Gordon Holmes spinocerebellar ataxia: a gonadotrophin deficiency syndrome resistant to treatment with pulsatile gonadotrophin‐releasing hormone

Abstract

The Gordon Holmes spinocerebellar ataxia syndrome (GHS) is associated with idiopathic hypogonadotrophic hypogonadism (IHH). There are conflicting reports in the literature as to whether the primary neuroendocrine defect is of hypothalamic GnRH secretion, as with most causes of IHH, or of pituitary resistance to GnRH action. Because of the anatomical inaccessibility of the hypophyseal portal circulation, direct measurement of GnRH levels in human subjects is not possible. Previous investigators have attempted to unravel this problem through the use of GnRH stimulation tests and the limitations of this approach may explain the differing results obtained. We used the more physiological approach of treating a male GHS patient for four weeks with GnRH, 7–10 μg/pulse, delivered subcutaneously at 90 minute frequency via a portable minipump. This therapy failed to induce any rise in plasma gonadotrophin and testosterone concentrations. By contrast, eight weeks treatment with exogenous gonadotrophins maintained physiological plasma testosterone concentrations and induced testicular enlargement with induction of spermatogenesis. The data indicate that the primary endocrinopathy in GHS is of pituitary gonadotrophin secretion and not of hypothalamic GnRH. Moreover, the patient did not harbour any mutation of the GnRH receptor gene. Two clinical observations are consistent with progressive involution of gonadotrophic function, rather than a congenital gonadotrophin deficiency. First, the patient's development was arrested at early mid‐puberty at the time of original presentation and, second, effective spermatogenesis was induced extremely rapidly during gonadotrophin treatment, suggesting prior exposure of the testes to FSH. Both spinocerebellar ataxia and pituitary dysfunction might thus have been in evolution since late childhood.

The Gonadotropin-Releasing Hormone Type I Receptor is Expressed in the Mouse Cerebellum

“…This is not reversed with GnRH treatment, suggesting pituitary insensitivity and, more specifically, insensitivity at the level of cells expressing the GnRH receptor [36]. The syndrome has been treated with exogenous gonadotropins [36] and steroids [37]. Gordon Holmes syndrome has been attributed to an autosomal recessive genetic defect [23], and, therefore, it may be tempting to speculate that the disorder is due to a harmful mutation in the GnRH receptor gene.…”

“…Persons with Gordon Holmes syndrome exhibit gonadal insufficiencies due to low serum levels of gonadotropins. This is not reversed with GnRH treatment, suggesting pituitary insensitivity and, more specifically, insensitivity at the level of cells expressing the GnRH receptor [36]. The syndrome has been treated with exogenous gonadotropins [36] and steroids [37].…”

Les hypogonadismes hypogonadotrophiques congénitaux masculins, quelles données récentes ?

“…Il associe une ataxie spinocérébelleuse autosomale récessive au déficit gonadotrope et reste non défini au plan génétique [35].…”

Coding sequence analysis of GNRHR and GPR54 in patients with congenital and adult-onset forms of hypogonadotropic hypogonadism

“…While the traditional definition of idiopathic hypogonadotropic hypogonadism is the absence of spontaneous sexual maturation in the setting of low gonadotropins and sex steroids, the past 10 years have been witness to a greater appreciation of the phenotypic richness of this disorder, with nuances in the patterns of sexual development (1-3), the presence or absence of luteinizing hormone (LH) pulsations (4,5), and associated anomalies (6)(7)(8). The past decade has also given rise to several new genes that have been implicated in idiopathic hypogonadotropic hypogonadism (IHH), including genes which play a role in the gonadotropin-releasing hormone (GnRH) neuronal migration, such as KAL1 (9,10), genes modulating GnRH release, such as GPR54 (11,12), and finally, genes which affect the responsiveness of the gonadotropes at the level of the pituitary gland such as GNRHR (13).…”