Immunologic sex differences and the female predominance in systemic lupus erythematosus

Inman, Robert D.

doi:10.1002/art.1780210718

Cited by 134 publications

(27 citation statements)

References 35 publications

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“…Furthermore, NZB mice of both sexes who were given androgen-containing capsules at 2 weeks of age failed to New Zealand NZB and NZB x NZW F , mice are models for the human autoimmune disorder systemic lupus erythematosus (SLE) (1). Since patients with SLE are predominantly female (2,3), the basis for this female preponderance has been sought in NZB x NZW F, mice. Female NZB/NZW F, mice have a more severe disease than do their brothers with earlier onset of antibodies to DNA (4) especially IgG anti-DNA (5), glomerulonephritis, and death (6)(7)(8).…”

Section: The Effect Of Sex Hormones On the Spontaneous Production Ofmentioning

confidence: 99%

Genetic studies in nzb mice

Raveché

Tjio

Steinberg

1980

Arthritis & Rheumatism

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Hybrid NZB X NZW or NZB X DBA/2 females have markedly accelerated development of autoimmunity when compared with their respective male littermates. This difference is attributable to the ability of male sex hormones to retard the expression of autoimmunity. In contrast to the sex differences in expression of autoimmunity in F1 mice, parental NZB males and females have only minor differences in disease expression. We have been investigating the basis for the difference in anti‐T cell antibody production between NZB and F1 mice. In this study, the appearance of antibodies cytotoxic for T cells (NTA) was studied in NZB and DBA/2 mice and in their F1 hybrids and backcross progeny. A major sex difference in NTA production was observed in the F1 hybrids; females produced more NTA than did males. Castration of males led to a marked increase in NTA production. Furthermore, the NTA production of castrated male and female F1 mice was significantly suppressed by administration of testosterone in Silastic capsules. In contrast to the studies in F1 mice, we found little difference between intact male and female parental NZB mice at any age studied. Furthermore, NZB mice of both sexes who were given androgen‐containing capsules at 2 weeks of age failed to demonstrate a decrease in NTA production. This result suggested an androgen insensitivity in NZB mice with regard to NTA production. This insensitivity, which appears to be a recessive trait, may help to explain why NZB mice do not manifest the sex differences in disease expression observed in the F1 hybrids.

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Section: The Effect Of Sex Hormones On the Spontaneous Production Ofmentioning

confidence: 99%

Genetic studies in nzb mice

Raveché

Tjio

Steinberg

1980

Arthritis & Rheumatism

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“…Females have stronger humoral and cell-mediated immune responses than males (3,18,22,59) and, in general, have a higher incidence of autoimmune diseases (31,33,40,48,57). Although estrogen has been reported to enhance immunity, estrogen therapy has been shown to attenuate inflammation in carrageenaninduced pleurisy in rats and myocardial reperfusion injury and to improve outcome after cerebral ischemia (15,47,56).…”

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confidence: 99%

Modulatory effects of estrogen in two murine models of experimental colitis

Verdú

Deng

Berčík

et al. 2002

American Journal of Physiology-Gastrointestinal and Liver Physi

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The association between oral contraceptives or pregnancy and inflammatory bowel disease is unclear. We investigated whether 17β-estradiol modulates intestinal inflammation in two models of colitis. Female mice were treated with 17β-estradiol alone or with tamoxifen, tamoxifen alone, 17α-estradiol, or placebo. Dinitrobenzene sulfonic acid (DNB)- or dextran sodium sulfate (DSS)-induced colitis were assessed macroscopically, histologically, and by myeloperoxidase (MPO) activity. Malondialdehyde and mRNA levels of intercellular adhesion molecule-1 (ICAM-1), interferon-γ (IFN-γ), and interleukin-13 (IL-13) were determined. In DNB colitis, 17β-estradiol alone, but not 17β-estradiol plus tamoxifen, or 17α-estradiol reduced macroscopic and histological scores, MPO activity and malondialdehyde levels. 17β-Estradiol also decreased the expression of ICAM-1, IFN-γ, and IL-13 mRNA levels compared with placebo. In contrast, 17β-Estradiol increased the macroscopic and histological scores compared with placebo in mice with DSS colitis. These results demonstrate anti-inflammatory and proinflammatory effects of 17β-estradiol in two different models of experimental colitis. The net modulatory effect most likely reflects a combination of estrogen receptor-mediated effects and antioxidant activity and may explain, in part, conflicting results from clinical trials.

