We undertook the present analysis to determine if there was an effect of lower dose (< 30 Gy) HPT RT on the risk of pregnancy among female participants in the CCSS who had received no or very low (< 0.1 Gy) doses of ovarian RT. We identified a decreased risk of pregnancy among those who had received HPT RT doses of ≥ 22 Gy.
The normal menstrual cycle consists of the follicular phase and the luteal phase. The onset of the luteal phase is defined by a surge of LH release which coincides with ovulation (19
). When fertilization has occurred, post-ovulatory progesterone production is maintained by pituitary LH secretion until implantation occurs, at which time placental human chorionic gonadotropin (HCG) stimulation of the corpus luteum maintains progesterone levels (20
Luteal phase deficiency or delayed endometrial maturation, resulting from a subnormal mid-cycle LH ”surge” and inadequate progesterone production from the corpus luteum (22
) may be one of the causal factors for implantation failure and early pregnancy loss (5
) and recurrent miscarriage (25
). Horta et al. demonstrated an increased frequency of low progesterone levels in the luteal phase, based on basal body temperature records, among women with a history of habitual abortion (25
). Li et al. defined the luteal phase on the basis of basal body temperature records and reported that the mid-luteal progesterone was < 30 nmol/L in 17.4% of 144 women with a history of recurrent, consecutive, first trimester miscarriages (26
). Jordan et al., utilizing the integrated serum progesterone level (sum of daily serum progesterone levels from the day after the LH surge to the day before the next menstrual period), defined luteal phase deficiency as an integrated serum progesterone level < 80 ng-days/ml. The basal body temperature record was an insensitive predictor of luteal phase deficiency in this study and timed endometrial biopsy was only modestly sensitive, identifying only 57% of those with an integrated serum progesterone level < 80 ng-days/ml (7
It is important to note however that several studies have shown that variability in the length of the luteal phase may be normal, even among fertile women (7
). Furthermore detailed data concerning endometrial histology have indicated that substantial variability in the histological characteristics of secretory phase endometrium is also normal (7
) and have demonstrated that traditional histological dating of the endometrium is not a valid clinical diagnostic tool. It has not been possible in the current questionnaire based study of childhood survivors to perform evaluation of endometrial histology, which would not be indicated based on these data. The delayed endometrial morphological development reported with LPD does not reflect circulating progesterone concentrations (5
). Low circulating luteal phase progesterone concentrations may however have important consequences upon subtle aspects of endometrial function at the time of required receptivity.
Bath et al. reported that LH excretion, evaluated using daily early morning urine samples from day 1 of a menstrual cycle for a minimum of two cycles, was decreased in acute lymphoblastic leukemia (ALL) patients treated with 24 Gy CRT compared to controls. Moreover, the luteal phase was significantly shorter in ALL patients than normal controls (12.2 ± 0.3 days versus 13.6 ± 0.4 days; p = 0.01), with a high frequency of short (≤ 11 days) luteal phases in the ALL patients (4
). These data demonstrated that luteal phase deficiency occurred in some menstrual cycles of some female ALL survivors who received prophylactic CRT.
There is some evidence that female survivors of acute leukemia are less likely to have liveborn infants. Nygaard et al. reported that the cumulative percentage of female ALL survivors who reported a pregnancy by age 25 years was 41.0% (95% CI, 21.9 to 60.1) for those treated with chemotherapy only and was 18.4% (95% CI, 3.0 to 33.8) (p = 0.043) for those whose treatment included both chemotherapy and prophylactic CRT(18 to 24 Gy) (27
). Byrne at al. reported that the unadjusted fertility rate for female survivors of ALL was significantly lower than that of their siblings. They were unable to demonstrate an effect of treatment with an alkylating agent on the first pregnancy rates, but did demonstrate that the risk of first pregnancy was decreased (relative risk=, 0.27; 95% CI, 0.09 to 0.82) (p = 0.03) among those whose age at first pregnancy was 18 to 21 years and who received prophylactic CRT (18 to 24 Gy) within two years of menarche (28
Early pregnancy loss, such as could occur in the presence of luteal phase deficiency, can be difficult to diagnose. Wilcox et al. reported that 22% (43/198) of biochemically documented pregnancies were clinically unrecognized (29
). Vaginal bleeding following pregnancy loss before six weeks of gestation was 0.4 days longer than a woman’s average menstrual bleed, but was associated with less blood loss. These events are unlikely to be recognized by the women as loss of pregnancies (30
). The impact of these events could only be demonstrated if the fertility of a sufficiently large population of women at risk due to lower dose (< 30 Gy) HPT RT, such as the participants in the CCSS, could be studied.
This study has a number of strengths. The CCSS is the largest, most thoroughly characterized cohort of survivors of cancer diagnosed during childhood or adolescence and utilizes a sibling comparison group. Thus, important questions regarding the frequency of outcomes that may be modified by treatment exposures, as well as the relationship of these exposures to significant, though uncommon, late events can be evaluated with substantial statistical power.
There are certain limitations that must be taken into account when interpreting our data. The subjects were ascertained retrospectively, with 15% of the eligible subjects lost to follow-up and 16% declining participation. Participants, however, did not differ from non-participants with regard to demographics or cancer and treatment characteristics (11
). The CCSS utilized self-administered questionnaires for ascertainment of pregnancy-related outcomes.
We have demonstrated that fertility is impaired in female CCS who received modest doses (22 to 27 Gy) of HPT RT and no or very low (< 0.1 Gy) doses of ovarian RT. The results suggest that an additional mechanism, luteal phase deficiency, may contribute to infertility. These data may be utilized to counsel patients and their parents prior to initiation of treatment and to guide evaluation of infertility in female CCS who received low-dose HPT irradiation.