Premature ovarian insufficiency: pathogenesis and therapeutic potential of mesenchymal stem cell

J Mol Med (Berl). 2021 May;99(5):637-650. doi: 10.1007/s00109-021-02055-5. Epub 2021 Feb 27.


Primary ovarian insufficiency (POI) is defined as a reduction in ovarian function before the expected age of menopause. POI is known to increase the risk of cardiovascular disorders, osteoporosis, cognitive decline, and mood disorders, resulting in a reduced quality of life. Appropriate hormone replacement for premenopausal women decreases these adverse health risks and improves quality of life for women with POI, but does not prolong life expectancy. The potential etiologies of POI include chromosomal abnormalities and genetic mutations, autoimmune factors, and iatrogenic causes, including surgery, chemotherapy, and radiation therapy. A major association is suggested to exist between reproductive longevity and the DNA damage pathway response genes. DNA damage and repair in ovarian granulosa cells is strongly associated with POI. Depletion of oocytes with damaged DNA occurs through different cell death mechanisms, such as apoptosis, autophagy, and necroptosis, mediated by the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/forkhead transcription factors 3 (FOXO3) pathway. Mesenchymal stem cells (MSCs) are characterized by the ability of self-renewal and differentiation and play an important role in the regeneration of injured tissues. Transplantation of MSCs has been shown to functionally restore ovarian reserve in a POI mouse model. Recent advances in stem cell therapy are likely to be translated to new therapeutic options bringing new hope to patients with POI. The aim of this review is to summarize the pathogenic mechanisms that involve cell death and DNA damage and repair pathways and to discuss the stem cell-based therapies as potential therapeutic options for this gynecologic pathology.

Keywords: Cell death; DNA repair; Hormone replacement therapy; Menopause; Mesenchymal stem cells; Ovary; Premature ovarian insufficiency.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Apoptosis
  • Cell Differentiation / physiology*
  • Cell Self Renewal / physiology*
  • Disease Models, Animal
  • Female
  • Forkhead Box Protein O3 / metabolism
  • Humans
  • Mesenchymal Stem Cell Transplantation / methods*
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Primary Ovarian Insufficiency / metabolism
  • Primary Ovarian Insufficiency / pathology*
  • Primary Ovarian Insufficiency / therapy*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quality of Life
  • Treatment Outcome


  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human