Pulsatile GnRH Therapy May Restore Hypothalamus-Pituitary-Testis Axis Function in Patients With Congenital Combined Pituitary Hormone Deficiency: A Prospective, Self-Controlled Trial

Abstract

Context: The effectiveness of pulsatile gonadotropin-releasing hormone (GnRH) therapy in patients with congenital combined pituitary hormone deficiency (CCPHD) has not been investigated because of the limited number of patients, as well as these patients' presumed pituitary hypoplasia, poor gonadotrophic cell reserve, and impaired gonadotrophic response to GnRH.

Objective: To assess the pituitary response to pulsatile GnRH therapy in men with CCPHD.

Design: Prospective, self-controlled, 3-month clinical trial.

Settings: University endocrine clinic.

Patients: Men with hypogonadotropic hypogonadism caused by CCPHD.

Intervention: Pulsatile GnRH was administered subcutaneously for 3 months.

Main outcome measures: Primary endpoints were total serum testosterone, testicular volume, and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. Secondary endpoints included occurrence of spermatogenesis.

Results: A total of 40 men with CCPHD completed the study. Of these, 60% (24 of 40) showed a good response to pulsatile GnRH treatment (response group). At 3 months, their LH and FSH levels increased to within the normal range and their testosterone levels increased to 8.67 ± 4.83 nmol/L. Of the patients in the response group, 33.3% (8 of 24) of them achieved spermatogenesis. The remaining 40% (16 of 40) of patients had a poor response to pulsatile GnRH treatment. Magnetic resonance imaging (MRI) did not reveal any correlation between pituitary response and pituitary height and/or integrity of the pituitary stalk.

Conclusions: This study suggests that gonadotrophs in patients with CCPHD can exist and be functional-even with MRI evidence of pituitary hypoplasia or dysplasia. Pulsatile GnRH therapy restored pituitary-testis axis function in 60% of patients with CCPHD. These results may directly guide the clinical therapeutic choice.

Trial registration: ClinicalTrials.gov NCT02705014.

Copyright © 2017 Endocrine Society

Figures

Figure 1.

(a, b) Serum gonadotropin levels, (c) total testosterone levels, and (d) testicular volume increased during 1 to 3 months of pulsatile GnRH treatment in the response group (n = 24). T, testosterone.

Figure 2.

Changes to (a, b) gonadotropins, (c) testosterone, and (d) testicular volume during pulsatile GnRH therapy in the poor-response group (n = 16). In general, gonadotropin levels and testicular volumes tended to increase gradually during the 3 months of treatment. In (c), the number of patients sharing the same testosterone values is indicated above the line. T, testosterone.