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An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
The ovarian phenotype of the aromatase knockout (ArKO) mouse
K L Britt1, A E Drummond, M Dyson
1Prince Henry's Institute of Medical Research, P.O. Box 5152, Vic. 3168, Clayton, Australia.
Abstract:
Targeted disruption of exon 9 of the cyp19 gene gives rise to a non-functional aromatase enzyme incapable of converting androgens to oestrogens. The aromatase knockout (ArKO) mouse is, thus, characterised by a dysfunctional pituitary-gonadal axis, which manifests in non-detectable levels of oestrogen in serum. These mice also exhibit elevated levels of circulating gonadotrophins (luteinising hormone (LH) and follicle stimulating hormone (FSH)) and testosterone. The ArKO mouse is infertile due to folliculogenic disruption and a failure to ovulate. The age-dependent ovarian phenotype revealed a block in follicular development at the antral stage and a complete absence of corpora lutea. By 21-23 weeks of age haemorrhagic cystic follicles were present and by 1 year there were abnormal follicles, an absence of secondary and antral follicles and atretic primary follicles. Interstitial tissue remodelling was extensive and exemplified by an increase in collagen deposition and an influx of macrophages, coincident with the loss of follicles. In mice, maintained on a soy-free and, thus, phytoestrogen-free diet, the ovarian phenotype was accelerated and exacerbated. In conclusion, the ovarian phenotype of the ArKO mouse can be attributed to the altered hormonal environment brought about by the absence of aromatase and the failure of androgens to be converted to oestrogens in the presence of elevated gonadotropins.
Insights
Aromatase knockout mice lack functional aromatase, leading to infertility and disrupted ovarian development due to altered hormone levels. Their ovarian phenotype is worsened by phytoestrogen-free diets.
Area of Science:
- Reproductive biology
- Endocrinology
- Genetics
Background:
- Aromatase (encoded by the CYP19 gene) is crucial for converting androgens to estrogens.
- Estrogens play a vital role in the female reproductive axis and ovarian function.
- Aromatase knockout (ArKO) mouse models provide a tool to study estrogen deficiency in vivo.
Purpose of the Study:
- To investigate the reproductive and ovarian consequences of aromatase deficiency in ArKO mice.
- To characterize the hormonal milieu and ovarian phenotype in ArKO mice.
- To assess the impact of phytoestrogen absence on the ArKO ovarian phenotype.
Main Methods:
- Generation of aromatase knockout (ArKO) mice via targeted disruption of the CYP19 gene.
- Analysis of serum hormone levels, including estrogens, gonadotropins (LH, FSH), and testosterone.
- Histological examination of ovarian morphology and follicular development at various ages.
- Assessment of the impact of a phytoestrogen-free diet on ovarian phenotype.
Main Results:
- ArKO mice exhibited non-detectable serum estrogen levels and elevated LH, FSH, and testosterone.
- Infertility in ArKO mice was linked to disrupted folliculogenesis and lack of ovulation.
- Ovarian phenotype included blocked follicular development at the antral stage, absence of corpora lutea, and progressive follicular degeneration.
- Phytoestrogen-free diet accelerated and exacerbated the ovarian abnormalities in ArKO mice.
Conclusions:
- The ArKO mouse model demonstrates that aromatase absence leads to a dysfunctional pituitary-gonadal axis and infertility.
- The observed ovarian phenotype is a direct consequence of the altered hormonal environment, specifically the lack of estrogen synthesis from androgens and elevated gonadotropins.
- Dietary phytoestrogens can modulate the severity of reproductive and ovarian defects in estrogen-deficient models.
