Prevention of autoantibody formation and prolonged survival in New Zealand black/New Zealand white F1 mice fed dehydroisoandrosterone.

Lucas, Julie Ann; Ahmed, S. Ansar; Casey, M.Linette; MacDonald, Paul C.

doi:10.1172/jci111929

Cited by 142 publications

(61 citation statements)

References 22 publications

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“…DHEA supplementation had beneficial effects in human SLE (van Vollenhoven et al 1998) and murine models of SLE (Lucas et al 1985), in atherosclerosis models in rabbits (Gordon et al 1988), virus or parasite infection in rodents (Rasmussen et al 1995, Loria et al 1988, mouse tuberculosis (Hernandez-Pando et al 1998), and in an animal model of type 2 diabetes with elevated serum tumor necrosis factor (TNF) (Kimura et al 1998). The common reason for the positive effects of DHEA in the mentioned chronic diseases is probably inhibition of NF-B (Yamada et al 1994, Spencer et al 1997.…”

Section: Introductionmentioning

confidence: 99%

Conversion of dehydroepiandrosterone to downstream steroid hormones in macrophages

Schmidt¹,

Kreutz²,

Löffler³

et al. 2000

Journal of Endocrinology

130

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Dehydroepiandrosterone (DHEA) is a ubiquitous adrenal hormone with immunomodulatory effects such as inhibition of the production of monokines. Whether DHEA itself or the downstream steroids are the immunomodulatory effector hormones in target cells is not known. In this study, we investigated the conversion of DHEA to downstream steroid hormones in target macrophages.Within 1 day of culture with radiolabeled DHEA, monocyte-derived macrophages converted DHEA to significant amounts of 5-derivatives such as 16OH-DHEA, 3 ,17 -androstenediol (A'diol), and 3 ,16 , 17 -androstenetriol (A'triol). However, the production of 4-steroids (androstenedione (A'dione), testosterone (T), and 16OH-T) and estrogens (estrone, estradiol, and estriol) was relatively low. Further cultivation of macrophages for 5 days with radiolabeled DHEA resulted in a significant (P<0·05) increase of the molar amounts of A'triol (P=0·012), 16OH-T (P=0·008), and estriol (P=0·003). In contrast to monocyte-derived macrophages, monocytes did not express aromatase mRNA, which was demonstrated by RT-PCR (P<0·01). Furthermore, DHEA in macrophages significantly inhibited one of the downstream converting enzymes, the aromatase, which was not demonstrated in the presence of the typical macrophage activator, lipopolysaccharide (LPS) (P<0·01).In conclusion, conversion of DHEA to physiologically relevant amounts of 5-and 4-steroids and estrogens was demonstrated in monocyte-derived macrophages. The conversion depends on maturation of monocytes and local factors such as the presence of LPS. The conversion of DHEA leads to an increase of downstream effector hormones in target macrophages which may be an important factor for local immunomodulation.

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Section: Introductionmentioning

confidence: 99%

Conversion of dehydroepiandrosterone to downstream steroid hormones in macrophages

Schmidt¹,

Kreutz²,

Löffler³

et al. 2000

Journal of Endocrinology

130

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show abstract

“…Decreases of ϳ50% in circulating levels of DHEA and DHEAS have been observed in patients with SLE (7,8). Previous studies in animal models of SLE have demonstrated improvement with androgen administration, including DHEA (9)(10)(11)(12)(13)(14). In addition to serving as a precursor for other androgenic and estrogenic steroids (5), there is evidence that DHEA has an immunomodulatory role, including upregulation of interleukin-2 (IL-2) and down-regulation of IL-6 expression (9,(15)(16)(17), both of which have been reported to be abnormal in SLE (18)(19)(20).…”

mentioning

confidence: 99%

Effects of prasterone on disease activity and symptoms in women with active systemic lupus erythematosus

