Annex and References for Neuroendocrine Dysfunctions in Critical Illness, ME/CFS and FM

For:  Neuroendocrine Dysfunctions in Prolonged Critical Illness: Relevance for Chronic Fatigue Syndrome ME/CFS and Fibromyalgia Pt. I

Annex: Some interactions between neuroendocrine axes and interactions of neuroendocrine axes with the immune system.

The neuroendocrine axes interact with each other. Moreover, these axes also interact with the immune system. While the feedback loops which would tend to revert a body to healthy homeostasis have been studied at length, the sum of the interactions between neuroendocrine axes and interactions of neuroendocrine axes with the immune system might also create alternative hypo-metabolic “steady states” which we are only now beginning to understand.

The implication for treatment of ME/CFS, fibromyalgia, and prolonged critical illness is that if you pull on one lever (e.g. supply T3 hormones or inhibit the action of cytokines), the whole system may move. The essential question is: what lever to pull?

I’ve collected some of the interactions below. This is by far not an exclusive list.

HPA <-> HPT·         CRH inhibits the release of TSH (Riedel et al., 1998)

·         High cortisol may drive the hypothalamic suppression of thyroid hormones (Boelen et al., 2004).

HPS <-> HPT·         GH mediates a suppressive effect on the thyroid hormone-inactivating enzyme, D3. Thus GH increases the deiodination of T4 to T3 (Weekers et al., 2004).
HPA <-> HPS·         Glucocorticoids inhibit GH secretion. CRH stimulates the release of GHIH. CRH is of course controlled by cortisol levels (Riedel et al., 2002)

·         The IGFBP-1 elevation in acute critical illness may, in addition to a possible effect of cortisol, be caused by the stimulatory action of cytokines on IGFBP-1, (Baxter, 2001)

HPG <-> HPS·         Testosterone and estrogen stimulate GH secretion;
HPG <-> HPA·         Oestrogens have also been shown to ameliorate the physiological response to stress. In perimenopausal women exposed to time-restricted mental arithmetic as a stressor, supplementation with oestradiol significantly blunted the increases in both systolic blood pressure and diastolic blood pressure, and in levels of plasma cortisol, of ACTH, of epinephrine and of norepinephrine in response to the challenge (Komesaroff, et al., 1999)
HPT <-> HPP·         TRH also stimulates the pituitary to produce prolactin (dopamine inhibits prolactin secretion).
HPG <-> immune system·         Blood cells of CFS patients have significantly lower oestrogen receptors, consistent with an CFS patients consistent with an immune-mediated pathogenesis of CFS (Gräns et al. 2007)


HPP <-> immune system·         The changes in PRL may be interpreted as related to changes in immune function during the course of critical illness. The evidence for this includes the presence of PRL receptors on human T- and B- lymphocytes and the PRL dependency of T- lymphocytes for maintaining immune competence (cited in Van den Berghe, 2000)
HPT <-> immune system·         cytokines depress thyroid hormone activity

·         low thyroid hormone activity contributes to oxidative stress

·         oxidative stress stimulates the production of pro-inflammatory cytokines – thereby completing the circle

·         circulating thyroid hormone levels have profound effects of on the activity of monocytes, lymphocytes macrophages, neutrophils, dendritic cells and natural killer cells

(see previous blog post)



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