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Controlled Clinical Trial
. 2013 Nov;98(11):4464-74.
doi: 10.1210/jc.2013-1069. Epub 2013 Sep 12.

Twice-daily subcutaneous injection of kisspeptin-54 does not abolish menstrual cyclicity in healthy female volunteers

C N Jayasena  1 , A N Comninos, G M K Nijher, A Abbara, A De Silva, J D Veldhuis, R Ratnasabapathy, C Izzi-Engbeaya, A Lim, D A Patel, M A Ghatei, S R Bloom, W S Dhillo
Affiliations
Controlled Clinical Trial

Twice-daily subcutaneous injection of kisspeptin-54 does not abolish menstrual cyclicity in healthy female volunteers

C N Jayasena et al. J Clin Endocrinol Metab. 2013 Nov.

Abstract

Background: Kisspeptin is a critical hypothalamic regulator of reproductive function. Chronic kisspeptin administration causes profound tachyphylaxis in male monkeys and in women with functional hypothalamic amenorrhea. The pharmacological effects of chronic kisspeptin exposure in healthy women with normal menstrual cycles have not been studied previously.

Aim: Our aim was to determine the effects of follicular-phase kisspeptin-54 treatment on menstrual cyclicity in healthy women.

Methods: We performed a prospective, single-blinded, 1-way crossover study. Healthy women received twice-daily sc injections of kisspeptin (6.4 nmol/kg) or 0.9% saline during menstrual days 7-14 (n = 5 per treatment arm). Serial assessments of basal reproductive hormones, ultrasound parameters, LH pulsatility, and acute sensitivity to GnRH and kisspeptin-54 injection were performed.

Results: Menstrual cyclicity persisted in all women after follicular-phase kisspeptin-54 treatment. Chronic exposure to kisspeptin-54 did not abolish acute stimulation of LH after injection of kisspeptin-54 or GnRH. In addition, kisspeptin-54 treatment was associated with a shorter mean length of the menstrual cycle (mean length of menstrual cycle was 28.6 ± 1.4 days with saline vs 26.8 ± 3.1 days with kisspeptin, P < .01), earlier onset of highest recorded serum LH (mean menstrual day of highest LH was 15.2 ± 1.3 with saline vs 13.0 ± 1.9 with kisspeptin, P < .05), and earlier onset of the luteal phase (mean menstrual day of progesterone increase was 18.0 ± 2.1 with saline vs 15.8 ± 0.9 with kisspeptin, P < .05).

Conclusion: Our data suggest that 1 week of exogenous kisspeptin-54 does not abolish menstrual cyclicity in healthy women. Further work is needed to determine whether kisspeptin could be used to treat certain anovulatory disorders.

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Figures

Figure 1.
Figure 1.
Study protocol diagram. Five healthy women underwent a 1-way crossover protocol. Twice-daily injections of saline and kisspeptin-54 (KP54) were administered between days 7 and 14 during months 1 and 2 of the protocol, respectively. During each month of the protocol, subjects underwent a baseline GnRH test (day 1) and 8-hour blood sampling (day 6) before commencing injections. During the injection period (days 7–14), subjects underwent a 4-hour study (day 7) and two additional 8-hour studies (days 11 and 14) immediately after injection of saline or kisspeptin-54. A GnRH test was performed 24 hours after cessation of saline or kisspeptin treatment (day 15). USS denotes ultrasound examination and measurement of reproductive hormones. Day 1 was defined as the first day of menstrual bleeding.
Figure 2.
Figure 2.
Acute changes in plasma kisspeptin levels in healthy women receiving twice-daily injections of saline or kisspeptin-54. A–C, Time profiles of plasma kisspeptin IR after sc bolus injection of saline or kisspeptin-54 (KP54) at time 0 on menstrual days 7 (A), 11 (B), and 14 (C) of the study protocol. D, Bar graph comparing mean preinjection kisspeptin IR after saline or kisspeptin-54 throughout the study protocol. All subjects commenced twice-daily treatment with saline or kisspeptin-54 on the morning of menstrual day 7 after their basal blood sample and finished treatment on the morning of day 14. Data are presented as mean ± SEM. *, P < .05; **, P < .01.
Figure 3.
Figure 3.
Acute changes in serum reproductive hormones in healthy women receiving twice-daily injections of saline or kisspeptin-54. A–C, Acute increases in serum LH after sc bolus injection of saline or kisspeptin-54 (KP54) at time 0 on menstrual days 7 (A), 11 (B), and 14 (C) of the study protocol. All subjects underwent treatment during menstrual days 7 and 14 with twice-daily sc bolus of saline or kisspeptin-54 injections. D, Summary bar graph comparing mean area under curve (AUC) LH increase after saline or kisspeptin-54 on days 7, 11, and 14 of the study protocol. Data are presented as mean ± SEM. *, P < .05; **, P < .01.
Figure 4.
Figure 4.
Levels of serum reproductive hormones throughout the menstrual cycle in healthy women receiving twice-daily injections of saline or kisspeptin-54. A, Comparison of cycle length in individual healthy women undergoing twice-daily sc bolus injections of saline or kisspeptin-54 (KP54) between menstrual days 7 and 14 of the study protocol. B–D, Levels of serum LH (B), FSH (C), and estradiol (D) during the menstrual cycle in healthy women undergoing twice-daily sc bolus injections of saline or kisspeptin-54 between menstrual days 7 and 14. E, Comparison of peak serum LH in individual healthy women undergoing twice-daily sc bolus injections of saline or kisspeptin-54 between menstrual days 7 and 14 of the study protocol. F and G, Levels of serum progesterone (F) and comparison of menstrual day of onset of the luteal phase (G) in individual healthy women undergoing twice-daily sc bolus injections of saline or kisspeptin-54 between menstrual days 7 and 14 of the study protocol. The luteal phase of the menstrual cycle was defined as beginning when serum progesterone was elevated >10 nmol/L. Data are presented as mean ± SEM. *, P < .05; **, P < .01.
Figure 5.
Figure 5.
Changes in radiological markers during the menstrual cycle of healthy women receiving twice-daily injections of saline or kisspeptin-54. A–C Mean values for diameter of largest ovarian follicle (A), number of ovarian follicles (B), and endometrial thickness (C) in healthy women undergoing twice-daily sc bolus injections of saline or kisspeptin-54 (KP54) (6.4 nmol/kg) between menstrual days 7 and 14. Data are presented as mean ± SEM.
Figure 6.
Figure 6.
Changes in LH pulsatility during the menstrual cycle of healthy women receiving twice-daily injections of saline or kisspeptin-54. All women underwent frequent blood sampling for 8 hours on menstrual days 6, 11, and 14 of the study protocol. Twice-daily sc bolus injections of saline or kisspeptin-54 (KP54) (6.4 nmol/kg) were self-administered between menstrual days 7 and 14. A and B, Mean values for secretory mass (A) and estimated pulses per 24 hours (B). C–E, Levels of pulsatile (C), basal (D), and total (E) LH secretion during each 8-h sampling study. Data are presented as mean ± SEM. *, P < .05; **, P < .01.
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