Estrogen increases the severity of anaphylaxis in female mice through enhanced endothelial nitric oxide synthase expression and nitric oxide production

Abstract

Background Clinical observations suggest that anaphylaxis is more common in adult women compared to adult men, although the mechanistic basis for this gender bias is not well understood Objectives To document gender dependent differences in a mouse model of anaphylaxis and explore the role of female sex hormones and the mechanisms responsible. Methods Passive systemic anaphylaxis was induced in female and male mice by histamine, as well as IgE or IgG receptor aggregation. Anaphylaxis was assessed by monitoring body temperature, release of mast cell mediators and/or hematocrit and lung weight as a measure of vascular permeability. A combination of ovariectomy, estrogen receptor antagonism, and estrogen administration techniques were used to establish estrogen involvement. Results Anaphylactic responses were more pronounced in female than in male mice. The enhanced severity of anaphylaxis in female mice was eliminated after pretreatment with an estrogen receptor antagonist or ovariectomy, but restored after administration of estradiol in ovariectomized mice, demonstrating that the sex-specific differences are due to the female steroid estradiol. Estrogen did not affect mast cell responsiveness or anaphylaxis onset. Instead, it increased tissue expression of endothelial nitric oxide synthase (eNOS). Blockage of NOS activity with the inhibitor L-NAME or genetic eNOS deficiency abolished the gender-related differences. Conclusion Our study defines a contribution of estrogen, through its regulation of eNOS expression and NO production, to vascular hyper-permeability and intensified anaphylactic responses in female mice, providing additional mechanistic insights into risk factors and possible implications for clinical management in the further exploration of human anaphylaxis.

Risk of anaphylaxis after vaccination in children and adults

“…Although precise biological mechanisms underlying sex-specific responses to vaccines are unknown, genetic and hormonal factors are considered important. 33 Sex hormones have been shown to modulate immune responses, 40,41 and Hox et al 42 recently found that sex-specific differences in a mouse model of anaphylaxis were due to the female steroid estradiol.…”

Neuroendocrinology of the skin

“…Treatment of mice with LH, FSH, or estradiol increased the number and extent of MC degranulation in the ovaries [164,165]. Estrogen receptors are also expressed on bladder [166][167][168] and lung [169,170] MCs. Human MCs also express progesterone [171,172] and testosterone [173] receptors, but their activation appears to have an inhibitory effect.…”

Fibromyalgia Syndrome in Need of Effective Treatments

“…Recent studies have reported that estradiol augments immune (Kovats, 2015) and allergic (Hox et al, 2015) reactions. We showed that MCs express estrogen receptors (Pang et al, 1995) and that 17b-estradiol augmented substance P (SP)-induced MC activation (Theoharides et al, 1993).…”