Benefit of pregnancy in inflammatory arthritis.
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Arthritis↗
Biomedical subjects
R H Straub
Publications and source records attributed to R H Straub.
Possible role of leptin in hypoandrogenicity in patients with systemic lupus erythematosus and rheumatoid arthritis.
BACKGROUND: Hypoandrogenicity is common in obesity and in chronic inflammatory diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Adrenal androgens such as androstenedione (ASD) and dehydroepiandrosterone (DHEA) sulphate are low, which partly depends on the influence of TNF in chronic inflammatory diseases. Leptin is stimulated by TNF and is associated with hypoandrogenicity in non-inflammatory conditions. OBJECTIVE: To study the interrelation between serum levels of leptin and adrenal steroids in SLE and RA. METHODS: In a retrospective study, serum levels of leptin, ASD, DHEA, and 17-hydroxyprogesterone (17OHP) were measured by ELISA, and serum levels of cortisol by radioimmunoassay in 30 patients with RA, 32 with SLE, and 54 healthy control subjects (HS). RESULTS: In SLE and RA but not HS, serum levels of ASD correlated negatively with serum levels of leptin (p<0.01) independently of prior prednisolone treatment in patients with SLE (p = 0.013) and tended to be independent of prednisolone in patients with RA (p = 0.067). In a partial correlation analysis, this interrelation remained significant after controlling for daily prednisolone dose in both patient groups. In both patient groups, serum leptin levels correlated negatively with the molar ratio of serum ASD/serum cortisol and serum ASD/serum 17OHP, and positively with the molar ratio of serum DHEA/serum ASD. CONCLUSIONS: The negative correlation of serum leptin and ASD or, particularly, ASD/17OHP, together with its known anti-androgenic effects indicate that leptin is also involved in hypoandrogenicity in patients with SLE and RA. Leptin may be an important link between chronic inflammation and the hypoandrogenic state.
17-alpha-Hydroxyprogesterone↗
Renal clearance and daily excretion of cortisol and adrenal androgens in patients with rheumatoid arthritis and systemic lupus erythematosus.
BACKGROUND: In rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), patients demonstrate low levels of adrenal hormones. OBJECTIVE: To investigate whether increased renal clearance and daily excretion contribute to this phenomenon. METHODS: Thirty patients with RA, 32 with SLE, and 54 healthy subjects (HS) participated. Serum and urinary levels of cortisol, cortisone, 17-hydroxyprogesterone (17OHP), androstenedione, dehydroepiandrosterone (DHEA), and DHEA sulphate (DHEAS) were measured. RESULTS: Clearance of DHEAS and DHEA was lower in patients than in HS, and clearance of androstenedione was somewhat higher in patients than in HS, but daily excretion of this latter hormone was low. Clearance of cortisol, cortisone, and 17OHP was similar between the groups. The total molar amount per hour of excreted DHEA, DHEAS, and androstenedione was lower in patients than HS (but similar for cortisol). Serum DHEAS levels correlated with urinary DHEAS levels in HS and patients, whereby HS excreted 5-10 times more of this hormone than excreted by patients. Low serum levels of adrenal androgens and cortisol in patients as compared with HS were confirmed, and proteinuria was not associated with changes of measured renal parameters. CONCLUSIONS: This study in patients with RA and SLE demonstrates that low serum levels of adrenal androgens and cortisol are not due to increased renal clearance and daily loss of these hormones. Decreased adrenal production or increased conversion or conjugation to downstream hormones are the most likely causes of inadequately low serum levels of adrenal hormones in RA and SLE.
17-alpha-Hydroxyprogesterone↗
Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity.
Sex hormones seem to play an important role as modulators of the autoimmune disease onset/perpetuation. Generally, steroid hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone (and glucocorticoids) as natural immunosuppressors. Synovial fluid levels (SF) of proinflammatory estrogens relative to androgens are significantly elevated in both male and female rheumatoid arthritis (RA) patients, as compared to controls, which is most probably due to increase of local enzymatic aromatase activity. Serum levels of estrogens have been found altered in RA patients, particularly estradiol in man. Thus, available steroid prehormones are rapidly converted to proinflammatory estrogens in the synovial tissue in the presence of inflammatory cytokines (i.e., TNFalpha, IL-1, IL-6). The increased estrogen concentrations observed in RA SF of both sexes are characterized mainly by the hydroxylated forms, in particular, 16alpha-hydroxyestrone, showing a mitogenic tumor growth stimulating role. Altered serum hydroxylated estrogens have been found also in serum of systemic lupus erythematosus (SLE) patients. As a matter of fact, our recent studies indicate that 17-beta estradiol (E2) clearly enhanced the expression of markers of cell growth and proliferation, whereas testosterone (T) induced an increase of markers indicating DNA damage and apoptosis. In particular, our data further shows that the enhancing role of estrogens on immune/inflammatory response is exerted by activating the NFkB complex pathway. In conclusion, locally increased estrogens (i.e., synovial tissue in RA or skin in SLE) might exert activating effects on cell proliferation, including macrophages and fibroblasts, suggesting new roles for estrogens in autoimmunity.
