Dehydroepiandrosterone modulates the PTEN/PI3K/AKT signaling pathway to alleviate 4-vinylcyclohexene diepoxide-induced premature ovarian insufficiency in rats

Exp Anim. 2024 Jul 9;73(3):319-335. doi: 10.1538/expanim.23-0179. Epub 2024 Mar 16.


Dehydroepiandrosterone (DHEA) is frequently integrated as an adjuvant in over a quarter of controlled ovarian hyperstimulation (COH) protocols, despite the ongoing debate regarding its impact. This study aimed to evaluate the efficacy and mechanism of action of DHEA on ovarian follicular development and ovarian response in rats with varying ovarian reserves. The study involved 75 rats categorized into 15 distinct groups. The ovarian tissues of rats in both the normal ovarian reserve group and the premature ovarian insufficiency (POI) group, induced by 4-vinylcyclohexene diepoxide (VCD) injection, were subjected to histomorphological and biochemical analyses following the administration of DHEA, either alone or in combination with COH. Follicle counting was performed on histological sections obtained from various tissues. Serum concentrations of anti-Müllerian hormone (AMH) and the quantification of specific proteins in ovarian tissue, including phosphatase and tensin homolog of chromosome 10 (PTEN), phosphoinositide 3-kinase (PI3K), phosphorylated protein kinase B (pAKT), cyclooxygenase 2 (COX-2), caspase-3, as well as assessments of total antioxidant status and total oxidant status, were conducted employing the ELISA method. The impact of DHEA exhibited variability based on ovarian reserve. In the POI model, DHEA augmented follicular development and ovarian response to the COH protocol by upregulating the PTEN/PI3K/AKT signaling pathway, mitigating apoptosis, inflammation, and oxidative stress, contrary to its effects in the normal ovarian reserve group. In conclusion, it has been determined that DHEA may exert beneficial effects on ovarian stimulation response by enhancing the initiation of primordial follicles and supporting antral follicle populations.

Keywords: 4-vinylcyclohexene diepoxide; controlled ovarian hyperstimulation; dehydroepiandrosterone; phosphatase and tensin homolog of chromosome 10/phosphoinositide 3-kinase/protein kinase B (PTEN/PI3K/AKT) signaling pathway; premature ovarian insufficiency.

MeSH terms

  • Animals
  • Cyclohexenes* / pharmacology
  • Dehydroepiandrosterone* / administration & dosage
  • Dehydroepiandrosterone* / pharmacology
  • Female
  • Ovarian Follicle / drug effects
  • Ovarian Follicle / metabolism
  • Ovarian Reserve / drug effects
  • Ovary / drug effects
  • Ovary / metabolism
  • PTEN Phosphohydrolase* / metabolism
  • Phosphatidylinositol 3-Kinases* / metabolism
  • Primary Ovarian Insufficiency* / chemically induced
  • Primary Ovarian Insufficiency* / metabolism
  • Proto-Oncogene Proteins c-akt* / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction* / drug effects
  • Vinyl Compounds*


  • 4-vinyl-1-cyclohexene dioxide
  • PTEN Phosphohydrolase
  • Vinyl Compounds
  • Cyclohexenes
  • Proto-Oncogene Proteins c-akt
  • Dehydroepiandrosterone
  • Phosphatidylinositol 3-Kinases
  • Pten protein, rat