Mayer Loretta P, Devine Patrick J, Dyer Cheryl A, Hoyer Patricia B
Department of Physiology, University of Arizona, Tucson, Arizona 85724, USA.
Biol Reprod. 2004 Jul;71(1):130-8. doi: 10.1095/biolreprod.103.016113. Epub 2004 Mar 3.
The follicle-depleted postmenopausal ovary is enriched in interstitial cells that produce androgens. This study was designed to cause follicle depletion in mice using the industrial chemical, 4-vinylcyclohexene diepoxide (VCD), and characterize the steroidogenic capacity of cells in the residual ovarian tissue. From a dose-finding study, the optimal daily concentration of VCD was determined to be 160 mg/kg. Female B6C3F(1) immature mice were treated daily with vehicle control or VCD (160 mg kg(-1) day(-1), 15 days, i.p.). Ovaries were removed and processed for histological evaluation. On Day 15 following onset of treatment, primordial follicles were depleted and primary follicles were reduced to about 10% of controls. On Day 46, primary follicles were depleted and secondary and antral follicles were reduced to 0.7% and 2.6% of control, respectively. Seventy-five percent of treated mice displayed disruptions in estrous cyclicity. All treated mice were in persistent diestrus (acyclic) by Day 58. Plasma FSH levels were increased (P < 0.05) relative to controls on Day 37 and had plateaued by Day 100. Relative to age-matched cyclic controls, by Day 127, the significant differences in VCD-treated mice included reduced ovarian and uterine weights, elevated plasma LH and FSH, and reduced plasma progesterone and androstenedione. Furthermore, plasma 17beta-estradiol levels were nondetectable. Unlike controls, immunostaining for LH receptor, and the high density lipoprotein receptor (SR-BI), was diffuse in ovarian sections from VCD-treated animals. Ovaries from Day 120 control and VCD-treated animals were dissociated and dispersed cells were placed in culture. Cultured cells from ovaries of VCD-treated animals produced less LH-stimulated progesterone than control cells. Androstenedione production was nondetectable in cells from cyclic control animals. Conversely, cells from VCD-treated animals produced androstenedione that was doubled in the presence of insulin and LH (1 and 3 ng/ml). Collectively, these data demonstrate that VCD-mediated follicle depletion results in residual ovarian tissue that may be analogous to the follicle-deplete postmenopausal ovary. This may serve as a useful animal model to examine the dynamics of follicle loss in women as ovarian senescence ensues.
卵泡耗竭的绝经后卵巢富含产生雄激素的间质细胞。本研究旨在使用工业化学品4 - 乙烯基环己烯二环氧化物（VCD）使小鼠卵泡耗竭，并表征残留卵巢组织中细胞的类固醇生成能力。通过剂量探索研究，确定VCD的最佳每日浓度为160 mg/kg。雌性B6C3F(1)未成熟小鼠每天接受载体对照或VCD（160 mg kg⁻¹天⁻¹，共15天，腹腔注射）处理。取出卵巢并进行组织学评估。在治疗开始后的第15天，原始卵泡耗竭，初级卵泡减少至对照的约10%。在第46天，初级卵泡耗竭，次级卵泡和窦状卵泡分别减少至对照的0.7%和2.6%。75%的处理小鼠出现发情周期紊乱。到第58天，所有处理小鼠均处于持续间情期（无周期）。与对照组相比，血浆促卵泡生成素（FSH）水平在第37天升高（P < 0.05），并在第100天趋于平稳。与年龄匹配的有周期对照组相比，到第127天，VCD处理小鼠的显著差异包括卵巢和子宫重量减轻、血浆促黄体生成素（LH）和FSH升高、血浆孕酮和雄烯二酮降低。此外，血浆17β - 雌二醇水平无法检测到。与对照组不同，VCD处理动物卵巢切片中促黄体生成素受体和高密度脂蛋白受体（SR - BI）的免疫染色呈弥漫性。将第120天对照和VCD处理动物的卵巢解离，将分散的细胞进行培养。VCD处理动物卵巢的培养细胞产生的促黄体生成素刺激的孕酮比对照细胞少。有周期对照动物细胞中未检测到雄烯二酮的产生。相反，VCD处理动物的细胞产生雄烯二酮，在存在胰岛素和促黄体生成素（1和3 ng/ml）时增加一倍。总体而言，这些数据表明VCD介导的卵泡耗竭导致残留卵巢组织，可能类似于卵泡耗竭的绝经后卵巢。这可作为一个有用的动物模型，用于研究女性卵巢衰老过程中卵泡丢失的动态变化。
