Continuous Kisspeptin Administration in Postmenopausal Women: Impact of Estradiol on Luteinizing Hormone Secretion

Abstract

Context: Kisspeptin stimulates the reproductive endocrine cascade in both men and women. Circulating sex steroids are thought to modulate the ability of kisspeptin to stimulate gonadotropin-releasing hormone (GnRH)-induced luteinizing hormone (LH) release.

Objective: To probe the effects of sex steroids on kisspeptin-stimulated GnRH-induced LH pulses.

Participants: Eight healthy postmenopausal women.

Intervention: Subjects underwent every-10-minute blood sampling to measure GnRH-induced LH secretion at baseline and in response to a continuous kisspeptin infusion (12.5 µg/kg/h) over 24 hours. A subset of the participants also received kisspeptin (0.313 µg/kg) and GnRH (75 ng/kg) intravenous boluses.

Results: Postmenopausal women are resistant to the stimulatory effect of continuous kisspeptin on LH secretion. Postmenopausal women receiving estradiol replacement therapy are also resistant to kisspeptin initially, but they demonstrate a significant increase in LH pulse amplitude in direct proportion to the circulating estradiol concentration and duration of kisspeptin administration.

Conclusions: Kisspeptin administration has complex effects on GnRH, and by extension, on LH secretion. The ability of kisspeptin to affect LH secretion can be modulated by the ambient sex-steroid milieu in a time- and dose-dependent manner.

Trial registration: ClinicalTrials.gov NCT01438073.

Copyright © 2017 Endocrine Society

Figures

Figure 1.

Eleven studies from eight PMW undergoing every-10-minute blood sampling and 24-hour kisspeptin infusions of 12.5 μg/kg/h (gray shaded box). G, 75 ng/kg GnRH by IV bolus; K, 0.313 μg/kg kisspeptin by IV bolus; mean E2, mean serum estradiol across study.

Figure 2.

(a) Mean LH with standard deviation; (b) mean LH pulse amplitude with standard deviation; (c) number of LH pulses in 6 hours for eight kisspeptin infusion studies for the pre, start, and end time points, comparing off-estradiol (−E2) studies for subjects no. 200, 201, 215, and 230 to on-estradiol (+E2) studies for subjects no. 200, 215, 230, and 232.

Figure 3.

Linear regression of the relationship between LH parameters and estradiol by predetermined time points. (a) Preinfusion (pre), (b) start, and (c) end time for mean LH, mean LH pulse amplitude, and number of pulses in 6 hours. Included studies: off-estradiol (−E2) subjects no. 200, 201, 215, and 230, and on-estradiol (+E2) subjects no. 200, 215, 230, and 232. The three remaining studies in which a GnRH bolus was given during the “start” time period were excluded.