By Nelson Chao, MD
2008-01-01
Dr. Chao indicated no relevant conflicts of interest.
Lee HJ, Selesniemi K, Niikura Y, et al. Bone
marrow transplantation generates immature oocytes and rescues long-term
fertility in a preclinical mouse model of chemotherapy-induced
premature ovarian failure. J Clin Oncol. 2007;25:3198-204.
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Figure 1
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Infertility is a devastating adverse effect of systemic
chemotherapy. Hematopoietic cell transplantation (HCT) is now a
treatment for chemotherapy-induced ovarian failure. HCT is the
treatment of choice for many malignancies and non-cancerous conditions.
Full donor chimerism is frequently seen in the hematopoietic system.
Recent experimental models and studies in HCT recipients have
documented donor cells in vascular endothelium, various organs, and
even in the recipient’s fingernails. This recent report from Lee, et
al. adds another twist to these observations. We have known that the
preparatory regimens for HCT are associated with near absolute ovarian
failure and infertility due to the ablative regimens utilized
(although, there have been reports of pregnancies especially in younger
women). The current dogma is that women are born with a fixed number of
oocytes that are not replenished and that the chemotherapy with or
without radiation destroys the oocytes. This dogma was challenged in
2005 when investigators reported in a controversial manuscript that
adult mice continued to produce new eggs and that these eggs could have
arisen from bone marrow cells.1
In this current study, Lee, et al. tested if and how HCT (in this case
using murine marrow cells) could restore fertility in mice treated with
chemotherapy. Females administered nonlethal doses of chemotherapy (12
mg/kg of busulfan and 120 mg/kg of cyclophosphamide) without HCT became
infertile, with the majority (10 of 13 mice) achieving three or fewer
live-birth pregnancies and none achieving six live-birth pregnancies.
On the other hand, 90 percent of the mice that received HCT one week
after the same chemotherapy achieved at least four live-birth
pregnancies, 80 percent (eight of 10 mice) achieved five pregnancies,
and 70 percent (seven of 10 mice) achieved six pregnancies. It is
important to note that in this preclinical model, the mice were six to
10 weeks old. (They were quite young.)
The data demonstrate that if HCT is performed within
one week of the chemotherapy, the procedure leads to restoration of
long-term fertility. To the investigators’ surprise, while they were
able to track a few donor-derived oocytes in the ovaries, the pups were
of recipient origin (none were of donor origin). What happened in these
studies? Is the ovary similar to the testes where the germ cells
continuously generate new gametes? The data suggest that the infusion
of donor bone marrow cells led to the rescue of a significant number of
recipient follicles. These data are reminiscent of effects of other
cell populations, such as mesenchymal stem cells, where the effect is
that of repair or recruitment of endogenous host cells that allow for
repair of the cell of interest or of the stromal support cells. The
data raise many questions. Is the infusion of bone marrow cells simply
enhancing clearance of damaged cells, decreasing inflammation,
re-establishing stromal/nurse cells, enhancing overall health,
recruiting important host cells to help with fertility, or restarting
the production of oocytes? Regardless of the answers that will come
with further research, if bone-marrow-derived cells can help preserve
fertility, this could go a long way in mitigating one of the most
devastating adverse events for young women receiving systemic
chemotherapy.
- Powell, K. Skeptics demand duplication of controversial fertility claim. Nat Med. 2005:11;911.
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