A grafted ovarian fragment rescues host fertility after chemotherapy
Authors: Batchvarov Iordan Stefanov , Taylor Rachel Williamson , Bustamante-Marín Ximena , Czerwinski Michael , Johnson Erika Segear , Kornbluth Sally , Capel Blanche 
Published: September 2016

STUDY QUESTION
Can host fertility be rescued by grafting of a fragment of a healthy ovary soon after chemotherapy?

SUMMARY ANSWER
We found that grafting a green fluorescent protein (GFP)-positive fragment from a healthy isogenic ovary to the left ovary of a chemo-treated host rescued function and fertility of the grafted host ovary, and resulted in the production of host-derived offspring as late as the sixth litter after chemotherapy (CTx) treatment, whereas none of the ungrafted controls produced a second litter.

WHAT IS KNOWN ALREADY
In women and girls undergoing chemotherapy, infertility and premature ovarian failure are frequent outcomes. There are accumulating reports of improved endocrine function after autotransplantation of an ovarian fragment, raising the possibility that the transplant is beneficial to the endogenous ovary.

STUDY DESIGN, SIZE, DURATION
We first established a CTx treatment regimen that resulted in the permanent loss of fertility in 100% of female mice of the FVB inbred strain. We grafted an isogenic ovary fragment from a healthy female homozygous for a GFP transgene to the left ovary of 100 CTx-treated hosts, and compared fertility to 39 ungrafted controls in 6 months of continuous matings, using GFP to distinguish offspring derived from the graft, and those derived from the host.

PARTICIPANTS/MATERIALS, SETTING, METHODS
Immunofluoresece and western blot analysis of 39 treated ovaries during and 15 days after CTx treatment revealed elevated apoptosis, rapid loss of granulosa cells and an increased recruitment of growing follicles. Using immunofluorescence and confocal imaging, we tracked the outcome of the grafted tissue over 4 months and its effect on the adjacent and contralateral ovary of the host.

MAIN RESULTS AND THE ROLE OF CHANCE
Fifty-three percent of grafted females produced a second litter whereas none of the ungrafted females produced a second litter. The likelihood that this could occur by chance is very low (P < 0.0001).

LIMITATIONS, REASONS FOR CAUTION
These results are shown only in mice, and whether or how they might apply to chemotherapy patients subjected to different CTx regimens is not yet clear.

WIDER IMPLICATIONS OF THE FINDINGS
Our experiments prove that rescue of a chemo-treated ovary is possible, and establish a system to investigate the mechanism of rescue and to identify the factors responsible with the long-term goal of developing therapies for preservation of ovarian endocrine function and fertility in women undergoing chemotherapy.

LARGE SCALE DATA
No large datasets were produced.

STUDY FUNDING/COMPETING INTEREST(S)
Duke University Medical Center Chancellor's Discovery Grant to BC; ESJ was supported by an NRSA 5F31CA165545; SK was supported by NIH RO1 GM08033; RWT was supported by the Duke University School of Medicine Ovarian Cancer Research Fellowship; XBM was supported by CONICYT. The authors have no conflicts of interest to declare.