madman
Super Moderator
* We evaluated, for the first time in humans, whether chronic subcutaneous (SC) administration of kisspeptin-10 (KP10) can sustain gonadotropin secretion without desensitization.
* This study provides the first evidence that chronic SC KP-10 administration can sustain gonadotropin secretion in humans for up to 12 days without inducing tachyphylaxis.
* An intermittent infusion strategy preserves kisspeptin receptor sensitivity while effectively activating the hypothalamic-pituitary-gonadal axis.
Introduction
Kisspeptin is a key hypothalamic regulator of GnRH secretion with major therapeutic potential for hypogonadotropic hypogonadism. While acute kisspeptin administration robustly stimulates gonadotropin release in humans, concerns regarding receptor tachyphylaxis have limited its chronic clinical use. We evaluated, for the first time in humans, whether chronic subcutaneous (SC) administration of kisspeptin-10 (KP10) can sustain gonadotropin secretion without desensitization.
Methods
In a randomized, single-blind, crossover, placebo-controlled study, healthy eugonadal men (18-40 years) received chronic SC KP10 infusion via two administration paradigms: (1) continuous infusion (180 nmol/hr for 5 days, n=4), with LH/FSH sampling every 15 minutes for 8 hours on days 1 and 5; (2) intermittent infusion (150 nmol/hr for 8 hours daily with 16 hours off for 12 days, n=7), with 15-minute sampling for up to 8 hours on days 1, 8, and 12. In a subset (n=4), an intravenous KP10 bolus (1 nmol/kg) was administered immediately after day-12 infusion cessation to assess receptor responsiveness. Separate saline visits (n=12) served as controls.
Results
Continuous 5-day KP10 infusion induced robust gonadotropin responses on both days. Mean gonadotropin increases from baseline were significantly greater than saline (LH -0.16 ±0.19; FSH -0.19 ±0.08 IU/L), on day 1 (LH 4.11 ±0.68 IU/L, P< 0.0001; FSH 0.84 ±0.27 P=0.0003) and day 5 (LH 1.65 ±0.32, P=0.0039; FSH 0.34 ±0.21, P=0.049), indicating partial but incomplete attenuation by day 5.
Intermittent 12-day KP10 administration sustained gonadotropin secretion, with mean LH increases from baseline significantly exceeding saline (-0.16 ±0.19 IU/L), on day 1 (1.68 ±0.25 IU/L; P< 0.0001), day 8 (1.04 ±0.22 IU/L; P=0.006), and day 12 (1.14 ±0.33 IU/L; P=0.003), with no significant decline across days. FSH showed similar patterns (mean increase in FSH from baseline in IU/L: saline -0.19 ±0.07, vs. day 1, P< 0.0001; vs. day 8, P=0.030; vs. day 12, P=0.003). Critically, an intravenous KP10 bolus after 12 days elicited preserved gonadotropin increases compared to saline (LH: 3.25 vs 2.76 IU/L; FSH: 0.61 vs 0.07 IU/L), confirming absence of receptor desensitization.
Conclusion
This study provides the first evidence that chronic SC KP-10 administration can sustain gonadotropin secretion in humans for up to 12 days without inducing tachyphylaxis. An intermittent infusion strategy preserves kisspeptin receptor sensitivity while effectively activating the hypothalamic-pituitary-gonadal axis. These findings establish a clinically feasible protocol with strong translational potential for treating conditions characterized by hypothalamic kisspeptin deficiency, including functional hypothalamic amenorrhea and obesity-related hypogonadism.
* This study provides the first evidence that chronic SC KP-10 administration can sustain gonadotropin secretion in humans for up to 12 days without inducing tachyphylaxis.
* An intermittent infusion strategy preserves kisspeptin receptor sensitivity while effectively activating the hypothalamic-pituitary-gonadal axis.
Introduction
Kisspeptin is a key hypothalamic regulator of GnRH secretion with major therapeutic potential for hypogonadotropic hypogonadism. While acute kisspeptin administration robustly stimulates gonadotropin release in humans, concerns regarding receptor tachyphylaxis have limited its chronic clinical use. We evaluated, for the first time in humans, whether chronic subcutaneous (SC) administration of kisspeptin-10 (KP10) can sustain gonadotropin secretion without desensitization.
Methods
In a randomized, single-blind, crossover, placebo-controlled study, healthy eugonadal men (18-40 years) received chronic SC KP10 infusion via two administration paradigms: (1) continuous infusion (180 nmol/hr for 5 days, n=4), with LH/FSH sampling every 15 minutes for 8 hours on days 1 and 5; (2) intermittent infusion (150 nmol/hr for 8 hours daily with 16 hours off for 12 days, n=7), with 15-minute sampling for up to 8 hours on days 1, 8, and 12. In a subset (n=4), an intravenous KP10 bolus (1 nmol/kg) was administered immediately after day-12 infusion cessation to assess receptor responsiveness. Separate saline visits (n=12) served as controls.
Results
Continuous 5-day KP10 infusion induced robust gonadotropin responses on both days. Mean gonadotropin increases from baseline were significantly greater than saline (LH -0.16 ±0.19; FSH -0.19 ±0.08 IU/L), on day 1 (LH 4.11 ±0.68 IU/L, P< 0.0001; FSH 0.84 ±0.27 P=0.0003) and day 5 (LH 1.65 ±0.32, P=0.0039; FSH 0.34 ±0.21, P=0.049), indicating partial but incomplete attenuation by day 5.
Intermittent 12-day KP10 administration sustained gonadotropin secretion, with mean LH increases from baseline significantly exceeding saline (-0.16 ±0.19 IU/L), on day 1 (1.68 ±0.25 IU/L; P< 0.0001), day 8 (1.04 ±0.22 IU/L; P=0.006), and day 12 (1.14 ±0.33 IU/L; P=0.003), with no significant decline across days. FSH showed similar patterns (mean increase in FSH from baseline in IU/L: saline -0.19 ±0.07, vs. day 1, P< 0.0001; vs. day 8, P=0.030; vs. day 12, P=0.003). Critically, an intravenous KP10 bolus after 12 days elicited preserved gonadotropin increases compared to saline (LH: 3.25 vs 2.76 IU/L; FSH: 0.61 vs 0.07 IU/L), confirming absence of receptor desensitization.
Conclusion
This study provides the first evidence that chronic SC KP-10 administration can sustain gonadotropin secretion in humans for up to 12 days without inducing tachyphylaxis. An intermittent infusion strategy preserves kisspeptin receptor sensitivity while effectively activating the hypothalamic-pituitary-gonadal axis. These findings establish a clinically feasible protocol with strong translational potential for treating conditions characterized by hypothalamic kisspeptin deficiency, including functional hypothalamic amenorrhea and obesity-related hypogonadism.
