Research Paper Volume 12, Issue 10 pp 9686—9713

Ovulation and ovarian wound healing are impaired with advanced reproductive age

Jamie N. Mara1, , Luhan T. Zhou1, , Megan Larmore2, , Brian Johnson2, , Rebecca Ayiku1, , Farners Amargant1, , Michele T. Pritchard3, , Francesca E. Duncan1, ,

  • 1 Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
  • 2 Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA
  • 3 Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA

Received: December 30, 2019       Accepted: March 31, 2020       Published: May 14, 2020
How to Cite

Copyright © 2020 Mara et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Aging is associated with reduced tissue remodeling efficiency and increased fibrosis, characterized by excess collagen accumulation and altered matrix degradation. Ovulation, the process by which an egg is released from the ovary, is one of the most dynamic cycles of tissue wounding and repair. Because the ovary is one of the first organs to age, ovulation and ovarian wound healing is impaired with advanced reproductive age. To test this hypothesis, we induced superovulation in reproductively young and old mice and determined the numbers of eggs ovulated and corpora lutea (CLs), the progesterone producing glands formed post-ovulation. Reproductively old mice ovulated fewer eggs and had fewer CLs relative to young controls. Moreover, reproductively old mice exhibited a greater number of oocytes trapped within CLs and expanded cumulus oocyte complexes within unruptured antral follicles, indicative of failed ovulation. In addition, post-ovulatory tissue remodeling was compromised with age as evidenced by reduced CL vasculature, increased collagen, decreased hyaluronan, decreased cell proliferation and apoptosis, impaired wound healing capacity, and aberrant morphology of the ovarian surface epithelium (OSE). These findings demonstrate that ovulatory dysfunction is an additional mechanism underlying the age-related loss of fertility beyond the reduction of egg quantity and quality.


CL: Corpus luteum, singular, corpora lutea, plural; ECM: Extracellular Matrix; OSE: Ovarian Surface Epithelium; IHC: Immunohistochemistry; PSR: Picrosirius Red; HABP: Hyaluronan Binding Protein; CC3: Cleaved Caspase 3.