Unlaid Eggs: Ovarian Damage after Low-Dose Radiation

Abstract

The total body irradiation of lymphomas and co-irradiation in the treatment of adjacent solid tumors can lead to a reduced ovarian function, premature ovarian insufficiency, and menopause. A small number of studies has assessed the radiation-induced damage of primordial follicles in animal models and humans. Studies are emerging that evaluate radiation-induced damage to the surrounding ovarian tissue including stromal and immune cells. We reviewed basic laboratory work to assess the current state of knowledge and to establish an experimental setting for further studies in animals and humans. The experimental approaches were mostly performed using mouse models. Most studies relied on single doses as high as 1 Gy, which is considered to cause severe damage to the ovary. Changes in the ovarian reserve were related to the primordial follicle count, providing reproducible evidence that radiation with 1 Gy leads to a significant depletion. Radiation with 0.1 Gy mostly did not show an effect on the primordial follicles. Fewer data exist on the effects of radiation on the ovarian microenvironment including theca-interstitial, immune, endothelial, and smooth muscle cells. We concluded that a mouse model would provide the most reliable model to study the effects of low-dose radiation. Furthermore, both immunohistochemistry and fluorescence-activated cell sorting (FACS) analyses were valuable to analyze not only the germ cells but also the ovarian microenvironment.

Keywords: fertility preservation; follicle count; low-dose radiation; mouse model; oocyte; ovarian damage.

Figure 1

Flow diagram displaying the included searches of databases concerning the mouse model.

Figure 2

Top: Overview of already established markers concerning ovarian damage including proliferation, apoptosis, differentiation and remodeling, DNA damage, fertility, immune system, cell cycle progression, tumor progression, tumor suppression, chromosomes, adipogenesis, and AKT/mTOR pathway after radiation in human and mouse models. Bottom: Development from PMF pool to young adulthood in mice and humans and human folliculogenesis and detail in PMF pool in humans at birth. Adapted from [54,55,56,57,58,59,60,61,62].