Exogenous kisspeptin administration as a probe of GnRH neuronal function in patients with idiopathic hypogonadotropic hypogonadism

Abstract

Context: Idiopathic hypogonadotropic hypogonadism (IHH) results from defective synthesis, secretion, or action of GnRH. Kisspeptin is a potent stimulus for GnRH secretion.

Objective: We probed the functional capacity of the GnRH neuronal network in patients with IHH.

Participants: Eleven subjects with congenital IHH (9 men and 2 women) and one male subject who underwent reversal of IHH were studied. Six of the twelve subjects had an identified genetic cause of their IHH: KAL1 (n = 1), FGFR1 (n = 3), PROKR2 (n = 1), GNRHR (n = 1).

Intervention: Subjects underwent q10 min blood sampling to measure GnRH-induced LH secretion at baseline and in response to intravenous boluses of kisspeptin (0.24 nmol/kg) and GnRH (75 ng/kg) both pre- and post-six days of treatment with exogenous GnRH (25 ng/kg sc every 2 h).

Results: All subjects with abiding IHH failed to demonstrate a GnRH-induced LH response to exogenous kisspeptin. In contrast, the subject who achieved reversal of his hypogonadotropism demonstrated a robust response to kisspeptin.

Conclusions: The functional capacity of the GnRH neuronal network in IHH patients is impaired, as evidenced by their inability to respond to the same dose of kisspeptin that effects a robust GnRH-induced LH response in healthy men and luteal-phase women. This impairment is observed across a range of genotypes, suggesting that it reflects a fundamental property of GnRH neuronal networks that have not been properly engaged during pubertal development. In contrast, a patient who had experienced reversal of his hypogonadotropism responded to exogenous kisspeptin.

Trial registration: ClinicalTrials.gov NCT00914823.

Figures

Figure 1.

Schematic of the study protocol.

Figure 2.

Baseline LH secretion and responses to kisspeptin and GnRH in two representative male (♂) subjects. The phenotype, Kallmann syndrome (KS) or normosmic IHH (nIHH), and genotype are noted for each subject. Results for subject 1 before and after priming with exogenous GnRH are shown in panels A and B, respectively. Similarly, results for subject 6 before and after priming are shown in panels C and D, respectively. Arrows indicate times of boluses. T, testosterone levels during the study. FSH values measured from first 2-h pool.

Figure 3.

Baseline LH secretion and responses to kisspeptin and GnRH in a female (♀) subject with normosmic IHH (nIHH) and GnRH resistance due to the specified GNRHR mutations. Upper panel: results before priming with exogenous GnRH (pre-priming). Lower panel: results after priming with a failure to prime due to GnRH resistance (post-priming). Arrows indicate times of boluses. E2, estradiol levels during the study. FSH values measured from the first 2-h pool.

Figure 4.

Responses to multiple boluses kisspeptin in a male (♂) and a female (♀) subject with Kallmann syndrome (KS) and evidence of endogenous GnRH neuronal activity. Arrows indicate times of boluses. Note escalating doses of kisspeptin provided to subject 9. T, testosterone; E2, estradiol levels during the study. FSH values measured from the first 2-h pool.

Figure 5.

Intact responses to kisspeptin in a male (♂) subject with reversal of IHH. Both studies were performed without pituitary priming. The left panel shows the single bolus protocol and demonstrates the presence of endogenous pulsatile LH secretion and a response to kisspeptin. The right panel shows the study performed with multiple kisspeptin boluses and demonstrates consistent pulses of LH secretion in response to kisspeptin. Dashed lines mark the times kisspeptin or GnRH were given. T, testosterone levels during the study. FSH values measured from the first 2-h pool.