Androgens↗
Patients with refractory Crohn's disease or ulcerative colitis respond to dehydroepiandrosterone: a pilot study.
BACKGROUND: Dehydroepiandrosterone is a steroid hormone used as an 'over-the-counter' drug in the USA. Treatment with dehydroepiandrosterone was effective in randomized controlled trials in patients with systemic lupus erythematosus. Dehydroepiandrosterone sulphate concentrations are decreased in patients with inflammatory bowel disease. Dehydroepiandrosterone inhibits nuclear factor-kappaB and the secretion of interleukin-6 and interleukin-12 via the peroxisome proliferator-activated receptor alpha. AIM: A phase II pilot trial was started to evaluate the effect of dehydroepiandrosterone in active inflammatory bowel disease. METHODS: Twenty patients with chronic active inflammatory bowel disease [seven Crohn's disease (Crohn's disease activity index, 242 +/- 51; mean +/- s.d.); 13 ulcerative colitis (clinical activity index, 7.8 +/- 2.1)] took 200 mg dehydroepiandrosterone per day orally for 56 days. RESULTS: Six of the seven patients with Crohn's disease and eight of the 13 patients with ulcerative colitis responded to treatment, with a decrease in the Crohn's disease activity index of > 70 points and a decrease in the clinical activity index of > 4 points, respectively. Six Crohn's disease patients and six ulcerative colitis patients went into remission (Crohn's disease activity index < 150; clinical activity index <or= 4). No patient withdrew from the study because of side-effects. CONCLUSIONS: In a pilot study, dehydroepiandrosterone was effective and safe in patients with refractory Crohn's disease or ulcerative colitis. Adjustment of the dehydroepiandrosterone dosage may further improve the treatment success.
Adjuvants, Immunologic↗
Early social stress in male Guinea-pigs changes social behaviour, and autonomic and neuroendocrine functions.
The present study was undertaken to investigate the effects of pre- and early postnatal social stress on the functioning of hormonal, autonomic and behavioural systems, by studying the distribution of sex hormone receptors in limbic brain systems. Dams had either lived in groups with a constant composition (= stable social environment) or in groups with changing compositions, i.e. every third day, two females from different groups were exchanged (= unstable social environment). The subjects were male offspring of dams who had either lived in a stable social environment during pregnancy and lactation (= control males) or in an unstable social environment during this period of life (= early stressed males). From days 20-80, the spontaneous behaviour of control males and early stressed males was recorded in their home cages. Five control males and five early stressed males were killed at 75 days, and five control males and five early stressed males at 120 days. Blood samples were taken to determine serum concentrations of cortisol, testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulphate and oestrogen. The adrenals were prepared to determine tyrosine hydroxylase activities and the brains were used to investigate the distribution of sex-hormone receptors in specific hypothalamic and hippocampal brain areas. Early stressed males showed a behavioural infantilization that was accompanied by significantly decreased adrenal tyrosine hydroxylase activities and dehydroepiandrosterone levels. Furthermore, early stressed males showed a down-regulation of androgen receptors in the medial preoptic area and the nucleus arcuatus of the hypothalamus, as well as of oestrogen receptor alpha in the hippocampus compared to control males. Thus, the present study provides clear evidence that early social stress induces changes in endocrine, autonomic and limbic brain function, which is mirrored by changes in male social behaviour.
Animals↗
Treatment of pouchitis with dehydroepiandrosterone (DHEA) - a case report.
