Twice-weekly administration of kisspeptin leads to long-term stimulation of reproductive hormone release in infertile women with hypothalamic amenorrhoea
Channa N Jayasena1, Gurjinder M K Nijher1,3, Ali Abbara1, Kevin G Murphy1, Adrian Lim2, Daksha Patel2, Amrish Mehta2, Catriona Todd2, Radha Ramachandran1,3, Mandy Donaldson3, Geoffrey Trew4, Mohammad A Ghatei1, Stephen R Bloom1 & Waljit S Dhillo1
Background: Hypothalamic amenorrhoea (HA) accounts for over 30% of cases of amenorrhoea in women of reproductive age. Current treatments have limited success rates and side effects. We have recently shown that a single injection of the novel hormone kisspeptin potently stimulates reproductive hormone release in women with HA. However, twice-daily kisspeptin administration to women with HA, results in tachyphylaxis due to desensitisation of the kisspeptin receptor. This suggests that less frequent administration of kisspeptin may lead to sustained reproductive hormone release in women with HA, which would have therapeutic implications.
Aim: To determine if long-term twice-weekly kisspeptin administration chronically stimulates reproductive hormone release in women with HA.
Methods: We performed an ethically approved prospective, randomised, single-blinded, parallel design study. Patients with HA received twice-weekly s.c. injection of either kisspeptin (6.4 nmol/kg) or saline (n=5/group) for 56 days. On days 0, 14, 28, 42 and 56, blood was sampled at regular intervals for 4 h post-injection for measurement of plasma LH and FSH.
Results: Women were more responsive to kisspeptin injection on day 0 than day 14 (mean maximal LH increase in IU/l: day 0, 21.5±10.7; day 14, 10.0±4.3; P<0.001). However there was no further significant drop in responsiveness to kisspeptin beyond day 14 (mean maximal LH increase in IU/l: day 28, 9.0±4.1; day 42, 8.9±3.5; day 56, 7.9±4.5; P>0.05 versus response on day 14). On the last (56th) day, women with HA were still 16 times more response to kisspeptin than saline. No adverse effects following kisspeptin administration were observed during the study.
Conclusion: In this first long-term study of kisspeptin administration to women with HA, we have demonstrated that twice-weekly kisspeptin administration stimulates reproductive hormone release in a sustained manner. Thus kisspeptin may be a future novel therapy for reproductive disorders.