Congenital idiopathic hypogonadotropic hypogonadism: evidence of defects in the hypothalamus, pituitary, and testes

Abstract

Context: Idiopathic hypogonadotropic hypogonadism (IHH) with normal smell (normosmic IHH) or anosmia (Kallmann syndrome) is associated with defects in the production or action of GnRH. Accordingly, most IHH patients respond to physiological pulsatile GnRH replacement by normalizing serum LH, FSH, and testosterone (T) levels and achieving gametogenesis; some patients, however, show atypical responses. Interestingly, several IHH-associated genes are expressed in multiple compartments of the hypothalamic-pituitary-gonadal axis.

Objective: The aim of the study was to investigate whether the clinical, biochemical, or genetic characteristics of IHH men with atypical responses to GnRH indicate alternative or additional defects in the hypothalamic-pituitary-gonadal axis.

Subjects: We studied 90 IHH men undergoing long-term pulsatile GnRH treatment over 30 yr.

Design and setting: We conducted a retrospective study of response to GnRH at a Clinical Research Center.

Interventions: Physiological regimens of pulsatile s.c. GnRH were administered for at least 12 months. Dose-response studies using i.v. GnRH pulses assessed the pituitary LH response.

Main outcome measures: We measured serum T, LH, FSH, and inhibin B levels, sperm in ejaculate, and determined the sequence of IHH-associated genes.

Results: Twenty-six percent of subjects displayed atypical responses to GnRH: 1) 10 remained hypogonadotropic and hypogonadal, demonstrating pituitary and testicular defects; 2) eight achieved spermatogenesis and normal T but only with hypergonadotropism, indicating impaired testicular responsiveness to gonadotropins; and 3) five remained azoospermic despite achieving adult testicular volumes and normal hormonal profiles, suggesting primary defects in spermatogenesis. Mutations were identified only in KAL1 across groups.

Conclusion: In addition to hypothalamic GnRH deficiency, IHH men can have primary pituitary and/or testicular defects, which are unmasked by GnRH replacement.

Figure 1

Algorithm for categorization of IHH men according to their clinical and biochemical response to long-term GnRH replacement.

Figure 2

IHH men with atypical responses to long-term physiological GnRH administration have distinguishing hormonal profiles. Horizontal dashed lines denote the upper and lower limits of serum hormone levels in healthy adult men (10). The gray shaded area denotes the 95% confidence interval of serum hormone levels in IHH patients who responded typically to GnRH by normalizing their LH, FSH, and T levels and producing mature sperm. Data points denote the mean ± sem of serum hormone levels in each class of subjects with atypical responses. Three atypical patterns of response to GnRH replacement are evident: 1) persistent hypogonadotropism and hypogonadism (group 1); 2) hypergonadotropism and eugonadism (group 2); and 3) Isolated azoospermia (group 3). ‡, Different from all other groups by definition, according to the flowchart of group classification shown in Fig. 1.

Figure 3

Reduced pituitary responsiveness to GnRH in a subset of IHH men with atypical response. The gray shaded area denotes the 95% confidence interval of GnRH-stimulated LH pulse amplitude in IHH patients with typical response to treatment. The pituitary responsiveness to GnRH is markedly reduced in group 1 patients, who remained hypogonadotropic and hypogonadal. The other two groups of patients with atypical responses had pituitary sensitivity to GnRH similar to that of patients who responded typically.