The Interplay between Estrogen and Fetal Adrenal Cortex

Abstract

Estrogen is a steroid hormone that regulates embryogenesis, cell proliferation and differentiation, organogenesis, the timing of parturition, and fetal imprinting by carrying chemical messages from glands to cells within tissues or organs in the body. During development, placenta is the primary source of estrogen production but estrogen can only be produced if the fetus or the mother supplies dehydroepiandrosterone (DHEA), the estrogen prohormone. Studies show that the fetal zone of the fetal adrenal cortex supplies 60% of DHEA for placental estrogen production, and that placental estrogen in turn modulates the morphological and functional development of the fetal adrenal cortex. As such, in developed countries where humans are exposed daily to environmental estrogens, there is concern that the development of fetal adrenal cortex, and in turn, placental estrogen production may be disrupted. This paper discusses fetal adrenal gland development, how endogenous estrogen regulates the structure and function of the fetal adrenal cortex, and highlights the potential role that early life exposure to environmental estrogens may have on the development and endocrinology of the fetal adrenal cortex.

Figure 1

The role of maternal, placental, and fetal units in the biosynthesis of estrone, estradiol, and estriol. (LDL: low-density lipoproteins; DHEA-S: dehydroepiandrosterone sulfate; OH: hydroxyl). This figure has been modified from [8, 14].

Figure 2

Illustration of the midgestation human fetal adrenal gland.

Figure 3

Representation of how placental estrogen during gestation modulates its own production. Placental estrogen has a positive and a negative feedback mechanism to ensure that physiological levels of estrogen are established. Estrogen produced by the placenta induces a positive feedback mechanism by promoting the conversion of cortisol to its biologically inactive metabolite cortisone through upregulation of 11β-HSD expression. Serum cortisone levels stimulate the fetal pituitary gland to produce ACTH which upregulates DHEA-S production from the fetal adrenal cortical zone and leads to placental estrogen production. In contrast, if placental estrogen concentrations are too high, placental estrogen can inhibit its own production by suppressing the responsiveness of the fetal adrenal zone to ACTH and lowering its production of DHEA-S. This figure has been modified from Albrecht et al. [36].