A 24-Hour Study of the Hypothalamo-Pituitary Axes in Huntington's Disease

Abstract

Background: Huntington's disease is an inherited neurodegenerative disorder characterised by motor, cognitive and psychiatric disturbances. Patients exhibit other symptoms including sleep and mood disturbances, muscle atrophy and weight loss which may be linked to hypothalamic pathology and dysfunction of hypothalamo-pituitary axes.

Methods: We studied neuroendocrine profiles of corticotropic, somatotropic and gonadotropic hypothalamo-pituitary axes hormones over a 24-hour period in controlled environment in 15 healthy controls, 14 premanifest and 13 stage II/III Huntington's disease subjects. We also quantified fasting levels of vasopressin, oestradiol, testosterone, dehydroepiandrosterone sulphate, thyroid stimulating hormone, free triiodothyronine, free total thyroxine, prolactin, adrenaline and noradrenaline. Somatotropic axis hormones, growth hormone releasing hormone, insulin-like growth factor-1 and insulin-like factor binding protein-3 were quantified at 06:00 (fasting), 15:00 and 23:00. A battery of clinical tests, including neurological rating and function scales were performed.

Results: 24-hour concentrations of adrenocorticotropic hormone, cortisol, luteinizing hormone and follicle-stimulating hormone did not differ significantly between the Huntington's disease group and controls. Daytime growth hormone secretion was similar in control and Huntington's disease subjects. Stage II/III Huntington's disease subjects had lower concentration of post-sleep growth hormone pulse and higher insulin-like growth factor-1:growth hormone ratio which did not reach significance. In Huntington's disease subjects, baseline levels of hypothalamo-pituitary axis hormones measured did not significantly differ from those of healthy controls.

Conclusions: The relatively small subject group means that the study may not detect subtle perturbations in hormone concentrations. A targeted study of the somatotropic axis in larger cohorts may be warranted. However, the lack of significant results despite many variables being tested does imply that the majority of them do not differ substantially between HD and controls.

Fig 1. Analysis of ACTH and cortisol in control, premanifest and stage II/III HD cohorts.

A: Mean ACTH concentrations over 24 hour sampling period in the three groups. B: Mean ACTH concentrations over 24 hour sampling period in the three groups. C: FT analysis of ACTH plotting strength/power (%) against frequency (minutes) of ACTH oscillations for the three groups. D: FT analysis of cortisol plotting strength/power (%) against frequency (minutes) of cortisol oscillations for the three groups. E: Mean molar cortisol:ACTH ratio over 24 hour sampling period in the three groups.

Fig 2. Analysis of GH in control, premanifest and stage II/III HD cohorts.

A: Mean GH concentrations over 24 hour sampling period in the three groups. B: FT analysis of GH plotting strength/power (%) against frequency (minutes) of GH oscillations for the three groups.

Fig 3. Analysis of LH in control, premanifest and stage II/III HD cohorts.

A: Mean LH concentrations over 24 hour sampling period for female subjects in the three groups. B: Mean LH concentrations over 24 hour sampling period for male subjects in the three groups. C: FT analysis of LH plotting strength/power (%) against frequency (minutes) of LH oscillations for the three groups.

Fig 4. Analysis of FSH in control, premanifest and stage II/III HD cohorts.

A: Mean FSH concentrations over 24 hour sampling period for female subjects in the three groups. B: Mean FSH concentrations over 24 hour sampling period for male subjects in the three groups. C: FT analysis of FSH plotting strength/power (%) against frequency (minutes) of FSH oscillations for the three groups.