BACKGROUND: Dehydroepiandrosterone (DHEA) inhibits activation of nuclear factor kappa B (NF-kappaB), which is known to be activated in inflammatory lesions of ulcerative colitis, via PPARalpha. In a pilot trial DHEA was effective for the treatment of active ulcerative colitis. Pouchitis is a common complication after proctocolectomy for ulcerative colitis and still a therapeutical challenge. CASE: DHEA 200 mg/d was tested in chronic active pouchitis in a 35-year-old female patient. DHEA was given for eight weeks, and follow up for further eight weeks was performed. The number of stools dropped from 15-18/d to 8/d, the addition of mucus, which was observed initially, was absent during treatment. The consistence of stools improved from liquid/soft to soft/solid. Abdominal pain resolved and endoscopical signs of inflammation improved. Eight weeks after termination of treatment with DHEA, the patient again suffered from 12 to 18 soft to liquid stools per day and mild abdominal pain. CONCLUSION: Therapeutic effects of DHEA in pouchitis should be evaluated systematically.
Adjuvants, Immunologic↗
Hypothalamic-pituitary-adrenocortical and gonadal functions in rheumatoid arthritis.
Rheumatoid arthritis (RA) as well as most autoimmune disorders results from a combination of several predisposing factors including the relations between epitopes of the trigger agent (i.e., virus, self-antigens) and histocompatibility epitopes (i.e., HLA), the status of the stress response system including the hypothalamic-pituitary-adrenocortical axis (HPA) and the sympathetic nervous system (SNS), as well as the gonadal hormones (hypothalamic-pituitary-gonadal axis, HPG), with estrogens implicated as enhancers of the immune response and androgens and progesterone as natural suppressors. The regular observation of reduced cortisol and adrenal androgen secretion during testing in RA patients not treated with glucocorticoids should clearly be regarded as "relative adrenal insufficiency" in the setting of a sustained inflammatory process, as shown by high interleukin (IL)-6 levels. In polymyalgia rheumatica, several pathogenetic and clinical aspects of the disease might well overlap RA, at least with elderly onset RA (EORA). Therefore, reduced production of adrenal hormones (i.e., cortisol, DHEAS) at baseline in active and untreated patients with polymyalgia rheumatica was detected. The defect was mainly related to altered adrenal responsiveness to ACTH stimulation (i.e., increased 17-OHP), at least in untreated patients with polymyalgia rheumatica. Finally, normal serum estrogen and low androgen levels, but high synovial fluid estrogen and much lower androgen levels, have been found in RA patients, supporting the fundamental role of the peripheral sex hormone metabolism in the manifestations of the disease.
Animals↗
[Neuroendocrine-immunologic mechanisms in rheumatic diseases--a congress report].
Neuro-endocrine immune mechanisms play an important immunomodulatory role for rheumatic diseases as evidenced by long-recognized effects of glucocorticoids, gender, pregnancy, hemiparalysis, and stress on various clinical and epidemiological aspects. Recently, some regulatory pathways have been identified between the neuroendocrine and immune systems which seem to be altered in these diseases. Cooperation between the autonomic nervous system and the hypothalamic pituitary adrenal axis (HPA axis) is important to dampen the reaction of the immune system. In chronic inflammatory diseases such as rheumatic diseases these systems have become deficient. Moreover, hyperexcitability of sensory nerves due to peripheral and central neuronal sensitization can support the local inflammatory process.
Arousal↗
In polymyalgia rheumatica serum prolactin is positively correlated with the number of typical symptoms but not with typical inflammatory markers.
OBJECTIVES: Hyperprolactinaemia has been associated with the active phase of human systemic lupus erythematosus and rheumatoid arthritis. In the present study, we investigated the role of prolactin (PRL) in relation to the number of typical symptoms and serum markers of systemic inflammation in patients with polymyalgia rheumatica (PMR). METHODS: One hundred and two PMR patients presented with typical symptoms such as adynamia, bilateral muscular pain in shoulders, upper arms or neck, bilateral muscular pain in the pelvic girdle, headache, morning stiffness, arthralgia, symptoms of depression, fever, initial weight loss (>4 kg/month), and transient visual symptoms. If one of the mentioned symptoms was present, the corresponding item was scored with one point (maximum unweighted item points=10). PRL, interleukin-2 (IL-2), IL-6, IL-1 receptor antagonist (IL-1ra), tumour necrosis factor (TNF), soluble IL-2 receptor (sIL-2R), and soluble vascular cell adhesion molecule (sVCAM) were measured by enzyme-linked immunosorbent assay in patients and 31 age-matched healthy controls. RESULTS: Fifteen PMR patients with elevated PRL had a higher number of symptoms as compared with patients with normal levels (P=0.003). PRL was correlated with the number of symptoms (all PMR patients: r(rank)=+0.380, P<0.001) and duration of morning stiffness (all PMR patients: r(rank)=+0.335, P=0.002) irrespective of prior corticosteroid treatment. However, PRL did not correlate with markers of systemic inflammation such as erythrocyte sedimentation rate, C-reactive protein, serum IL-1ra, IL-2, sIL-2R, IL-6, TNF, and sVCAM. CONCLUSION: The number of symptoms in PMR patients was positively correlated with PRL, but PRL was not correlated with serum markers of inflammation. This indicates that PRL is not a pro-inflammatory stimulus in patients with PMR. The inter-relationship between PRL and symptoms or duration of morning stiffness may be more a sign of central nervous system involvement, as it can be observed in people with depressed mood or under psychological stress.
