The gonadotrophin response to intravenous kisspeptin positively correlates with baseline oestradiol levels in healthy women during the early follicular phase of the menstrual cycle.

Dr. S. Narayanaswamy, Dr. C. Jayasena, Miss N. Ng, Dr. R. Ratnasabapathy, Dr. J. Prague, Mrs D. Papadopoulou, Dr. A. Comninos, Dr. A. Abbara, Prof. M. Ghatei, Prof. S. Bloom and Prof. W. Dhillo


Background: Kisspeptin is a recently identified hormone which potently stimulates hypothalamic gonadotrophin releasing hormone secretion resulting in gonadotrophin release. Kisspeptin is emerging as a novel therapeutic agent as it can stimulate the reproductive axis whilst remaining under negative feedback control and therefore, may avoid excess replacement of gonadotrophins or sex steroids in patients with reproductive disorders. Women are markedly more responsive to exogenous kisspeptin during the pre-ovulatory phase when compared with the follicular phase of menstrual cycle. However, it is not known whether the effects of kisspeptin are related to circulating sex steroid levels in patients during the follicular phase of the menstrual cycle.


Aim: To study the effects of baseline oestradiol on gonadotrophin secretion after intravenous kisspeptin-54 administration to healthy females in the early follicular phase of the menstrual cycle.


Study: This was a prospective, single-blinded placebo-controlled study. Ethical approval was obtained from the local research ethics committee (12/LO/0507). The effects of intravenous kisspeptin-54 on gonadotrophin secretion were assessed over 8 hours in 4 healthy women at 0.1, 0.3 and 1.0nmol/kg/hr doses. Each participant received vehicle and all three doses of kisspeptin. Studies were performed during days 2-6 of the menstrual cycle, with one study visit scheduled each month per subject. Ten minutely blood sampling was conducted over the 8 hours to measure luteinising hormone (LH), follicle stimulating hormone (FSH) and oestradiol.


Results: All doses of kisspeptin-54 increased LH release compared to vehicle (mean AUC LH in h/IU/L: 2470 697.2, vehicle; 3214 575.2, 0.1nmol/kg/hr; 6887 1934, 0.3nmol/kg/hr, P<0.05 vs vehicle; 6252 2146, 1.0nmol/kg/hr, P<0.05 vs vehicle). Baseline oestradiol levels positively correlated with the LH response to the two highest doses of kisspeptin-54 (0.3 and 1.0nmol/kg/hr), but did not with vehicle or the lowest dose 0.1nmol/kg/hr kisspeptin-54 (correlation between mean AUC LH in h/IU/L and baseline oestradiol in pmol/L: vehicle, r2=0.62, P=0.42; 0.1nmol/kg/hr, r2=0.1, P=0.68; 0.3nmol/kg/hr, r2=0.90, P<0.05; 1.0nmol/kg/hr, r2=0.94, P<0.05).


Conclusion: Our data suggest that baseline oestradiol levels may be an important determinant of the gonadotrophin response to kisspeptin treatment in women in the follicular phase of the menstrual cycle. Therefore, as kisspeptin may be used therapeutically in the future, baseline oestradiol levels should be taken into consideration when evaluating response to treatment. Further studies are required to determine if optimisation of oestradiol levels in follicular phase with oestradiol supplementation can improve the gonadotrophin response to kisspeptin.