ESPE Abstracts

Introduction: Patients homozygous for mutation in the PCSK-1 gene present clinically with severe congenital diarrhea and variable hormonal defects due to lack of enzyme/prohormone processing by Prohormone Convertase 1/3 (PC1/3). Although absence of spontaneous puberty has been reported in patients with PCSK-1 mutations, no peptide hormone(s) in the hypothalamus-pituitary-gonadal axis (HPG) have been reported to be dependent on PC1/3 cleavage. Here we studied the effect of GnRH administration in a patient with PCSK-1 loss of function.

Methods and Results: Genetic evaluation of a consanguineous kindred presenting with congenital diarrhea and hormonal deficiencies, revealed them to be homozygous for the malfunctioning N309K mutation in the PCSK-1 gene. The oldest patient an 18 years old female presented classically with congenital diarrhea followed by obesity, cortisol, growth hormone and thyroid hormone insufficiency. Pubertal development, secondary sexual characteristics and regular menstruation were achieved only following hormone replacement therapy. Repeated GnRH stimulation tests between 13-15 years of age showed a prepubertal pattern with only minimal increase of LH. Aiming to study the response of pituitary gonadotrophic cells at 18 years of age, hormonal replacement therapy was discontinued for 60 days. GnRH stimulation test was then performed prior and post a week of pituitary “priming” by 300ng/Kg/d of GnRH. Prepriming GnRH test results indicated no significant increase in gonadotropin response compared to almost undetectable basal levels (basal: LH 0.04 IU/L FSH 1.12 IU/L, Peak LH 0.79 IU/L FSH - 3.38 IU/L). Interestingly post priming GnRH stimulation test did not show a significantly improved gonadotrophic cell response in basal or in peak levels of gonadotropins (LH 0.09-1.36 IU/L and FSH 1.08-4.56 IU/L).

Conclusion: The homozygous N309K mutation in the PCSK-1 gene causes hypogonadotrophic hypogonadism, absence of spontaneous puberty and primary amenorrhea responsive to estrogen replacement therapy. Significant priming with GnRH failed to stimulate gonadotropin secretion in response to acute GnRH stimulation, indicating a novel crucial role of PC1/3 in production and processing of gonadotropins within pituitary gonadotrophic cells. Further studies to dissect specific pituitary related PC1/3 function are underway.