Biomedical subjects

Carmen Pizzorni

Publications and source records attributed to Carmen Pizzorni.

9 recordsLinked to original sources

PubMed2006

Circadian rhythms: glucocorticoids and arthritis.

Circadian rhythms are driven by biological clocks and are endogenous in origin. Therefore, circadian changes in the metabolism or secretion of endogenous glucocorticoids are certainly responsible in part for the time-dependent changes observed in the inflammatory response and arthritis. More recently, melatonin (MLT), another circadian hormone that is the secretory product of the pineal gland, has been found implicated in the time-dependent inflammatory reaction with effects opposite those of cortisol. Interestingly, cortisol and MLT show an opposite response to the light. The light conditions in the early morning have a strong impact on the morning cortisol peak, whereas MLT is synthesized in a strictly nocturnal pattern. Recently, a diurnal rhythmicity in healthy humans between cellular (Th1 type) or humoral (Th2 type) immune responses has been found and related to immunomodulatory actions of cortisol and MLT. The interferon (IFN)-gamma/interleukin (IL)-10 ratio peaked during the early morning and correlated negatively with plasma cortisol and positively with plasma MLT. Accordingly, the intensity of the arthritic pain varies consistently as a function of the hour of the day: pain is greater after waking up in the morning than in the afternoon or evening. The reduced cortisol and adrenal androgen secretion, observed during testing in rheumatoid arthritis (RA) patients not treated with glucocoticoids, should be clearly considered as a "relative adrenal insufficiency" in the presence of a sustained inflammatory process, and allows Th1 type cytokines to be produced in higher amounts during the late night. In conclusion, the right timing (early morning) for the glucocorticoid therapy in arthritis is fundamental and well justified by the circadian rhythms of the inflammatory mechanisms.

Animals↗

PubMed2006

Anti-TNF and sex hormones.

Whenever serum estrogen concentrations are normal in rheumatoid arthritis (RA) patients, lower androgen concentrations (i.e., testosterone, androstenedione, and dehydroepiandrosterone sulfate [DHEAS]) are detected in the serum as well as in the synovial fluid of male and female RA patients. The presence in the RA synovial fluid of a significant altered sex hormone balance resulting in lower immunosuppressive androgens and higher immuno-enhancing estrogens, might determine a favorable condition for the development of the immunomediated RA synovitis. The inflammatory cytokines (i.e., TNF-alpha), particularly increased in RA synovitis, are able to markedly stimulate the aromatase activity in peripheral tissues and, therefore, induce the peripheral metabolism from androgens to estrogens. The effects of TNF blockers (and generally of anticytokine agents) on peripheral sex hormone levels seem exerted in a faster way at the level of the RA synovial tissue (before any influence on serum levels) where they seem to block the conversion from androgens (anti-inflammatory) to estrogens (proinflammatory) induced by aromatase. Therefore, the beneficial effects of restoring synovial androgens might be clinically more evident in male RA patients (as recently observed in ANTARES study) since they suffer more for the lack of androgens (anti-inflammatory) on account of the action of TNF-alpha on peripheral hormonal conversion. However, therapy (3 months) with anti-TNF did not change serum levels of typical sex hormones in patients with RA, although baseline values were largely different from controls. In patients with at least long-standing RA, this indicates that alterations of serum sex hormones and altered activity of respective converting enzymes are imprinted for a long-lasting period over at least 12 weeks.

Animals↗

PubMed2005

Capillaroscopy.

Raynaud's phenomenon (RP) is the most common and significant clinical condition with an indication for a microvascular analysis to be carried out as soon as possible. Microvascular involvement is a key feature of RP and several rheumatic diseases are characterised by the presence of RP. Nailfold capillary microscopy shows an impressive cost/effectiveness ratio: it is simple, non-invasive and inexpensive. Well recognised nailfold videocapillaroscopic patterns (NVC) have been described mainly in systemic sclerosis (SSc) patients with secondary RP. The peripheral microvascular damage in SSc is characterised by increasing structural alterations of the capillaries (giant capillaries and microhaemorrhagies) with a progressive decrease in their density. The detection of the scleroderma NVC pattern allows an early distinction between the primary RP (functional, not disease associated) and the secondary RP (disease associated). Other major NVC patterns have been described in the field of rheumatic diseases. Interestingly, correlations are evident between the NVC and the clinical symptoms, severity of the disease and the laboratory findings.