Aged↗
Cortisol, dehydroepiandrosterone sulfate, and androstenedione levels in patients with polymyalgia rheumatica during twelve months of glucocorticoid therapy.
This paper aims to evaluate adrenal gland hormone levels in patients with polymyalgia rheumatica (PMR) during glucocorticoid (GC) therapy. A lower than expected basal production of cortisol was found in active and glucocorticoid-untreated PMR patients, particularly females. The abrupt onset of PMR with clinical features similar to those of the steroid-withdrawal syndrome or adrenal insufficiency, as well as the clinical response to GC therapy in elderly people already age-disposed to an inadequate adrenal and anti-inflammatory response, might represent the most significant pathophysiological basis of the disease.
Adrenal Cortex↗
Influence of cytokines and growth factors on distinct steroidogenic enzymes in vitro: a short tabular data collection.
Cytokines (IL-1, IL-6, IL-8, IL-11, TNF, IFN-gamma, and TGF-beta) and growth factors (EGF, bFGF, aFGF, and KGF) play an important role in modulation of hormone secretion by directly influencing specific enzyme steps of steroidogenesis in various endocrine cell types. For this tabular data collection, the following enzyme steps were considered: steroidogenic acute regulatory protein (StAR), side chain cleavage enzyme (P450scc), 3 beta-hydroxysteroid dehydrogenase, 17-alpha-hydroxylase/17,20-lyase (P450c17), 17-beta-hydroxysteroid-dehydrogenase, aromatase complex, 5-alpha-reductase, P450c21, DHEAS sulfatase, and DHEA sulfotransferase. This collection summarizes the current information on how the mentioned cytokines and growth factors influence particular enzyme steps.
17-Hydroxysteroid Dehydrogenases↗
The endotoxin-induced increase of cytokines is followed by an increase of cortisol relative to dehydroepiandrosterone (DHEA) in healthy male subjects.
Dehydroepiandrosterone (DHEA) and DHEA sulphate (DHEAS) inhibit T-helper lymphocyte type 2 immune reactions and exert anti-inflammatory effects in some chronic inflammatory diseases. Both DHEA and, in particular, DHEAS levels are dramatically decreased in chronic inflammatory diseases whereas cortisol levels remain stable or are elevated. However, the time course of cortisol relative to DHEA production is not known. We tested whether administration of endotoxin to healthy male subjects can induce an early predominance of cortisol relative to DHEA and DHEAS. It is demonstrated that endotoxin induces a dose-dependent increase of cortisol in relation to DHEA (no effect at 0.2 ng endotoxin/kg body weight (b.w.), clear effect at 0.4 and 0.8 ng/kg b.w., p<0.05) and DHEAS (tested at 0.4 ng/kg b.w., P=0.014). The increase of cortisol relative to DHEA appears 4 h after endotoxin injection and 2 h after a strong increase of interleukin (IL)-6 relative to tumour necrosis factor (TNF). In addition, an increase of cortisol relative to 17OH-progesterone was observed. The ratio of serum IL-6/TNF was positively correlated with the ratio of serum cortisol/DHEA (R(Rank)=0.472, P=0.041) and serum cortisol/17OH-progesterone (R(Rank)=0.514, P=0.048). In conclusion, dissociation of cortisol relative to DHEA, DHEAS or 17OH-progesterone appears very early during a systemic inflammatory response which is associated with an increase of IL-6 relative to TNF. As in chronic inflammatory diseases, during an acute inflammatory response with endotoxin, these physiological hormone changes are probably necessary to achieve adequate cortisol levels at the expense of adrenal androgens.
