Oncofertility and Preservation of
Reproductive Capacity in Children and
Young Adults*
W. Hamish B. Wallace, MD, FRCP
With increasing numbers of survivors from cancer at a young age, the issue of fertility preservation has assumed
greater importance. This review describes normal ovarian and testicular function and summarizes what is known
about the effect of chemotherapy and radiotherapy on the gonads and uterus. All young patients with cancer or leu-
kemia should have their fertility prognosis discussed before the initiation of treatment. Sperm and embryo cryopre-
servation should be considered standard practice and be widely available for those at significant risk of infertility. For
prepubertal girls, ovarian tissue cryopreservation should be considered if the risk of premature menopause is high,
but for the prepubertal boy there are no established techniques in current practice. Cancer 2011;117(10 suppl):2301–
10.
V
C 2011 American Cancer Society.
KEYWORDS: gonads, uterus, chemotherapy, radiotherapy, fertility preservation.
Cancer in childhood and adolescence is rare, with approximately 1400 new cases per year diagnosed in patients aged
< 16 years in the UK, and a cumulative risk of approximately 1 in 500 by the age of 15 years. Information for teenagers
and young adults is less easy to find, but in 2005 there were 2250 cases of cancer diagnosed in individuals ages 15 to 24
years in the United Kingdom (Cancer Incidence and Mortality By Cancer Network, UK, 2005. Available at: www.nci-
n.org.uk). With long-term survival rates in excess of 70%, it is anticipated that, by the year 2010, approximately 1 in 640
to 715 members of the adult population will be a long-term survivor of childhood cancer.
1-3
Impaired fertility in both males and females and adverse pregnancy outcomes are major concerns for the increas-
ing population of survivors of childhood and young adult cancer. The challenge facing professionals is how to provide
curative treatment while balancing the potential loss or impairment of fertility. Chemotherapy regimens differ
widely in their effect on fertility. Highly gonadotoxic regimens include alkylating agents such as procarbazine. Radio-
therapy also carries a high risk when there is a direct or scatter dose to the gonad. There are an increasing number of
retrospective studies but very few prospective studies assessing gonadal function and fertility in survivors of childhood
cancer in relation to treatment received. One of the difficulties is that treatment regimens are constantly evolving,
and there is a need for many years of follow-up for children treated prepubertally to determine accurately the fertility
outcome.
In addition to uncertainty over the risk of infertility associated with different treatment regimens, techniques avail-
able for fertility preservation in children and young adults are limited and their risk-to-benefit ratio unclear. With
improved survival, there is a responsibility to improve our understanding of the risks to the gonads associated with
DOI: 10.1002/cncr.26045, Received: September 20, 2010; Revised: December 8, 2010; Accepted: December 10, 2010, Published online April 27, 2011 in Wiley
Online Library (wileyonlinelibrary.com)
Corresponding author: W. Hamish B. Wallace, MD, FRCP, Royal Hospital for Sick Children, Edinburgh EH9 1LF, Scotland, UK; Fax: (011) 00441315360430; Hamish.
wallace@nhs.net
Department of Pediatric Haematology/Oncology, Royal Hospital for Sick Children, Edinburgh, Scotland, United Kingdom
Some of the ideas and thoughts presented in this review have been published in review articles authored or coauthored by the author.
The articles in this supplement represent presentations and discussions at the ‘‘International Workshop on Adolescents and Young Adults with Cancer: Towards
Better Outcomes in Canada’’ that was held in Toronto, Ontario, March 11-13, 2010.
*Workshop on Adolescents and Young Adults with Cancer: Towards Better Outcomes in Canada, Supplement to Cancer.
Cancer May 15, 2011 2301
Original Article

successful treatment and address what can be done to pre-
serve fertility, before treatment starts, in the minority of
patients who are at high risk of infertility or premature
menopause.
