SAT-211 Gonadotrophin Rise Following Kisspeptin Analogue (MVT-602) Is Increased In Women With Hypothalamic Amenorrhoea Compared To Healthy Women

Background Hypothalamic amenorrhoea (HA) is a condition characterised by reduced GnRH pulsatility as a result of low body weight, excessive exercise, or psychological stress. HA leads to anovulatory infertility and osteoporosis. Kisspeptin is a neuropeptide that is known to be a key regulator of hypothalamic GnRH function. Hypothalamic kisspeptin expression is reduced, and kisspeptin receptor expression increased, in a rodent model of HA. We have previously demonstrated that a continuous infusion of the native form of kisspeptin (kisspeptin-54; KP54) can restore GnRH pulsatility in women with HA, but excessive doses cause tachyphylaxis. Kisspeptin analogue (MVT-602) is a modified form of kisspeptin with a longer half-life compared to native kisspeptin-54 (1.5-2.2h vs 0.5h). Importantly, the more prolonged gonadotrophin profile induced by MVT-602 could enable restoration of physiological hormonal secretion with less frequent administration than by KP54, and thus mitigate against the risk of tachyphylaxis. We therefore investigated the hormonal response to MVT-602 in women with HA to evaluate its potential future utility in the treatment of anovulatory infertility. Methods A previous dose-finding study during the follicular phase of healthy women determined that no further increase in gonadotrophin rise was observed at doses of MVT-602 higher than 0.03nmol/kg. We therefore compared the gonadotrophin rise following a subcutaneous bolus of MVT-602 at a dose of 0.03nmol/kg in 6 women with HA compared to 9 healthy women studied during the follicular phase of their menstrual cycle (day 1-4). Serum gonadotrophin and oestradiol levels were monitored every 30mins for 24hrs. Groups were compared by unpaired t test. Results The maximal rise in LH following MVT-602, was over two-fold greater in women with HA compared to healthy women in the follicular phase (mean±SD of maximal change in LH: HA 18.3±11.0iU/L, follicular phase 7.4±2.7iU/L; P=0.01). The time to peak LH was expedited in women with HA (time to first peak: HA 380±53mins, follicular phase 1067±415mins; P=0.002). Serum FSH rise was also augmented by over four-fold in women with HA (mean±SD of maximal change in FSH: HA 10.0±4.4iU/L, follicular phase 2.2±1.6iU/L; P=0.0003). Maximal rise in oestradiol was higher in women with HA (700pmol/L) when compared with healthy women (297pmol/L; P=0.03). Conclusion In women with HA, the rise in gonadotrophins following MVT-602 is more pronounced and occurs sooner than in healthy women during the follicular phase. The augmented and sustained rise in oestradiol highlights the potential for MVT-602 to be used as an ovulation induction agent in women with anovulatory HA. Therefore, further research is indicated to evaluate repeated administration of MVT-602 as a novel therapeutic approach to restore fertility in HA.