NeuroEndocrine Axis & Multiple Sclerosis

We investigated the basal and dynamic regulation of the HypoThalamo- Pituitary-Adrenal (HPA), HypoThalamo-Pituitary-Thyroid (HPT) and Hypothalamo-Pituitary-Gonadal Axes and Prolactin secretion in 52 patients with Clinically Definite Multiple Sclerosis.

These patients also had Gadolinium enhanced Brain MRI scans and were divided into Relapsing/Remitting, Secondary/Progressive and Primary/Progressive subgroups.

These subgroups were compared with healthy controls and a group of patients with Other Neurological Diseases. The Cortisol diurnal rhythm was preserved in all groups of patients.

The time- integrated Cortisol response to human CorticoTropin-Releasing Hormone (CRH) stimulation was lower in the patients with Secondary/Progressive Multiple Sclerosis, compared with patients with Primary/Progressive Multiple Sclerosis and healthy subjects.

The time-integrated beta- Endorphin response to CRH was greater in the patients with Relapsing/Remitting Multiple Sclerosis compared with the others. Feedback regulation assessed by Dexamethasone suppression was normal.

Serum Testosterone was low in 24% of male Multiple Sclerosis patients and Oestradiol was low in 25% of Pre-Menopausal female Multiple Sclerosis patients, whereas Prolactin and the HPT function were normal.

Correlations with C-Reactive Protein (CRP) and MRI suggest that activation of the HPA axis in Multiple Sclerosis patients is secondary to an active inflammatory stimulus.

Copyright © 1997 by Oxford UnivPress

In 31 patients with Multiple Sclerosis (MS) the Endocrine functions of the HypoThalamus, the Pituitary and several peripheral Endocrine Glands were assessed with a combined Pituitary test.

3/31 patients had an Endocrine Disease: one primary HypoThyroidism, one primary Amenorrhea and one primary male Hypogonadism. We found no patient with Endocrine Disease of the HypoThalamus, the Pituitary or the Adrenals.

However, the poststimulatory secretion of Cortisol, Growth Hormone or Thyroid-Stimulating Hormone was impaired in 7/31 patients, suggesting a possible preclinical Endocrine insufficiency in these patients.

DeMyelinating lesions of fiber bundles in and adjacent to the HypoThalamus (i.e. the Fornix. Anterior Commissure, Internal Capsule, and Optic System) may be the basis for Autonomic and Endocrine alterations in Multiple Sclerosis (MS) patients.

Therefore we investigated the presence and Immunological activity of lesions in HypoThalamic fiber bundles of 17 MS patients and 14 controls. In the MS group, 16 of 17 patients showed DeMyelinated lesions.

The incidence of active lesions was high (60%) and outnumbered chronic inactive lesions in the Internal Capsule (p = 0.005).

In 4 of 17 MS patients, Axonal damage was observed and in 3 of 17 MS patients Gray Matter lesions were apparent. Duration of MS was inversely related to the active HypoThalamic MS lesion score (r = -0.72, p = 0.001).

Since comparison of HypoThalamic lesions with MS lesions in other areas of the Brain in the same patients (n = 7) showed a great similarity both as stage and appearance was concerned.

This negative relation in all likelihood reflects the clinical consequences of high disease activity throughout the whole Brain.

In controls no DeMyelinating lesions were seen but in 11 control cases HLA expression was observed that was lower than that present in MS patients (p = 0.02).

In the median eminence region that lacks a Blood-Brain Barrier, all controls showed a strong HLA expression around the blood vessels.

We conclude that systematic pathological investigation of the HypoThalamus in MS patients reveals an unexpected high incidence of active lesions that may impact on HypoThalamic functioning.

During Multiple Sclerosis (MS), an inflammatory DeMyelinating disease of the Central Nervous System (CNS), activation of the HypoThalamo-Pituitary-Adrenal (HPA) Axis is considered to modulate the Immune System in such a way that the probability of recovery from a relapse is increased.

In a series of postmortem studies we observed a significant activation of CorticoTropin Releasing Hormone (CRH) Neurons and increased Cortisol in the CerebroSpinal Fluid (CSF) of MS patients, indicating activation of the HPA Axis in this disease.

On the other hand, Sepsis, while elevating Cortisol in control subjects, did not associate with a further increase of Cortisol in MS patients. Thus, the activated HPA-System in MS does not respond to an acute inflammatory stimulus.

In order to investigate the role of chronic inflammation in the CNS in the activation of the HPA Axis in MS, MS lesions in the HypoThalamus were quantified and InterLeukin-6 (IL-6) levels in the CSF were determined.

There was no difference in IL-6 levels between MS and control patients. A positive correlation was found between Cortisol and IL-6 in control subjects with Sepsis, but not in MS patients with Sepsis or MS and control groups without Sepsis.

Thus, IL-6 in the CSF of MS patients is not the cause of the activation of the HPA System in MS. We found a remarkably high incidence (95% of the patients) of MS lesions in the HypoThalamus, of which the majority (60%) were active.

The more active lesions were present in the HypoThalamus, the shorter the disease duration to the moment of death, indicative of a worse disease course. Preliminary data show suppression of the activation of CRH Neurons by active HypoThalamic MS lesions.

We propose that this suppression of CRH Neurons by active HypoThalamic MS lesions causes the concomitant unfavorable disease course via an inadequate Cortisol response during relapses of MS.

In this postmortem study, we investigated the relationship between Multiple Sclerosis (MS) lesions in the HypoThalamus and the state of activity of CorticoTropin-Releasing Hormone (CRH)-producing Neurons that control the HypoThalamus-Pituitary-Adrenal (HPA) Axis.

A high incidence (15/16) of MS lesions was found in the HypoThalamus, of which more than 50% was active, that is, contained activated Macrophages.

MS patients have increased numbers of CRH-ImmunoReactive Neurons coexpressing VasoPressin (CRH/VP Neurons), a sign of chronic activation of CRH Neurons and increased CRH mRNA expression.

Active MS lesions correlated with a low number of hyperactive CRH/VP Neurons. High Human Leukocyte Antigen (HLA)-DR, -DP, -DQ expression, a measure for Macrophage and Microglial activation, correlated with low CRH mRNA expression.

The nearer the HLA expression was situated to the CRH Neurons, the stronger the inhibiting effect, suggesting that activated Microglial Cells or Macrophages suppress these Neurons.

The more active MS lesions were present in the HypoThalamus, the shorter was the disease duration until the moment of death, indicating an unfavorable course of the disease.