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This mini-review focused on the role of fetal androgens and estrogens in …

Biology Articles » Reproductive Biology » Contributions of androgen and estrogen to fetal programming of ovarian dysfunction » Fetal androgen deficiency

Fetal androgen deficiency
- Contributions of androgen and estrogen to fetal programming of ovarian dysfunction

Within the ovary, androgens are synthesized mainly within theca cells and the ovarian stroma, while mural granulosa cells convert theca-cell derived androstenedione into testosterone and dihydrotestosterone (DHT). Since androgen receptors are expressed in the fetal ovary [17] and in oocytes, granulosa and theca cells, and ovarian stroma in the mature, adult ovary [18-20], androgen action can effect many components of ovarian development and cyclical function [21].

Discrete experimental induction of fetal androgen deficiency induced by the administration of flutamide to pregnant rhesus monkeys during either early or late gestation fails to alter age at menarche and at first ovulation in exposed female fetuses [22]. Fetal deficiencies in female androgen biosynthesis induced by congenital defect or experimentally induced knockout of mitochondrial steroidogenic acute regulatory protein (StAR; [23]), and steroid biosynthetic enzyme, P450c17 [24,25], however, produce obvious defects in ovarian function, but androgen deficiencies also persist into postnatal life. Androgen deficiencies in adult female StAR knockout mice result in undectectable circulating levels of testosterone, extremely low levels of progesterone and corticosterone, and a poorly developed reproductive tract, indicative of hypoestrogenism [23]. Not surprisingly, the ovaries fail to show major follicle development or the presence of corpora lutea, but they do become enlarged due to hypertrophy of the stroma under endogenous hypergonadotropic over-stimulation. Similar to the androgen deficiency produced by defective or absent StAR, women deficient in the biosynthetic enzyme, P450c17, show marked impairment in androgenic, estrogenic and glucocorticoid biosynthesis [26], as well as anovulatory, hypergonadotropic hypogonadism. The ovaries are devoid of major follicle development, but experimentally-induced gonadotropic ovarian hyperstimulation for in vitro fertilization (IVF) induces the growth of dominant follicles that yield fertilizable oocytes at retrieval. None of the fertilized oocytes, however, progress beyond the 7-cell embryonic stage [24], and fail to reach developmental stages when they are completely dependent on the embryonic genome [27]. Such impaired embryonic developmental competence probably reflects a sub-optimal intra-follicular estrogenic environment due to deficient production of androgen precursors for estrogen biosynthesis by mural granulosa cells [28].

When life-long androgen deficiencies do not concomitantly result in fetal estrogen deficiencies, such as in androgen receptor knockout (ARKO) female mice, there are only subtle impairments in adult ovarian function (Table 1). While ovarian follicle counts are similar to those in wild type mice, ARKO mice have fewer estrus cycles, smaller litter sizes, yield fewer oocytes upon gonadotropic hyperstimulation, and exhibit a diminished granulosa cell layer within follicles and smaller-sized corpora lutea [29]. Androgens may thus play important roles in the adult ovary supporting ovarian follicle and oocyte maturation, as found by Bondy and colleagues [30-32] when they treated adult female rhesus monkeys with testosterone. Unlike estrogens, however, androgens are not apparently required during fetal life for normal ovarian development.

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