Studies repeatedly implicate a key role for fetal estrogen in the normal development of ovarian morphology and function (Table 1). Exposure of fetal female baboons to a hypoestrogenic environment, by treating their pregnant mothers with an aromatase inhibitor during mid- to late gestation, halves the numbers of primordial follicles found in fetal ovaries at late gestation [33], and drastically reduces the numbers of oocyte-granulosa cell microvilli [34] that are essential for oocyte nutrition and oocyte-granulosa cell intra-follicular communication [35]. Concomitant treatment of pregnant mothers with aromatase inhibitor and estradiol prevents the late gestation ovarian consequences induced by inhibitor treatment, alone, and specifically implicates estradiol in the normal development of ovarian follicles [33,34]. Whether these fetal ovarian deficiencies translate into abnormal adult ovarian function is not yet known.
Estrogen deficiencies that are manifest beyond fetal life, as found in estrogen receptor or aromatase knockout female mice, while confounded in terms of manifesting specific fetal programming effects, provide additional insight into discrete components of estrogen action involved in ovarian development and function. ERα receptor expression is found in theca cells and ovarian stroma, while ERβ receptor is located in granulosa cells of growing follicles [36,37]. Given their differing ovarian locations, it is not surprising that the inability of estrogen to bind to the ERα receptor (ERKO) produces different abnormalities than those found in ERβ receptor knockout (BERKO) mice. ERKO female mice exhibit an ovarian phenotype of chronic anovulation, cystic and hemorrhagic follicles, absent corpora lutea, interstitial/stromal hyperplasia, and elevated plasma estradiol and testosterone levels in the presence of luteinizing hormone (LH) excess [38]. Since gonadotropin-releasing hormone (GnRH) analogue treatment normalizes LH levels and ovarian morphology in ERKO mice, and gonadotropin ovarian hyperstimulation results in ovulation, many of the ovarian abnormalities appear secondary to the loss of ERα-mediated negative feedback regulation of LH at the hypothalamus-pituitary level [39,40]. In contrast to ERKO mice, BERKO animals are ovulatory, circulating LH levels are normal, and females give birth to live young, albeit with reduced numbers of corpora lutea and smaller litter sizes [41]. The ovarian phenotype in BERKO mice thus reflects impairments in estrogen action within the ovary related to follicle maturation and differentiation [42,43]. In aromatase knockout (ArKO) mice, devoid of estrogen synthesis rather than estrogen action, the numbers of primordial follicles are reduced apparently due to their lack of formation from fetal germ cell nests and to precocious activation of follicle growth from the primordial pool [44]. In the complete absence of estrogen, ArKO females are anovulatory, folliculogenesis is arrested at the antral stage, and the ovaries manifest hemorrhagic cysts due to endogenous hypergonadotropism [45].
Unexpectedly, the adult ovarian phenotype of double estrogen receptor knockout mice (αβERKO) is masculinized, with a concomitant reduction in oocyte number. An absence of estrogen action was previously considered relatively unimportant in female mammalian differentiation [4], except for differentiation of the brain [46]. Structures resembling testicular seminferous tubules, however, are present in the ovaries of αβERKO mice, the ovaries express two genes involved in Sertoli cell differentiation, sulfated glycoprotein-2 and Sox9, and an additional gene involved in androgen biosynthesis, 17β-Hsd-3, that is normally expressed only in Leydig cells [39,47]. There is even more dramatic masculinization of the ovaries of ArKO mice. Postpubertally, ArKO ovaries possess Sertoli and Leydig cells, express Sox9, and over-express genes coding for androgen biosynthesis [48]. Since both αβERKO and ArKO mice possess female and not male reproductive tracts, and follicles contain oocytes and not male-like germ cells, estrogen appears to play a key role in maintaining adult ovarian somatic cell phenotype [48] rather than in differentiating a fetal ovary. In humans, in comparison, while congenital aromatase deficiency leads to hyperandrogenic, multicystic ovarian phenotypes, and elevated LH and FSH levels are normalized by exogenous estrogen treatment [24], the ovaries of such women have yet to be examined for the presence of testicular structures and gene expression.
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