Introduction: Hypothalamic amenorrhoea (HA) is a condition characterised by reduced GnRH pulsatility and is a common cause of anovulatory subfertility. Kisspeptin is an endogenous neuropeptide that regulates hypothalamic GnRH function. Hypothalamic kisspeptin expression is reduced, and kisspeptin receptor expression is increased, in a rodent model of HA. The kisspeptin analogue MVT-602 has a 3-4-fold longer half-life than native kisspeptin-54 (t1/2 0.5 h). We investigated the endocrine response to MVT-602 in women with HA to evaluate its potential as a treatment for anovulatory subfertility.
Methods: A previous dose-finding study in healthy women determined that no further increase in gonadotrophin response was observed at doses of MVT-602 greater than 0.03 nmol/kg. We therefore compared the response to MVT-602 0.03 nmol/kg in healthy women during the follicular phase (n=9) to women with HA (n=6). Reproductive hormone levels were measured every 30 mins for 24 h and at 48 h. Intervention groups were compared by MannWhitney U test.
Results: Median (IQR) maximal rise in LH following MVT-602, was over three-fold greater in women with HA at 17.8 iU/l (7.4, 30.7) compared to healthy women at 5.6 iU/l (4.4, 9.6; P=0.02). Median (IQR) maximal rise in FSH was over seven-fold greater in women with HA at 10.6 iU/l (5.0, 13.6) in comparison to healthy women at 1.4 iU/l (0.4, 3.1; P=0.001). Oestradiol rise was also greater in women with HA at 547 pmol/l (373, 1218) than in healthy women at 371 pmol/l (118, 420; P=0.03). The first peak in LH also occurred sooner in women with HA at 6.0 h (5.9, 6.9) when compared to healthy women at 21.0 h (10, 22.5; P=0.01).
Conclusion: In women with HA, the rise in gonadotrophins following the kisspeptin analogue, MVT-602, is more pronounced and occurs sooner than in healthy women. The augmented and sustained rise in oestradiol demonstrates the potential for MVT-602 to restore reproductive health in anovulatory women with HA.