Research Papers
Sex- and stress-steroids interactions and the immune system: evidence for a neuroendocrine-immunological sexual dimorphism

https://doi.org/10.1016/S0739-7240(98)00028-9Get rights and content

Abstract

It is well established that sexual dimorphism exits within the immune system. Females have higher levels of immunoglobulins, greater antibody response to antigens, and higher incidence of autoimmune diseases, such as systemic lupus erythematosus, Grave’s disease, and Hashimoto thyroiditis than males. Spontaneous autoimmune syndromes in mice are more prevalent and of greater severity in females compared with males, and the course of the disease can be modulated by changes in levels of gonadal steroids. A sexual dimorphism is also present in the pituitary-adrenal function: females have higher corticosterone levels and higher corticosteroidogenesis.

In the context of the immune-neuroendocrine interactions, we investigated the effects of gonadectomy and sex hormone therapy on endotoxin-stimulated hypothalamo-pituitary-adrenal axis. Whereas endotoxin-induced corticosterone release is invariable throughout the different stages of the oestrus cycle, gonadectomy in both male and female mice leads to enhanced adrenal and immune responses to endotoxin. Interestingly, these enhanced adrenal and immune responses can be completely reversed by testosterone treatment regardless of the sex of the mice. Studies performed over development confirm the role of endogenous testosterone in modulating the endotoxin-induced corticosterone secretion. Indeed, corticosterone response to endotoxin is maximal before puberty when endogenous testosterone levels are low and declines in postpubertal and adult mice.

In conclusion, all these data support a sex steroid hormone basis for a neuroendocrine-immunologic sexual dimorphism.

Section snippets

Sexual dimorphism in the immune response

In the bidirectional communication between the endocrine and the immune systems, a sexual dimorphism seems to exist at both levels. Sex steroids play an important modulatory role in the regulation of the immune function explaining the sexual dimorphism observed in the immune response. Indeed compared with male mice or rats, females have higher levels of serum immunoglobulins, greater and more prolonged antibody responses, shorter skin allograft rejection time, as well as a higher incidence of

Sexual dimorphism in the endocrine response

Besides the sexual dimorphism in the immune response, there is also a sexual dimorphism in the pituitary-adrenal function. Compared to males, female rats have higher basal levels of plasma corticosterone, higher diurnal rise in plasma corticosterone, higher corticosteroidogenesis by adrenal slices in vitro, and ACTH or stress produce higher and more prolonged elevated plasma corticosterone levels in female than in male rats. There is also a sex difference in rat pituitary glucocorticoid

Modulatory effects of the sex-steroids on the hypothalamo-pituitary-adrenal and immune axis responses to LPS

In the bidirectional communication between the endocrine and immune system, it has been suggested that inflammation-induced activation of the hypothalamo-pituitary-adrenal (HPA) axis may represent a potent negative feedback mechanism through which the immune system, by stimulating the HPA axis and therefore the production of immunosuppressive glucocorticoids, avoids an overshoot of the inflammatory and febrile effect (9) during the acute phase response (Figure 1 ). This production of

Influence of sex steroids on LPS-induced immune response

We also investigated whether gonadal steroids do influence or modulate the LPS-induced immune response. To this purpose, we measured the effect of LPS on the release of plasma TNFα in intact mice of both sexes, in gonadectomized mice as well as in gonadectomized mice receiving sex hormone replacement therapy.

Plasma TNFα levels in basal conditions did not vary with the sex of the mice or with bilateral gonadectomy alone or followed by sex steroid treatment. Plasma TNFα levels were similar in all

Sexual dimorphism of the HPA axis function during development

Because testosterone levels vary over development, and to determine whether physiological testosterone changes may modulate the HPA axis response to endotoxins, we measured plasma corticosterone response to endotoxin in prepubertal (7, 15, and 30-d-old) mice—these are periods of development with low testosterone levels—and in postpubertal and adult mice (45 and 60-d-old)—periods of development with normal testosterone levels (16).

The results obtained at 7 and 15 d of age show the existence of

Acknowledgements

This research was supported by the Swiss National Fondation, Grants No. 31-39749.93 and 31-050748.97/1. The authors wish to thank Mrs. L. Trieste for typing the manuscript.

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