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

Crit Rev Toxicol. 2016;46(5):420-36. doi: 10.3109/10408444.2016.1140718. Epub 2016 Feb 25.


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; Authorization and Restriction of Chemicals; Evaluation; LH; Leydig cells; Registration; corticosterone; cortisol; endocrine disruptor screening program; estradiol; in utero; ovary; programing; testes; testosterone.

Publication types

  • Review

MeSH terms

  • Animals
  • Drug Evaluation, Preclinical / methods
  • Endocrine Disruptors / pharmacology*
  • Female
  • Glucocorticoids
  • Humans
  • Hypothalamo-Hypophyseal System / drug effects
  • Male
  • Pituitary-Adrenal System / drug effects
  • Reproduction / drug effects*
  • Reproduction / physiology
  • Stress, Physiological / physiology


  • Endocrine Disruptors
  • Glucocorticoids