Clinical Trials as Topic↗

PubMed2002

Sex hormones and rheumatoid arthritis.

Sex hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone as natural immune-suppressors. In male rheumatoid arthritis (RA) patients, androgen replacement seems to ameliorate the disease and supports their involvement in the pathophysiology of the disease. The combination of androgens with cyclosporin A or methotrexate has been found to potentiate the apoptosis of monocytic inflammatory cells as well as to reduce the cell growth at least in vitro. Considerable interest has been devoted in the last years as to whether the use of oral contraceptive pills (OCs) may have a protective effect on the risk of RA. The results of many controlled studies have been found contradictory. At the present time, no consensus has been achieved regarding OCs administration and its relationship to the prevention or development of RA. In addition, an association of estrogen receptor gene polymorphism with age at onset of RA has been observed and might further explain inter-individual clinical and therapeutical-response variations. Local increased estrogen concentrations and decreased androgen levels have been observed in RA synovial fluids and seem to play a more important role in the immune/inflammatory local response.

Androgens↗

PubMed2002

Androgens and estrogens modulate the immune and inflammatory responses in rheumatoid arthritis.

Generally, androgens exert suppressive effects on both humoral and cellular immune responses and seem to represent natural anti-inflammatory hormones; in contrast, estrogens exert immunoenhancing activities, at least on humoral immune response. Low levels of gonadal androgens (testosterone/dihydrotestosterone) and adrenal androgens (dehydroepiandrosterone and its sulfate), as well as lower androgen/estrogen ratios, have been detected in body fluids (that is, blood, synovial fluid, smears, salivary) of both male and female rheumatoid arthritis patients, supporting the possibility of a pathogenic role for the decreased levels of the immune-suppressive androgens. Several physiological, pathological, and therapeutic conditions may change the sex hormone milieu and/or peripheral conversion, including the menstrual cycle, pregnancy, the postpartum period, menopause, chronic stress, and inflammatory cytokines, as well as use of corticosteroids, oral contraceptives, and steroid hormonal replacements, inducing altered androgen/estrogen ratios and related effects. Therefore, sex hormone balance is still a crucial factor in the regulation of immune and inflammatory responses, and the therapeutical modulation of this balance should represent part of advanced biological treatments for rheumatoid arthritis and other autoimmune rheumatic diseases.

Androgens↗

PubMed2002

Modulation of cell growth and apoptosis by sex hormones in cultured monocytic THP-1 cells.

Several authors have reported the regulation of apoptotic phenomena by sex hormones in different cell lines, including T lymphocytes and mononuclear cells. Since androgens can modulate the programmed cell death in responsive cell lines, we decided to investigate the induction of apoptosis in THP-1 cells following their differentiation into macrophage-like cells and exposure to sex hormones. In addition, we decided to evaluate the proto-oncogene Bax and Fas (CD 95) and cleaved PARP (poly-adp-ribose-polymerase) expression in the same cultured cells. The results showed for the first time the dose-/time-dependent regulation of the apoptotic event in human monocytic THP-1 cells treated with different concentrations of androgens. No significant changes were observed for estrogen-treated and unstimulated control cells. In particular, the cells, after stimulation with androgens but not with estrogens, were found to be positive for the proto-oncogene Bax, Fas, and for cleaved subunits of PARP expression as demonstrated with different assays including immunocytochemical assay and Western blot analysis. In conclusion, these results support the possibility of sex hormone modulation of apoptosis in macrophage-like cells, with interesting therapeutic perspectives in rheumatoid arthritis.

Apoptosis↗

PubMed2002

Antiproliferative-antiinflammatory effects of methotrexate and sex hormones on cultured differentiating myeloid monocytic cells (THP-1).

