Endometriosis Triggers Excessive Activation of Primordial Follicles via PI3K-PTEN-Akt-Foxo3 Pathway

Arisa Takeuchi, Kaori Koga, Erina Satake, Tomoko Makabe, Ayumi Taguchi, Mariko Miyashita, Mariko Miyashita‐Ishiwata, Masashi Takamura, Miyuki Harada, Tetsuya Hirata, Yasushi Hirota, Osamu Yoshino, Osamu Wada-Hiraike, Osamu Wada‐Hiraike, Tomoyuki Fujii, Yutaka Osuga
The Journal of clinical endocrinology and metabolism · 2019 · vol. 104(11) , pp. 5547–5554 · doi:10.1210/jc.2019-00281 · PMID:31219551 · W2951322526
article OA: bronze CC0 ⤵ 35 in-corpus citations
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Endometriosis reduces ovarian reserve by excessively activating primordial follicles through the PI3K-PTEN-Akt-Foxo3 pathway, a process reversed by inhibiting this pathway.

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Abstract

CONTEXT: The ovarian reserve is reduced in patients with endometriosis. We hypothesize that the phosphatidylinositol 3-kinase (PI3K)-phosphatase and tensin homolog deleted on chromosome 10 (PTEN) Akt-Forkhead box O (Foxo3) pathway is involved in reducing the ovarian reserve. OBJECTIVE: To elucidate the signaling mechanism by which endometriosis decreases ovarian reserve. DESIGN: Studies were conducted by using a mouse model for endometriosis and human ovaries. The endometriosis mouse model was established and ammonium trichloro (dioxoethylene-o,o') tellurate (AS101), an inhibitor of PI3K-PTEN-Akt pathway, was administered to experimental mice. Human ovaries were collected during surgery from patients with endometrioma or from patients with no ovarian pathology (control ovaries). The number of follicles and expression of Foxo3, PTEN, phosphorylated mammalian target of rapamycin and phosphorylated Akt by oocytes in primordial follicles in mouse and human ovaries were detected by immunohistochemical staining and evaluated. RESULTS: In the endometriosis mouse model, the proportion of primordial follicles was diminished, and the proportion of primary, secondary, antral, and growing follicles was increased in comparison with controls. In both mouse and human ovaries, the PI3K-PTEN-Akt-Foxo3 pathway was activated in samples from endometriosis. Administration of AS101 restored the proportion of primordial follicles in endometriotic mice ovaries to control levels. CONCLUSIONS: The current study describes the excessive activation of primordial follicles and the role of the PI3K-PTEN-Akt-Foxo3 pathway in the reduction of ovarian reserve associated with endometriosis. Our results suggest that a PI3K-PTEN-Akt inhibitor should be considered for further investigation as promising medicines for the prevention of the ovarian reserve reduction in patients with endometriosis.

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Condition tags

mesh:D004715endometriosisendometrioma

MeSH descriptors

Endometriosis Ovarian Follicle Ovary Signal Transduction Animals Disease Models, Animal Endometriosis Female Forkhead Box Protein O3 Forkhead Box Protein O3 Humans Mice Ovarian Follicle Ovary Phosphatidylinositol 3-Kinases Phosphatidylinositol 3-Kinases Phosphorylation Proto-Oncogene Proteins c-akt Proto-Oncogene Proteins c-akt PTEN Phosphohydrolase

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Cited by (35)

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