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“…Castrated males have a female pattern of survival, whereas androgen-treated females, either intact or castrated, exhibit longer survival than control females (3,4). In humans, the predominance of reproductive age females who have SLE (19) and the frequent exacerbation of lupus activity following oral contraceptive therapy with estrogen-containing preparations (2) indicate an unfavorable effect of endogenous or exogenous estrogens. A disordered pattern of estrogen nietabolism has been found in both male and female SLE patients, resulting in excessive formation of 16-ahydroxylated metabolites which retain estrogenic potency (5).…”

Section: Discussionmentioning

confidence: 99%

Hormonal modulation in systemic lupus erythematosus. Preliminary clinical and hormonal results with cyproterone acetate

Jungers¹,

Kuttenn²,

Lioté³

et al. 1985

Arthritis & Rheumatism

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We prospectively studied the effects of hormonal modulation using the antigonadotropic drug, cyproterone acetate (CA), in 7 female patients who had moderately active systemic lupus erythematosus. CA was taken orally at a mean daily dose of 50 mg for 21-33 months by 6 patients (9 months by the seventh patient) without any side effects. The number of clinical lupus exacerbations during CA treatment was lower than that during the corresponding pretreatment period (15 of 170 patient-months versus 27 of 156 patient-months; P < 0.05), despite a reduction in the daily maintenance dose of corticosteroids or antimalarial drugs. Mean plasma testosterone levels were low initially and remained unchanged (0.66 -C 0.31 to 0.59 -C 0.23 nmoles/ liter), whereas plasma estradiol decreased markedly (from 0.6 f 0 38 to 0.11 f 0.03 nmoles/liter), resulting in a significant reduction in the estradio1:testosterone ratio (from 1.19 f 0.68 to 0.23 f 0.12) and in the plasma concentration of the sex hormone-binding protein. Thus, cyproterone acetate induced improvement in clinical lupus activity in parallel with the expected lower estradio1:testosterone balance.The predominance of females among patients with systemic lupus erythematosus (SLE) and the frequent exacerbation of the disease during pregnancy (1) or following oral contraceptive therapy (2) highly suggest that sex hormones influence disease activity. Animal studies have clearly demonstrated the deleterious effects of estrogens and the favorable effects of androgens on the course of murine lupus (3,4). Moreover, recent hormonal studies showed increased production of estrogenic metabolites in female SLE patients (9, and we observed low plasma androgen levels in women in remission or with active SLE (6), a finding recently confirmed by Labita et a1 (7).Such concordant experimental and clinical data led to consideration of a therapeutic use of sex hormones (hormonal modulation), in an attempt to achieve a higher androgen : estrogen balance in female SLE patients. Weak androgens with anabolic properties, such as nandrolone decanoate or danazol, were used in a few trials. However, the former was ineffective (S), and while the latter induced clinical improvement (S)), it was at the expense of a high incidence of side effects, as was observed in our own unpublished preliminary studies.We therefore attempted evaluation of another means of hormonal modulation by using cyproterone acetate, a synthetic hydroxyprogesterone derivative first known as a progestogen, which possesses antigonadotropic properties, and thus, in female subjects suppresses ovulation, depresses ovarian estrogen secretion (10-12), thereby acting as an oral contraceptive. Moreover, this molecule is devoid of anabolic

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Immunologic sex differences and the female predominance in systemic lupus erythematosus

Cited by 134 publications

References 35 publications

Genetic studies in nzb mice

Genetic studies in nzb mice

Modulatory effects of estrogen in two murine models of experimental colitis

Hormonal modulation in systemic lupus erythematosus. Preliminary clinical and hormonal results with cyproterone acetate

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