Normal Ovarian Function
It is widely believed that the human ovary establishes sev-
eral million nongrowing follicles (NGF) at around 5
months of gestational age, which is followed by a rapid
decline until menopause, when approximately 1000
remain at an average age of 50 to 51 years.4 With approxi-
mately 450 ovulatory monthly cycles in the normal
human reproductive lifespan from menarche until meno-
pause, this progressive decline in NGF numbers is attrib-
uted to follicle death by apoptosis. Premature menopause
is usually considered to be the cessation of menses before
the age of 40 years. Acute ovarian failure is used by some
researchers to describe the complete cessation of ovarian
function shortly after cancer treatment.
There have been several recent reports that have
challenged this long-held understanding of mammalian
reproductive biology by reporting the presence of mitoti-
cally active germ stem cells in juvenile and adult mouse
ovaries.5,6 There is no doubt that the presence of germ
stem cells within the mammalian ovary that are capable of
neo-oogenesis is controversial.7 If we can acquire a better
understanding of the establishment and decline of the
NGF population from conception to menopause, this will
be helpful in determining if neo-oogenesis occurs as part
of normal human physiological ageing. In this regard, we
have recently identified what to our knowledge is the first
model of human ovarian reserve from conception to men-
opause that best fits the combined histological evidence.8
This model allows us to estimate the number of NGF
present in the ovary at any given age (Fig. 1). It is interest-
ing to note that this model suggests that 81% of the
variance in NGF populations is due to age alone. The
remaining 19% is because of factors other than age (eg,
smoking, body mass index, parity, and stress). We can
speculate that, as chronological age increases, factors other
than age become more important in determining the rate
at which NGF are lost through apoptosis. By further anal-
ysis of this model, we have also shown that the rate of
NGF recruitment toward maturation increases from birth
to age 14 years and then declines with age until meno-
pause. The mechanisms responsible for controlling
NGF recruitment toward maturation in the human ovary
remain unclear, but it is unlikely to be coincidental that
the maximum age at recruitment is around the onset of
menarche and the establishment of regular menstrual
cycles.
Radiation and the Hypothalamic-Pituitary-
Ovarian Axis
The ovaries may be damaged and the number of NGF
present reduced after total body irradiation (TBI), ab-
dominal irradiation, or pelvic irradiation and the extent of
the damage is related to the radiation dose, fractionation
schedule, and patient age at the time of treatment.9 Earlier
studies have shown that the human oocyte is sensitive to
radiation, with an estimated median lethal dose (LD50) of
< 2 gray (Gy).10 The number of primordial follicles pres-
ent at the time of treatment, together with the dose
received by the ovaries, will determine the fertility ‘‘win-
dow’’ and influence the age of premature ovarian failure.
Ovarian failure has been reported in 90% of patients fol-
lowed long term after TBI (10-15.75 Gy) and in 97% of
females treated with total abdominal irradiation (20-30
Gy) during childhood.11,12 Using our knowledge and
understanding of the radiosensitivity of human oocytes, it
is now possible to predict the estimated sterilizing dose af-
ter any given dose of radiotherapy at any given age based
on the application of the mathematical solution to our
model for natural oocyte decline (Fig. 2).13 This will help
clinicians to provide more accurate information when
counseling women about their fertility prospects after
treatment of childhood cancer. Those women at an esti-
mated high risk for premature menopause should be con-
sidered for fertility preservation technologies.
Gonadotropin deficiency after high-dose cranial
irradiation (> 24 Gy in the treatment of brain tumors)
may be manifest as delayed puberty or absent menses and
can be treated with hormone replacement therapy. It is
interesting to note that early puberty is often reported,
particularly in females treated with cranial radiation doses
of< 24 Gy.14 However, it has been shown that after low-
dose cranial radiotherapy (18-24 Gy), there is a subtle
decline in hypothalamic-pituitary-ovarian function as
characterized by decreased luteinizing hormone (LH)
secretion, an attenuated LH surge, and shorter luteal
phases that are likely to herald incipient ovarian failure or
be associated with early pregnancy loss.15
Cancer Treatment and Ovarian Function
The ovary is also susceptible to chemotherapy-induced
damage, particularly after treatment with alkylating agents
such as cyclophosphamide, often as part of the treatment
of Hodgkin lymphoma (HL).16,17 Ovarian damage is
Original Article
2302 Cancer May 15, 2011