From the compendium presented above, the following statements become evident: 1) Inappropriately low secretion of cortisol in relation to inflammation is a typical feature of the inflammatory disease in patients with RA. 2) The secretion of adrenal androgens is significantly reduced, which is a problem in postmenopausal women and elderly men due to a lack of downstream sex hormones. 3) Serum levels of testosterone are markedly reduced in RA. 4) Sympathetic nerve fibers are markedly reduced in the synovial tissue of patients with RA, whereas proinflammatory sensory fibers (substance P) are present. 5) Substance P serves to continuously sense painful stimuli in the periphery, and the nociceptive input from the inflamed joint shows a large amplification in the spinal cord. This leads to continuous pain with stabilization of the afferent sensory input and continuous release of proinflammatory substance P into the lumen of the joint. From these facts it is obvious that alterations of the systemic antiinflammatory feedback systems contribute significantly to the pathogenesis of RA. Disease therapy directed at these alterations must provide a mechanism to replace the adrenal glands (glucocorticoids), the gonadal glands (androgens), and the sympathetic nervous system (adenosine increase by low-dose MTX, sulfasalazine, and salicylates) in order to integrate their immunosuppressive effects at the local site of synovial inflammation. Although local processes of the adaptive immune system are important in pathogenesis in the acute phase of RA, these mechanisms may be less important during the chronic phase of the disease in the absence of a specific trigger. We believe that a defect of systemic antiinflammatory feedback systems is an important factor in the perpetuation of RA. This review reinforces the belief that combined therapeutic approaches on a neuroendocrine immune basis are of crucial importance in a pathogenetically oriented therapy of RA.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1529-0131%28200103%2944%3A3%3C493%3A%3AAID-ANR95%3E3.0.CO%3B2-U

Involvement of the hypothalamic--pituitary--adrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis: viewpoint based on a systemic pathogenetic role.

The acute-phase response (APR) induces alterations in lipid metabolism, and our data suggest that this is associated with suppression of type II nuclear hormone receptors that are key regulators of...

https://www.physiology.org/doi/pdf/10.1152/ajpendo.00130.2004

Suppression of DHEA Sulfotransferase (Sult2A1) during the Acute Phase Response

Fibromyalgia-like symptoms such as muscle pain and tenderness, exhaustion, reduced exercise capacity, and cold intolerance, resemble symptoms associated with endocrine dysfunction like hypothyroidism, and adrenal or growth hormone insufficiency. To investigate the potential of management of endocrine abnormalities for relieve of symptoms of patients with fibromyalgia, we reviewed experimental and clinical studies of endocrine functioning and endocrine treatment. Serum GH, androgen, and 24-hour urinary cortisol levels of patients with fibromyalgia tend to be in the lower part of the normal range, while serum levels of thyroid hormone, female sex hormones, prolactin, and melatonin are normal. With exception of GH, these conclusions are based on studies in small samples. With respect to dynamic responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis, the dexamethasone suppression test and stimulation with ACTH show normal results, while patients show marked ACTH hypersecretion in response to severe acute stressors, perhaps indicative of chronic CRH hyposecretion. This finding and slightly altered responsiveness of growth hormone, thyroid hormone, and prolactin in pharmacologic stimulation tests suggest a central rather than peripheral origin of endocrine deviations. Because hormone level deviations were not severe, occurred in subgroups of patients only, and few controlled clinical trials were performed, there is--unless future research shows otherwise--little support for hormone supplementation as a general therapy in the common patient with fibromyalgia. In patients with clinically overt hormone deficiency, hormonal supplementation is an option. In patients with hormone levels that are in the lower part of the normal range, interventions aimed at pain, fatigue, sleep or mood disturbance, and physical deconditioning may indirectly improve endocrine functioning.