Petri¹,

Mease²,

Merrill³

et al. 2004

Arthritis & Rheumatism

132

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Objective. To determine whether prasterone administration results in improvement or stabilization of systemic lupus erythematosus (SLE) disease activity and its symptoms.Methods. Women with active SLE were treated with prasterone 200 mg/day plus standard SLE treatments or with placebo plus standard SLE treatments for up to 12 months in this randomized, double-blind investigation conducted at 27 centers. Standard SLE treatments included prednisone (<10 mg/day), antimalarials, and immunosuppressive agents; dosages were required to be stable for >6 weeks prior to enrollment and remain unchanged during protocol treatment. Re-

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“…Although the biologic function of DHEA in humans has not been ascertained, it has mild intrinsic androgenic properties, and in peripheral tissues, both DHEA and DHEAS can be converted to various other androgens as well as aromatized to estrogenic steroids (1). The potential for using DHEA in the treatment of SLE was suggested by such observations as the female predominance of SLE, the low circulating levels of DHEA and DHEAS in patients with active disease (2), the immunomodulatory effects of DHEA (3), and the delayed onset of and reduced mortality from SLE in NZB ϫ NZW mice that were fed DHEA (4).…”

mentioning

confidence: 99%

Dehydroepiandrosterone treatment of women with mild‐to‐moderate systemic lupus erythematosus: A multicenter randomized, double‐blind, placebo‐controlled trial

Chang¹,

Lan²,

Lin³

et al. 2002

Arthritis & Rheumatism

146

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Objective. To evaluate the efficacy and tolerability of dehydroepiandrosterone (DHEA) at a dosage of 200 mg/day in adult women with active systemic lupus erythematosus (SLE).Methods. In a multicenter randomized, doubleblind, placebo-controlled trial, 120 adult women with active SLE received oral DHEA (200 mg/day; n ‫؍‬ 61) or placebo (n ‫؍‬ 59) for 24 weeks. The primary end point was the mean change from baseline in the Systemic Lupus Activity Measure (SLAM) score at 24 weeks of therapy. Secondary end points included time to first flare, change in SLE Disease Activity Index (SLEDAI) score, and physician's and patient's global assessment scores at week 24.Results. The two groups were well balanced for baseline characteristics. Mean reductions in SLAM scores from baseline were similar and were not statistically significantly different between treatment groups (DHEA ؊2.6 ؎ 3.4 versus placebo ؊2.0 ؎ 3.8, mean ؎ SD). The number of patients with flares was decreased by 16% in the DHEA group (18.3% of DHEA-treated patients versus 33.9% of placebo-treated patients; P ‫؍‬ 0.044, based on time to first flare). The mean change in the patient's global assessment was statistically significant between the two groups (DHEA ؊5.5 versus placebo 5.4; P ‫؍‬ 0.005). The number of patients with serious adverse events, most of which were related to SLE flare, was significantly lower in DHEA-treated patients compared with placebo-treated patients (P ‫؍‬ 0.010). Expected hormonal effects, including increased testosterone levels and increased incidence of acne, were observed. No life-threatening reactions or serious safety issues were identified during this study.Conclusion. The overall results confirm that DHEA treatment was well-tolerated, significantly reduced the number of SLE flares, and improved patient's global assessment of disease activity.

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Prevention of autoantibody formation and prolonged survival in New Zealand black/New Zealand white F1 mice fed dehydroisoandrosterone.

Abstract: MethodsDehydroisoandrosterone, administered orally to New Zealand Black/New Zelnd White F1 hybrid mice, prevented the formation of antibodies to double-stranded DNA and prolonged survival in this murine model of lupus erythematosus.

Cited by 142 publications

References 22 publications

Conversion of dehydroepiandrosterone to downstream steroid hormones in macrophages

Conversion of dehydroepiandrosterone to downstream steroid hormones in macrophages

Effects of prasterone on disease activity and symptoms in women with active systemic lupus erythematosus

Dehydroepiandrosterone treatment of women with mild‐to‐moderate systemic lupus erythematosus: A multicenter randomized, double‐blind, placebo‐controlled trial

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