The pituitary gonadal axis is not responsive to GnRH administration in PCSK 1 dysfunction.

Introduction

Patients homozygous for mutation in the PCSK-1 gene present 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.

Methods and results

We are following up two consanguineous siblings homozygous for the N309K mutation in the PCSK-1 gene. The oldest patient, an 18 years old female presented with congenital diarrhea followed by obesity, cortisol, growth hormone and thyroid hormone insufficiency. Pubertal development and regular menstruation were achieved only following hormone replacement therapy. Repeated GnRH stimulation tests showed a prepubertal pattern.

Aiming to study the response of pituitary gonadotrophic cells, GnRH stimulation test was performed prior and post a week of pituitary “priming” by 300ng/Kg/d of GnRH. Prepriming GnRH test results indicated insignificant 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 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 responsive to estrogen replacement therapy. Priming with GnRH failed to stimulate gonadotropin secretion in response to acute GnRH stimulation, indicating a crucial role of PC1/3 in processing of gonadotropins within pituitary gonadotrophic cells.