https://www.rheumatic.theclinics.com/article/S0889-857X(01)00009-6/pdf

Evaluation and management of endocrine dysfunction in fibromyalgia

The cytosolic sulfotransferases (SULTs) are a multigene family of enzymes that catalyze the transfer of a sulfonate group from the physiologic sulfate donor, 3'-phosphoadenosine-5'-phosphosulfate, to a nucleophilic substrate to generate a polar product that is more amenable to elimination from the body. As catalysts of both xenobiotic and endogenous metabolism, the SULTs are major points of contact between the external and physiological environments, and modulation of SULT-catalyzed metabolism can not only affect xenobiotic disposition, but it can also alter endogenous metabolic processes. Therefore, it is not surprising that SULT expression is regulated by numerous members of the nuclear receptor (NR) superfamily that function as sensors of xenobiotics as well as endogenous molecules, such as fatty acids, bile acids, and oxysterols. These NRs include the peroxisome proliferator-activated receptors, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, liver X receptors, farnesoid X receptor, retinoid-related orphan receptors, and estrogen-related receptors. This review summarizes current information about NR regulation of SULT expression. Because species differences in SULT subfamily composition and tissue-, sex-, development-, and inducer-dependent regulation are prominent, these differences will be emphasized throughout the review. In addition, because of the central role of the SULTs in cellular physiology, the effect of NR-mediated SULT regulation on physiological and pathophysiological processes will be discussed. Gaps in current knowledge that require further investigation are also highlighted.

/pdf/regulation-of-the-cytosolic-sulfotransferases-by-nuclear-3xx8nqu40o.pdf

Regulation of the cytosolic sulfotransferases by nuclear receptors

The investigation of the hypothalamicpituitary-adrenal (HPA) axis in chronic inflammation has demonstrated: 1) an anti-inflammatory influence of the HPA axis; 2) low serum levels of adrenal androgen; 3) equivocal results with respect to levels of adrenocorticotropic hormone and cortisol; 4) inadequately low secretion of adrenal hormones in relation to inflammation (the disproportion principle); 5) modulating role of TNF and IL-6 on the HPA axis; 6) disturbed cooperativity of HPA axis and sympathetic nervous system (uncoupling); 7) observable glucocorticoid resistance; 8) the circadian rhythmicity explains morning symptoms; 9) new medications based on malfunction of the HPA axis (e.g. adapted to the circadian rhythm of hormones and cytokines); and 10) the newly described role of the HPA axis in the context of misguided energy regulation in chronic inflammatory diseases. This review discusses items 1-6 and 10, while the other items are presented elsewhere in this Supplement. Evidence is presented that the basis for many alterations is in an adaptive program positively selected for short-lived inflammatory responses (energy appeal reaction), which becomes a disease-inherent pathogenetic factor, if it continues too long, that can drive systemic disease sequelae of chronic inflammatory diseases such as the metabolic syndrome.

Alterations of the hypothalamic-pituitary-adrenal axis in systemic immune diseases - a role for misguided energy regulation.

Blood levels of dehydroepiandrosterone sulphate (DHEAS) were measured by radioimmunoassay (RIA) in patients with: a) polymyalgia rheumatica/giant cell arteritis (PMR:TA; N = 25), with and without cortisone derivative treatment (N = 10 and N = 15, respectively); and b) primary fibromyalgia (PF; N = 15). The mean DHEAS levels were found to be significantly reduced in PMR:TA, compared to those in PF (Geom. mean 820 vs. 2300 nmol/l, respectively; p < 0.001), and the reduction was more marked in patients on cortisone derivative treatment. The DHEAS levels found in PF were found to be normal and consistent with those previously reported in non-immune mediated rheumatological diseases such as osteoarthritis, and in healthy subjects, using the same method of analysis. The low levels found in patients with PM:TA are in accordance with those previously reported in immune-mediated diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, suggesting that diminution of DHEAS is a constant endocrinologic feature in these categories of patients. The pathophysiological significance of these low DHEAS levels needs to be investigated.

Blood dehydroepiandrosterone sulphate (DHEAS) levels in polymyalgia rheumatica/giant cell arteritis and primary fibromyalgia.

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Blood dehydroepiandrosterone sulphate (DHEAS) levels in polymyalgia rheumatica/giant cell arteritis and primary fibromyalgia.