Journal - Annals of the rheumatic diseases (ENGLAND )

Journal - The Journal of rheumatology (CANADA )

Abstract :

Sex emerges as a predominant risk and prognostic factor from epidemiological studies in a variety of rheumatic diseases. Investigations into the underlying mechanisms stress sex related differences in immune and inflammatory responses. Cartilage destruction is an essential feature of most arthropathies and plays an essential role in the symptomatology and progression of arthritis. Based on published evidence and recent experimental observations, we explore the possibility that sex differences in articular cartilage may be an important, though unrecognized, factor in the effects of sex and related hormones in the progression of articular disease.

Journal - The Journal of rheumatology (CANADA )

Abstract :

OBJECTIVE. To investigate sex differences in granulomatous inflammation and its effects upon articular cartilage and to assess the potential role of sex steroids in the process. METHODS. The cotton-pellet cartilage implant model was used with male and female mice in the presence and absence of gonadectomy and hormone replacement. The effects of granulomatous tissue upon articular cartilage was assessed and tissue content of interleukin 1 (IL-1) was determined. The expression of sex hormone receptors in inflammatory tissue was investigated by immunocytochemistry. RESULTS. Female mice showed a higher ability than males to degrade cartilage irrespective of the sex of the cartilage implanted. Gonadectomy resulted in a significant acceleration of cartilage damage in both sexes, which was reverted by estrogen replacement in females and androgen replacement in males. Female granulomata had significantly higher IL-1 content than those from males. Gonadectomy was associated with an increased IL-1 content in males but not in females, the effects being abolished by androgen replacement in males. Estrogen and androgen receptors were identified in inflammatory cells from the granulomatous tissue. CONCLUSION. Our data demonstrate that sex hormones affect inflammation induced cartilage degradation in male and female mice probably through the modulation of cytokine production and release in the granulomatous tissue. Further investigation on the effects of sex steroids in inflammation induced cartilage degradation may help elucidate their pathogenic role and therapeutic potential in human disease.

Journal - Arthritis and rheumatism (UNITED STATES )

Abstract :

OBJECTIVE. To investigate the effects of physiologic levels of sex steroids on inflammation and cytokine production and their consequential cartilage degradation. METHODS. We used an in vivo model of inflammation-induced cartilage degradation in female mice to study the effects of ovariectomy and hormone treatment, and in vitro culture systems to examine the influence of sex steroids on cartilage metabolism, interleukin-1 (IL-1) production by granulomatous tissue, and its effects on female mouse articular cartilage. RESULTS. Ovariectomy resulted in accelerated cartilage breakdown associated with increased production of IL-1 by granulomatous tissue. The effects of ovariectomy on cartilage were reversed by treatment with estradiol and androgen, but not by progesterone treatment. Estradiol and progesterone reduced both spontaneous and IL-1-induced cartilage degradation in vitro. Testosterone antagonized the effects of IL-1 on both proteoglycan loss and proteoglycan synthesis. CONCLUSION. These data suggest that sex steroids have an important influence on inflammation-induced cartilage breakdown in female animals, with protective effects of both estradiol and androgens. Multiple mechanisms may be involved, and they are likely to include direct immunomodulatory effects as well as interactions with the effects of cytokine and of the glucocorticoid response to inflammation.

Journal - The Journal of endocrinology (ENGLAND )

Abstract :

The influence of gender and sex hormones upon both the hypothalamic-pituitary-adrenal (HPA) axis and the immune and inflammatory responses is well recognized, but it is not clear to what extent the two effects are interdependent. We have investigated this interaction using a chronic inflammation model. Corticosterone levels were measured in mature BALB/c male and female mice, which were intact, sham-operated or gonadectomized. No significant differences were found between groups in baseline corticosterone, but systemic inflammation (cotton-induced granulomas) resulted in stimulation of the HPA axis in a reproducible pattern. Corticosterone levels were higher in sham-operated females than in males, but gonadectomy had opposing effects in the two genders, resulting in reduced levels in females but significantly increased levels in males. A similar pattern emerged after stimulation by ether exposure or injection of interleukin-1 beta. In the chronic inflammatory model, replacement of ovariectomized females with physiological levels of progesterone restored a response similar to that of intact females. Physiological levels of 5 alpha-dihydrotestosterone prevented the increase in corticosterone levels caused by castration in males and also resulted in reduced corticosterone levels in sham-operated females. Oestradiol treatment did not affect corticosterone levels. Release of interleukin-1 by peritoneal macrophages from intact and gonadectomized mice with chronic inflammation followed a similar pattern, females releasing more than males. These data suggest a complex inter-relationship between sex steroids, inflammatory stimuli and the HPA axis, such that females have a greater tendency than males to generate activating signals and in addition have a greater sensitivity to such factors.

Journal - Annals of the rheumatic diseases (ENGLAND )

Abstract :

OBJECTIVES--Rheumatoid arthritis (RA) is a disease which predominantly affects women. Interestingly, low serum androgen levels and clinical improvement with androgen replacement have been reported in male patients. The aetiopathogenic role of sex hormones in arthritis and their potential long term effects on joint destruction and disability remains unclear, however. This study was designed to investigate the potential influence of sex hormones on inflammation induced cartilage degradation in male rodents. METHODS--An in vivo model of cotton wrapped cartilage implants was used to assess the effects of androgen, oestradiol, and progesterone on inflammation induced cartilage degradation, and in vitro techniques were used to investigate the direct actions on cartilage metabolism and cytokine production in male animals. RESULTS--Orchidectomy resulted in accelerated cartilage damage which was reversed by replacement of physiological levels of androgens. Granulomatous tissue from castrated male rodents produced higher amounts of interleukin 1. Sex hormones reduced spontaneous proteoglycan loss in vitro but did not interfere with the effects of interleukin 1 on cultured cartilage. CONCLUSIONS--Androgens appear to protect cartilage from inflammation induced breakdown in male animals. These results support a pathogenic role for hypoandrogenism in rheumatoid arthritis and suggest that long term androgen replacement may help prevent joint damage and disability.

Journal - Clinical rheumatology (BELGIUM )

Abstract :

The aetiology of rheumatoid arthritis (RA) is unknown, although being female is generally recognized as the most important independent risk factor, the disease being 2 to 3 times more frequent in females than in males. The dramatic effect of pregnancy in rheumatoid arthritis has been documented for over 50 years. This review examines the evidence and possible mechanisms by which pregnancy modifies the disease process and may alter predisposition to the development of RA in later life.