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

The Gordon Holmes spinocerebellar ataxia syndrome (GHS) is associated with idiopathic hypogonadotrophic hypogonadism (IHH), There are conflicting repo rts in the literature as to whether the primary neuroendocrine defect is of hypothalamic GnRH secretion, as with most causes of IHH, or of pituitary r esistance 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 mo re physiological approach of treating a male GHS patient for four weeks wit h GnRH, 7-10 mu g/pulse, delivered subcutaneously at 90 minute frequency vi a a portable minipump. This therapy failed to induce any rise in plasma gon adotrophin and testosterone concentrations. By contrast, eight weeks treatm ent with exogenous gonadotrophins maintained physiological plasma testoster one concentrations and induced testicular enlargement with induction of spe rmatogenesis. The data indicate that the primary endocrinopathy in GHS is o f pituitary gonadotrophin secretion and not of hypothalamic GnRH, Moreover, the patient did not harbour any mutation of the GnRH receptor gene. Two cl inical observations are consistent with progressive involution of gonadotro phic function, rather than a congenital gonadotrophin deficiency, First, th e patient's development was arrested at early mid-puberty at the time of or iginal presentation and, second, effective spermatogenesis was induced extr emely rapidly during gonadotrophin treatment, suggesting prior exposure of the testes to FSH, Both spinocerebellar ataxia and pituitary dysfunction mi ght thus have been in evolution since late childhood.