Toothaker Jessica M, Roosa Kristen, Voss Alexandra, Getman Suzanne M, Pepling Melissa E
Department of Biology, Syracuse University, Syracuse, NY, USA.
Department of Biology, SUNY Oneonta, Oneonta, NY, USA.
Endocr Res. 2022 Feb-May;47(2):45-55. doi: 10.1080/07435800.2021.2011907. Epub 2021 Dec 4.
Assembly of oocytes into primordial follicles is essential for establishing the ovarian reserve required for female fertility. In mice, this process begins during embryonic development. Primordial germ cells form cysts by incomplete mitosis until 13.5 days post coitum (dpc). These cysts break apart just before birth. Some oocytes undergo apoptosis while surviving oocytes are enclosed by granulosa cells to form primordial follicles. Cyst breakdown and primordial follicle formation were previously shown to be inhibited by estradiol and estrogenic compounds in vitro, suggesting that estrogen is important for regulation of this process.
To determine the role of fetal estrogen in cyst breakdown and follicle formation these processes were quantified in aromatase deficient (ArKO) mice between 17.5 dpc and postnatal day (PND) 9. Ovaries of ArKO mice were also examined at 2-week intervals to determine if folliculogenesis is affected by lack of estrogen and the age at which the typical ArKO ovarian phenotype first appears.
Oocyte number, follicle assembly, and follicle development in ArKO mice did not differ from controls between 17.5 dpc and PND 9. At 2 weeks, ArKO ovaries still had oocytes in cysts while all oocytes were enclosed in follicles in wild type ovaries. From 2 to 8 weeks oocyte numbers were similar in all genotypes with a significant reduction at 10 weeks in ovaries from homozygous mutants. Abnormal hemorrhagic follicles were observed starting at 6 weeks, earlier than previously reported and hemosiderin deposits were found starting at 8 weeks.
These results suggest that a lack of fetal estrogen does not affect oocyte survival or the rate of primordial follicle formation perinatally, and maternal estrogen or other signals are the chief regulators. The appearance of abnormal hemorrhagic follicles observed as early as 6 weeks suggests that the lack of estrogen becomes problematic at this time.
卵母细胞组装成原始卵泡对于建立女性生育所需的卵巢储备至关重要。在小鼠中，这个过程始于胚胎发育期间。原始生殖细胞通过不完全有丝分裂形成囊肿，直到妊娠后13.5天（dpc）。这些囊肿在出生前破裂。一些卵母细胞发生凋亡，而存活的卵母细胞被颗粒细胞包裹形成原始卵泡。先前在体外研究表明，雌二醇和雌激素化合物可抑制囊肿破裂和原始卵泡形成，这表明雌激素对这一过程的调节很重要。
为了确定胎儿雌激素在囊肿破裂和卵泡形成中的作用，在17.5 dpc至出生后第9天（PND）对芳香化酶缺陷（ArKO）小鼠的这些过程进行了量化。还每隔2周检查一次ArKO小鼠的卵巢，以确定卵泡发生是否受雌激素缺乏的影响以及典型ArKO卵巢表型首次出现的年龄。
在17.5 dpc至PND 9期间，ArKO小鼠的卵母细胞数量、卵泡组装和卵泡发育与对照组无差异。在2周时，ArKO卵巢中仍有处于囊肿中的卵母细胞，而野生型卵巢中的所有卵母细胞都被包裹在卵泡中。从2周到8周，所有基因型的卵母细胞数量相似，纯合突变体卵巢在10周时显著减少。从6周开始观察到异常出血性卵泡，比先前报道的更早，从8周开始发现含铁血黄素沉积。
这些结果表明，胎儿雌激素的缺乏在围产期不影响卵母细胞存活或原始卵泡形成率，母体雌激素或其他信号是主要调节因子。早在6周就观察到异常出血性卵泡的出现，这表明此时雌激素缺乏成为问题。