Methotrexate (MTX) is believed to exert both antiproliferative and antiinflammatory effects in a dose-related manner in a majority of rheumatoid arthritis (RA) patients along with an abrupt flare of the disease after drug discontinuation. To investigate the antiproliferative and antiinflammatory actions of MTX and the combined action of sex hormones, we evaluated these effects in differentiated monocytic myeloid cells (THP-1) prestimulated with testosterone (T) or 17-beta estradiol (E2). The effects of MTX and T combined treatment (T/MTX) on THP-1 cells showed a significant inhibition of cell proliferation when compared with E2/MTX- treated cells or controls: 53% at 72 h versus E2-treated cells; 58% at 96 h versus E2-treated cells; and 41% versus controls, respectively. Bax and Fas CD95 expression was found increased in T-treated cells: 14% T at 48 h vs. E(2)-treated cells and controls; 45% T at 72 h versus E2-treated cells and controls; 97% at 96 h versus E2-treated cells and 37% versus controls for Bax: 33%, 41%, and 42% T versus E2-treated cells for Fas. Moreover, a significant decrease of IL-12 levels in T/MTX treated cells was found at any time when compared to E2-treated cells. In summary, the association of testosterone and MTX compared to MTX alone suggests possible synergistic actions. Therefore, the enhancing antiinflammatory effects exerted by androgens might represent a further explanation for the reduced frequency of inflammatory diseases in male subjects.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2002

Melatonin in rheumatoid arthritis: synovial macrophages show melatonin receptors.

The pineal neurohormone melatonin is widely recognized as exerting important immunoenhancing effects that act on specific receptors in immunocompetent cells. This action results in stimulation of cytokine production in lymphocytes and macrophages. Here we report that the nocturnal plasma concentration of melatonin in rheumatoid arthritis (RA) patients is higher than in healthy controls. Furthermore, melatonin is present in the synovial fluid of RA patients and synovial macrophages express a specific binding site. We suggest that melatonin may exert a disease-promoting role in RA.

Adult↗

PubMed2002

Adrenal gland hypofunction in active polymyalgia rheumatica. effect of glucocorticoid treatment on adrenal hormones and interleukin 6.

OBJECTIVE: To evaluate hypothalamic-pituitary-adrenal (HPA) axis function in patients with recent onset polymyalgia rheumatica (PMR) not previously treated with glucocorticoids; and to detect possible correlations between adrenal hormone levels, interleukin 6 (IL-6), and other acute phase reactants at baseline and during 12 months of glucocorticoid treatment. METHODS: Forty-one PMR patients of both sexes with recent onset disease and healthy sex and age matched controls were enrolled into a longitudinal study. Patients were monitored for serum cortisol, dehydroepiandrosterone sulfate (DHEAS), androstenedione (ASD), and clinical and laboratory measures of disease activity such as C-reactive protein and IL-6 concentrations at baseline and after 1, 3, 6, 9 and 12 months of glucocorticoid treatment. To assess dynamic HPA axis function, serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels were evaluated in another 8 patients with recent onset PMR not treated with glucocorticoid in comparison to controls after challenge with ovine corticotropin releasing hormone (oCRH) test. In addition, serum cortisol and 17-hydroxyprogesterone (17-OHP) levels were evaluated after stimulation with low dose (1 microg) intravenous ACTH. RESULTS: Serum cortisol and ASD levels of all PMR patients at baseline did not differ from controls. During followup, cortisol levels dipped at one and 3 months. Serum DHEAS levels in all patients were significantly lower than in controls at baseline. In female PMR patients a significant correlation was found at baseline between cortisol levels and duration of disease. Serum concentrations of IL-6 at baseline were significantly higher in PMR patients than in controls. During 12 months of glucocorticoid treatment IL-6 levels dropped significantly at one month; thereafter they remained stable and did not increase again despite tapering of the glucocorticoid dose. After oCRH stimulation, a similar cortisol response was found in patients and controls. After ACTH administration, a significant cortisol peak was detected in patients and controls, whereas no significant difference in cortisol area-under-the-curve (AUC) was found between the groups. In contrast, ACTH induced a significantly higher (p < 0.05) peak of 17-OHP and AUC in PMR patients than in controls. CONCLUSION: This study found reduced production of adrenal hormones (cortisol, DHEAS) at baseline in patients with active and untreated PMR. The defect seems mainly related to altered adrenal responsiveness to the ACTH stimulation (i.e., increased 17-OHP), at least in untreated patients. The 12 month glucocorticoid treatment of patients reduced the production of inflammatory mediators (i.e., IL-6) in a stable manner that persisted after glucocorticoids were tapered.

17-alpha-Hydroxyprogesterone↗