17-alpha-Hydroxyprogesterone↗
The process of aging changes the interplay of the immune, endocrine and nervous systems.
The immune, endocrine and nervous systems interact with each other by means of cytokines, hormones and neurotransmitters. Interaction is dependent on specific receptors and respective signaling pathways in target cells. During aging, changes occur on many levels of these global systems which depend on oxidative damage, non-enzymatic glycosylation, mitochondrial mutations, defects in cell cycle control, mitotic dysregulation, genome instability, telomere shortening and other chromosomal pathologies. An alteration of the numerical value of a parameter of one system can lead to changes of the numerical value of a variable of another system. In a non-linear dynamic process these changes can contribute to the aging phenotype. Although it is extremely difficult to dissect linear interrelations of three global systems during aging, this review attempts to identify some simple linear pathways. Furthermore, it is demonstrated that chronic inflammatory diseases may accelerate the aging process. This review also reveals that new statistical and computational methods are necessary to unravel the complexity of the aging process.
Aging↗
Involvement of the hypothalamic--pituitary--adrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis: viewpoint based on a systemic pathogenetic role.
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.
Arthritis, Rheumatoid↗
Early shifts of adrenal steroid synthesis before and after relief of short-term cholestasis.
BACKGROUND/AIMS: Chronic inflammatory diseases are characterised by a relative reduction of cortisol and adrenal androgens. The time point of appearance of these alterations is not known. Cholestasis may be a model of short-term inflammation to study early alterations of steroidogenesis. METHODS: We investigated 18 patients with cholestasis before and after therapeutic abolition of cholestasis (compared to nine control subjects, Co). RESULTS: Serum tumour necrosis factor (TNF) was increased in cholestatic patients as compared to Co (P at least <0.01). Co as compared to cholestatic patients without tumours had elevated levels of plasma adrenocorticotropic hormone (ACTH) and serum dehydroepiandrosterone sulfate (DHEAS) but serum cortisol levels were similar. Levels of ACTH and DHEAS in relation to serum IL-6 or TNF were higher in Co as compared to the cholestatic subgroup without tumours, whereas serum cortisol in relation to these cytokines was similar. In both subgroups of cholestatic patients, we observed the typical inflammation-dependent shift of adrenal hormones into the direction of cortisol in relation to DHEAS. Cholestatic patients with malignant tumours demonstrated an intermediate response pattern. CONCLUSIONS: Short-term cholestasis for 5-12 days induced marked alterations of adrenal steroidogenesis which partly resemble the changes observed in chronic inflammatory diseases.
Adrenal Glands↗
Differential age-related changes of hypothalamus - pituitary - adrenal axis hormones in healthy women and men - role of interleukin 6.
Aging is accompanied by marked changes of steroid hormone levels which vary among women and men. The age-related increase of cytokines such as interleukin (IL)- 6 may modulate the endocrine system. We aimed to investigate the role of IL-6 for the gender-specific changes of acrophase steroid hormone secretion in healthy subjects during aging. Out of 120 healthy subjects, 60 men and 48 women (non luteal phase) were recruited (age: 18 to 75 years). Age was positively correlated with IL-6 (female and male: p<0.001) and adrenocorticotropic hormone (ACTH) in women only (p<0.001). Age was negatively correlated with progesterone (female and male: p<0.001), cortisol (only female: p=0.003), androstenedione (female and male: p<0.001), but not 17OH progesterone. After correction for IL-6, the age-related decrease of steroid hormones was blunted in both gender groups except for androstenedione (female and male: p<0.005). Furthermore, the ratio of serum cortisol to plasma ACTH decreased with age only in women but not in men (female: p< 0.001). Correction for IL-6 did not markedly change the negative interrelationship between age and the mentioned ratio in these women. However, a linear regression analysis revealed that the increase of ACTH in relation to cortisol depends on serum free testosterone in men (p=0.042) and on serum free 17 beta-estradiol (p<0.001) together with serum IL-6 in women (p=0.021). In conclusion, IL-6 plays an important role for acrophase pituitary and peripheral hormone secretion in women only. The gender-specific changes of cortisol in relation to ACTH depend on the age-related decrease of the respective sex hormone in both gender groups and the increase of IL-6 in women. This study underlines the hormone-like role of IL-6 in the aging process of the endocrine system in women.
Adrenocorticotropic Hormone↗
Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis.
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Adenosine↗