Effects of elevated glucocorticoids on reproduction and development: relevance to endocrine disruptor screening

Abstract

This article reviews the influence of the hypothalamo–pituitary–adrenocortical (HPA) axis on mammalian male and female reproduction and development of offspring and its potential impact on the identification of endocrine disruptive chemicals by in vivo assays. In the adult male rat and baboon, stress suppresses testosterone secretion via a direct inhibitory effect of elevated glucocorticoids on Leydig cells. In adult female sheep, stress disrupts reproductive function via multi-stage mechanisms involving glucocorticoid-mediated suppression of LH secretion, LH action on the ovary and the action of estradiol on its target cells (e.g., uterus). While physiological concentrations of endogenous glucocorticoids are supportive of fetal development, excessive glucocorticoids in utero (i.e., maternal stress) adversely affect mammalian offspring by “programing” abnormalities that are primarily manifest postpartum. The influence of stress on reproduction and development can also be mediated by 11β-hydroxysteroid dehydrogenase (HSD), a bi-directional oxidative:reductive pathway, which governs the balance between biologically active (reduced) endogenous glucocorticoid and inactive (oxidized) metabolites. This pathway is mediated primarily by two isozymes, 11β − HSD1 (reductase) and 11β-HSD2 (oxidase) which act both in an intracrine (intracellular) and endocrine (systemic) fashion. The 11β-HSD pathway appears to play a variety of physiological roles in mammalian reproduction and development and is a target for selected xenobiotics. The effects of the HPA axis on mammalian reproduction and development are potential confounders for in vivo bioassays in rodents employed to identify endocrine disruptive chemicals. Accordingly, consideration of the impact of the HPA axis should be incorporated into the design of bioassays for evaluating endocrine disruptors.

Keywords:

• 11β-hydroxysteroid dehydrogenase
• ACTH
• corticosterone
• cortisol
• endocrine disruptor screening program
• estradiol
• in utero
• Leydig cells
• LH
• ovary
• programing
• Registration
• Evaluation
• Authorization and Restriction of Chemicals
• testes
• testosterone

Acknowledgements

The current review was inspired by a presentation previously made by the author at a symposium of the Society of Toxicology meetings in 2003. This symposium was subsequently published and is cited in the current review (Cooke et al. 2004). The material in the current review was significantly modified and updated from the earlier presentation and expanded to include its relationship to the assessment of endocrine disruptors. The author wishes to acknowledge Dr. Roger O. McClellan and the four reviewers assigned to evaluate this manuscript for their important suggestions which led to significant improvement of the final version.

Declaration of interest

Raphael J. Witorsch is Professor Emeritus at Virginia Commonwealth University. This work received no external funding and represents the opinions of the author. Dr. Witorsch has served as a consultant on endocrine disruption to a variety of entities among these the Personal Care Products Council, Colgate-Palmolive Company, and the American Chemistry Council.

Notes

1. In addition to being a glucocorticoid antagonist, RU-486 is a progestin antagonist. Progestins have been associated with effects on male reproduction and development (Lue et al. 2013; Quadros et al. 2002), female reproduction (Telleria et al. 1997), and gestation (Cheon et al. 2003; van der Schoot et al. 1991) in rats. The fact that RU-486 is a competitive inhibitor for both the glucocorticoid and progestin receptors introduces a degree of uncertainty regarding the specificity of this antagonist.