Abstract
Background Kisspeptin is a hypothalamic neuropeptide that is requisite for normal reproductive health. A subcutaneous bolus of the native form of kisspeptin (kisspeptin-54; KP54) induces an LH-surge lasting 12-14hrs, to safely mature oocytes during in vitro fertilisation (IVF) treatment. The kisspeptin analogue, MVT-602, has a longer half-life (t1/2 1.5-2.2h) than native KP54 (t1/2 0.5h), which could therefore confer significant advantages as an oocyte maturation trigger in the treatment of infertility. Whilst MVT-602 has been shown to stimulate LH release in men, its effects in women have not previously been investigated. To address this, we studied the effect of MVT-602 on gonadotrophin release in healthy women for the first time. Methods A two-phase dose-finding study was undertaken during the early follicular phase (Day 1-4) of 12 healthy women aged 18-35yrs with regular menstrual cycles. During phase 1, a broad dose-range for MVT-602 was determined: three women received a single subcutaneous bolus of one of five doses of MVT-602 (0.003, 0.03, 0.1, 0.3, or 1.0nmol/kg) in successive menstrual cycles. Reproductive hormones were measured every 30min for 14hrs post-MVT-602, and again at 24hrs and 48hrs post-injection. During phase 2, an additional 9 women received either KP54 (9.6nmol/kg), or MVT-602 at doses of 0.01 or 0.03nmol/kg during the follicular phase of successive menstrual cycles, following which reproductive hormone levels were monitored every 30mins for 24hrs post-injection. Intervention groups were compared by one-way ANOVA with post hoc Tukey’s test. ResultsPhase 1: Peak serum LH levels occurred between 14-24hrs and no further increases occurred with MVT-602 at doses greater than 0.03 nmol/kg. Phase 2: Peak amplitude of serum LH was found to be similar following KP54 and MVT-602 (mean±SD of peak LH KP54 12.3 ±5.3iU/L; MVT-602 0.01nmol/kg 11.4 ±4.2iU/L; MVT-602 0.03nmol/kg 11.1 ±3.0iU/L, p>0.05). However, time to peak LH was later following MVT-602 (22hrs) when compared with KP54 (4.9hrs; P<0.0001). Thus, the area under the curve (AUC) for LH exposure was significantly increased following MVT-602 when compared with KP54 (mean±SD of AUC LH KP54 9,095 ±5,632iU.min/L; MVT-602 0.01nmol/kg 18,129 ±6,471iU.min/L, P=0.02 vs KP54; MVT-602 0.03nmol/kg 20,086 ±6,227iU.min/L, P=0.004 vs KP54). Conclusion A single subcutaneous bolus of MVT-602 in healthy women resulted in an LH surge of similar amplitude, but of longer duration than by KP54. During studies evaluating the utility of KP54 as a trigger of oocyte maturation in IVF treatment, extending the duration of LH surge with a second bolus of KP54 safely optimised oocyte maturation. Thus, the prolonged gonadotrophin surge induced by MVT-602 could be of significant utility not only to safely optimise oocyte maturation in IVF treatment, but also to treat other reproductive disorders affecting women’s health.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have