The effects of kisspeptin-10 on reproductive hormone release show sexual dimorphism in humans

Abstract

Background: Kisspeptin peptides are critical in human reproductive physiology and are potential therapies for infertility. Kisspeptin-10 stimulates gonadotropin release in both male and female rodents. However, few studies have investigated the effects of kisspeptin-10 on gonadotropin release in humans, and none have investigated the effect in women. If kisspeptin is to be useful for treating reproductive disease, its effects in both men and women must be established.

Aim: To compare the effects of kisspeptin-10 administration on reproductive hormone release in healthy men and women.

Methods: Intravenous bolus kisspeptin-10 was administered to men and women (n = 4-5 per group). Subcutaneous bolus and i.v. infusion of kisspeptin-10 was also administered to female women (n = 4-5 per group). Circulating reproductive hormones were measured.

Results: In healthy men, serum LH and FSH were elevated after i.v. bolus kisspeptin-10, at doses as low as 0.3 and 1.0 nmol/kg, respectively. In healthy women during the follicular phase of the menstrual cycle, no alterations in serum gonadotropins were observed after i.v. bolus, s.c. bolus, or i.v. infusion of kisspeptin-10 at maximal doses of 10 nmol/kg, 32 nmol/kg, and 720 pmol/kg/min, respectively. In women during the preovulatory phase, serum LH and FSH were elevated after i.v. bolus kisspeptin-10 (10 nmol/kg).

Conclusion: Kisspeptin-10 stimulates gonadotropin release in men as well as women during the preovulatory phase of menstrual cycle but fails to stimulate gonadotropin release in women during the follicular phase. The sexual dimorphism of the responsiveness of healthy men and women to kisspeptin-10 administration has important clinical implications for the potential of kisspeptin-10 to treat disorders of reproduction.

Figures

Fig. 1.

Plasma kisspeptin IR and serum reproductive hormone levels after iv bolus injection of kisspeptin-10 to healthy male volunteers. A–D, Time profiles for plasma kisspeptin IR (A) and changes in serum LH (B), FSH (C), and testosterone (D) during 4 h after iv bolus injection of saline or kisspeptin-10 to healthy male volunteers (n = 4–5 per group). For 10 nmol/kg vs. saline: ψ, P < 0.05; ψψ, P < 0.01; ψψψ, P < 0.001. For 3 nmol/kg vs. saline: λ, P < 0.05; λλλ, P < 0.001. For 1 nmol/kg vs. saline: Δ, P < 0.05; ΔΔΔ, P < 0.001. E–H, AUC for plasma kisspeptin IR (E) and changes in serum LH (F), FSH (G), and testosterone (H) during 4 h after iv bolus injection of saline or kisspeptin-10 to healthy male volunteers (n = 4–5 per group). *, P < 0.05; **, P < 0.01; ***, P < 0.001. T, Testosterone. Data are shown as mean ± sem.

Fig. 2.

Plasma kisspeptin IR and serum reproductive hormone levels after iv bolus injection of kisspeptin-10 to healthy female volunteers. A–D, Time profiles for plasma kisspeptin IR (A) and changes in serum LH (B), FSH (C), and estradiol (D) during 4 h after iv bolus injection of saline, kisspeptin-10 (KP10), or kisspeptin-54 (KP54) to healthy female volunteers. For 10 nmol/kg KP10 vs. saline: ψ, P < 0.05; ψψ, P < 0.01; ψψψ, P < 0.001. For 3 nmol/kg KP10 vs. saline: λλλ, P < 0.001. For 1 nmol/kg KP54 vs. saline: κ, P < 0.05; κκ, P < 0.01; κκκ, P < 0.001. For 10 nmol/kg KP10 (Preov) vs. saline: *, P < 0.05; **, P < 0.01; ***, P < 0.001. E–H, AUC for plasma kisspeptin IR (E) and changes in serum LH (F), FSH (G), and estradiol (H) during 4 h after iv bolus injection of saline or kisspeptin-10 to healthy female volunteers. *, P < 0.05; **, P < 0.01; ***, P < 0.001. Data are shown as mean ± sem. E2, Estradiol; Preov, preovulatory phase of the menstrual cycle.

Fig. 3.

Plasma kisspeptin IR and serum reproductive hormone levels after sc bolus injection of kisspeptin-10 to healthy female volunteers in the follicular phase of the menstrual cycle. A–D, Time profiles for plasma kisspeptin IR (A) and changes in serum LH (B), FSH (C), and estradiol (D) during 4 h after sc bolus injection of kisspeptin-10 to healthy female volunteers in the follicular phase of the menstrual cycle (n = 4–5 per group). For 32 vs. 2 nmol/kg: *, P < 0.05; ***, P < 0.001. For 16 vs. 2 nmol/kg: ƒƒƒ, P < 0.001. For 8 vs. 2 nmol/kg: ψψψ, P < 0.001. For 4 vs. 2 nmol/kg: λ, P < 0.05. E–H, AUC for plasma kisspeptin IR (E) and changes in serum LH (F), FSH (G), and testosterone (H) during 4 h after sc bolus injection of kisspeptin-10 to healthy female volunteers in the follicular phase of the menstrual cycle (n = 4–5 per group). *, P < 0.05; **, P < 0.01; ***, P < 0.001. E2, Estradiol. Data are shown as mean ± sem.

Fig. 4.

Plasma kisspeptin IR and serum reproductive hormone levels during iv infusion of kisspeptin-10 to healthy female volunteers in the follicular phase of the menstrual cycle. A–D, Time profiles for plasma kisspeptin IR (A) and changes in serum LH (B), FSH (C), and estrogen (D) during 4 h after commencement of a 90-min iv infusion of kisspeptin-10 to healthy female volunteers in the follicular phase of the menstrual cycle (n = 4–5 per group). For 720 vs. 20 pmol/kg · min: ***, P < 0.001. For 360 vs. 20 pmol/kg · min: ƒƒƒ, P < 0.001. For 180 vs. 20 pmol/kg · min: ψ, P < 0.05; ψψψ, P < 0.001. For 50 vs. 20 pmol/kg · min: Δ, P < 0.05. E–H, AUC for plasma kisspeptin IR (E) and changes in serum LH (F), FSH (G), and testosterone (H) during 4 h after commencement of a 90-min iv infusion of kisspeptin-10 to healthy female volunteers in the follicular phase of the menstrual cycle (n = 4–5 per group). **, P < 0.01; ***, P < 0.001. E2, Estradiol. Data are shown as mean ± sem.

Fig. 5.

Detailed time profiles of plasma kisspeptin IR after iv infusion of kisspeptin-10 to healthy male and female volunteers. A–D, Blood sampling was performed for measurement of plasma kisspeptin IR during 4 h after commencement of a 90-min iv infusion of kisspeptin-10 (360 pmol/kg · min) to healthy male volunteers (A and D) and female volunteers during the follicular (B and D) and preovulatory (C and D) phases of the menstrual cycle (n = 4–5 per group). For men vs. women during follicular phase: φφφ, P < 0.001; φ, P < 0.05. For men vs. women during preovulatory phase: ***, P < 0.001; *, P < 0.05. E, Blood sampling was performed at 1-min intervals immediately after stopping infusion of kisspeptin-10. Linear curve fits of natural log plasma kisspeptin IR (dotted lines) were similar for all three groups (P = 0.91). Data are shown as mean ± sem.