: an observational study reporting pregnancy outcomes and incidence of ovarian hyperstimulation syndrome

Abstract A retrospective, cohort study of high-risk patients undergoing IVF treatment was performed to assess if there is a difference in clinical pregnancy rate, live birth rate and the incidence of ovarian hyperstimulation syndrome, when a GnRH agonist (GnRHa) trigger with intensive luteal support is compared to human chorionic gonadotropin (hCG) with standard luteal support. The control group consisted of 382 high-risk patients having a GnRH antagonist protocol with 194 receiving an hCG trigger. All patients had ≥18 follicles ≥11mm or serum oestradiol >18,000pmol/l on the day of trigger. Patients had a single or double embryo transfer at cleavage or blastocyst stage. Logistic regression was used to adjust for differences between the groups. An intention-to-treat analysis of all cycles was performed. No statistically significant differences were observed in terms of positive pregnancy test, clinical pregnancy rate and live birth rate. Only one patient (0.3%) was hospitalized with severe OHSS in the GnRHa group, compared to 26 patients (13%) in the hCG group. In conclusion, GnRHa trigger is associated with similar pregnancy rates with hCG trigger and a significant reduction in hospitalization for severe OHSS after an intention to treat analysis was performed.

Kisspeptin-54 safely and effectively triggers oocyte maturation in women at high risk of the ovarian hyperstimulation syndrome (OHSS)

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.