Reproductive function, ovarian reserve and risk of premature menopause in Dutch female childhood cancer survivors

Advances in childhood cancer treatment over the past decades have significantly
improved survival, resulting in a rapidly growing group of childhood cancer
survivors (CCS). There is much concern, however, about the effects of treatment
on reproductive potential. In females there is evidence that both chemo- and/or
radiotherapy may adversely affect ovarian function, ovarian reserve and uterine
function, clinically leading to sub- or infertility, premature menopause and/or
adverse pregnancy outcomes.
In the literature to date, ovarian function and reserve are traditionally
assessed by measurements of the pituitary and sex hormones. These markers,
however, are of limited value when aiming to assess reproductive potential and
risk of premature menopause. New techniques (ultrasound measurements of the
ovaries and serum anti-Müllerian hormone (AMH) concentrations), which may
provide a better insight into ovarian function and reserve, are currently
restricted to research or to the assisted reproduction setting and have, to our
knowledge, rarely been used in CCS. In addition, the issue of premature
menopause has only gained attention in recent years since it is only now that
the first generation of female CCS is reaching their 40*s. Only two large
questionnaire-based studies have suggested a relationship between treatment and
risk of premature menopause. However, with the current Dutch trend to postpone
childbearing to the thirties, more insight into the effect of various cancer
treatments on ovarian reserve is important, not only to prevent involuntary
childlessness but also to prevent menopause-associated conditions such as
symptoms of oestrogen deficiency, osteoporosis and cardiovascular disease.

The overall aim of this study is to examine, in adult female CCS in the
Netherlands, the effects of treatment in general, and the effects of different
types of treatment, doses of drugs, radiation sites and doses, and age at time
of treatment, on: 1) ovarian function and actual fertility; 2) ovarian reserve
and premature menopause; 3) uterine function and pregnancy outcome.
This will enable us to:
• provide adequate counseling on family planning to female CCS
• identify subgroups of female CCS who are at high risk of premature menopause
and, therefore, are potential candidates for future testing of ovarian
function and
reserve

The study, set up as a retrospective cohort study, is coordinated by the VU
university medical center (VUmc), but performed in collaboration with the Dutch
Paediatric Oncology - and Stem Cell Transplant Centers, which are united in a
nationwide collaborative group for Late Effects Registration of Childhood
Cancer (LATER). Each center screens their CCS for late effects of treatment on
a regular basis with the intention to provide early diagnosis and treatment,
and to register morbidity in survivors in order to quantify treatment-specific
risks.

The study consists of two parts: a questionnaire and a clinical part. Eligible
CCS will receive a study invitation letter explaining the questionnaire survey
and the clinical study. In the clinical study, ovarian function and reserve
will be assessed from 1) blood levels of the hypothalamic-pituitary hormones,
sex hormones, inhibin A an B, and AMH, a novel marker of ovarian reserve
exclusively expressed in the gonads; 2) ultrasound measurements of ovarian
volume and the number of antral follicles in the ovaries. Uterine size and
blood flow, also assessed by ultrasound, will evaluate uterine function while
actual fertility, pregnancy outcomes and menopausal status will be assessed
from the mailed questionnaire.

In statistical analysis we will compare the outcomes of interest between the
5-year CCS and the control group and calculate the risks associated with
specific treatments within the CCS group.

Judging from the many questions female childhood cancer survivors have at the
different Late Effects of Treatment Outpatient Clinics in the Netherlands, many
young female CCS have serious concerns about their reproductive potential.
Since relatively little research has been performed in the area of female
reproductive potential and premature menopause after treatment for childhood
cancer, many of these questions remain unanswered.

With relatively simple methods (a questionnaire, a blood sample, and a
transvaginal ultrasound of the reproductive organs), which are not associated
with high burden or risk, it is possible to assess female fertility,
reproductive function and ovarian reserve.

This increased knowledge should lead to adequate counseling on family planning
and use of hormone replacement therapy. Potentially this study will also
contribute to the improvement of current gonadotoxic treatment protocols
without compromising survival but with improved quality of life.