Impaired fetal growth and subsequent adult cardiovascular disease [1] provide the best known example of fetal programming of adult pathology. Fetal programming is triggered when a stimulus or insult occurs at a gestational age critical for target organ differentiation, growth or development and induces permanent changes in organ size, structure or function. Developmental insults to the fetus, such as low calorie or low protein maternal diets, program for hypertension, insulin resistance, type 2 diabetes and obesity in adulthood [2]. Fetal glucocorticoid excess also programs many of the same adult traits induced by low calorie and low protein maternal diets, and has been proposed as the common physiological mechanism translating maternal environmental factors into impaired fetal growth and fetal programming of organ function [3].
Steroid hormone excess, including glucocorticoid and sex hormone excess during fetal life, is well known to induce permanent alterations in adult female phenotype. For example, fetal androgen excess induces female uro-genital virilization along with masculinized behavior, and neural anatomy and function [4], while fetal estrogen excess results in female reproductive tract abnormalities, including clear cell adenocarcinoma of the vagina and cervix, as well as increased risk of breast cancer [5]. Less is known, however, about fetal progestin excess which can mimic androgen excess in its fetal programming outcomes [6,7]. Steroid hormones mediate their classical or genomic actions by binding to nuclear receptors and engaging a variety of molecular chaperones permitting ultimate binding of the entire complex to steroid response elements on promoters of target genes [8]. Nonclassical or non-genomic actions of steroids, including rapid changes in cytoplasmic protein function without steroid-receptor complex binding to DNA, are mediated by cell membrane receptors such as GPR30, a G-protein coupled protein mediating rapid estrogen action (estrogen membrane receptor: [9]; androgen membrane receptor: [10]; progesterone membrane receptor: [11]). Whether prenatal steroid hormone programming of postnatal ovarian function involves either or both classical and non-classical action is not known. Studies to date have assumed a classical or genomic action.
It is certainly becoming clear that exposing female fetuses to androgen excess results in enlarged adult ovaries that are polyfollicular, anovulatory and hyperandrogenic, and resemble those found in women with polycystic ovary syndrome (PCOS: monkeys: [12]; sheep: [13]). Fetal estrogen excess, on the other hand, diminishes ovarian size and function while increasing anovulation in adulthood [14-16]. This mini-review will focus on the role of fetal androgens and estrogens in determining postnatal ovarian phenotype (summarized in Table 1), and the relevance of such fetal programming to reproductive health in women.
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