The onset of puberty and menarche marks a time of rapid linear growth, sexual development, and transition from childhood to maturity. As a result, children experience the appearance of secondary sexual characteristics, the adolescent growth spurt, and the establishment of fertility. This occurs as a consequence of CNS maturation and release of pituitary gonadotropins resulting in stimulation of gonadal end organs (testis/ovaries).21
The diagnosis and treatment of a childhood CNS malignancy prior to the onset of puberty has the potential to profoundly impact the timing and the tempo of both puberty and menarche. The clinical impact is particularly important as patients with early onset of puberty are at increased risk for premature epiphyseal fusion and shortened final height. The risk of short stature is compounded by the increased incidence of growth hormone deficiency in this population.22, 23
Large epidemiologic studies have identified small increases in risk for breast cancer among girls with early onset of puberty24
. Additionally, girls with true precocious puberty are at increased risk for a number of behavioral problems, increased social withdrawal, and potential sexual abuse.24, 25
Patients with delayed puberty and menarche are at increased risk for low bone mineral density and long-term risk for osteoporosis, in addition to incomplete sexual development and reduced fertility.26
Early identification of the association between CNS directed radiotherapy and early onset of puberty occurred in populations treated for childhood ALL. However, far less research has occurred describing alterations of pubertal and menarchal timing in patients with CNS tumors, who typically receive higher doses of RT than children treated for ALL. Investigations to date have been limited to case series or small retrospective studies with limited ability to identify risk factors for early maturity.9, 27-29
Brauner et. al., identified the risk for precocious puberty in patients with CNS tumors following cranial radiation doses of 24-45 Gy delivered to the hypothalamic-pituitary region in a case series of 6 patients.27
Five of these six children, in addition, had growth hormone deficiency, and a blunted growth spurt resulting in extremely short stature. Ogilvy-Stuart et. al., followed by reporting on a small retrospective cohort of 46 CNS tumor survivors suggesting that onset of puberty occurred at an earlier age in both sexes compared to population norms.9
Similarly, Oberfield, et. al., has reported, in a retrospective cohort of 36 patients, that females, but not males, experienced early onset of puberty after treatment for CNS tumors. Thus, the current study represents the largest population of CNS tumor survivors evaluated for early onset of menarche to date and includes a large sibling cohort for comparison. Our data demonstrate that female survivors of CNS tumor have a greater than fourteen-fold risk of developing menarche before the age of 10 years, compared to siblings.
Previously, both Ogilvy-Stuart et al and Oberfield et al, suggested that younger age at diagnosis was a significant risk factor for premature puberty. Our data further corroborate this increased risk for early puberty in younger children with CNS tumors. More difficult to determine in these smaller studies, however, is whether there is an effect of increasing doses of radiotherapy (dose-response effect) on the risk of early menarche. Our combined analysis of both ALL and CNS tumor populations provides data on over 1,000 patients who received a broad spectrum of radiation doses for analysis. It is clear from these data that a wide range of doses of RT to the H-P axis is associated with an increased risk of early menarche; the threshold for this effect lies somewhere below 20 Gy. However, while the test for trend suggests a statistically significant dose-response relationship exists, the small increase in risk across these dose ranges may be clinically insignificant.
Whole brain and/or focal radiation to the H-P axis places patients at risk not only for early puberty, but also for the gradual onset of hypothalamic-pituitary failure which may result in gonadotropin deficiency and subsequent pubertal delay.30
A previous evaluation of 251 patients, suggested a greater incidence of gonadotropin deficiency in patients who received 35-45 Gy compared to those who received only 20 Gy.31
Additionally, females who receive spinal radiation may have added risk of delayed puberty or menarche due to direct gonadal damage20
. In addition to quantifying this risk for delayed menarche among survivors of CNS tumors at greater than six-fold, our findings document that cranial RT doses >50 Gy confer the greatest risk for delayed menarche. The addition of spinal radiation augments this risk, such that patients who received both >50 Gy to the H-P axis and spinal RT have a twelve-fold increase in their risk of delayed menarche compared to patients with CNS tumors who did not receive RT. While exposure to alkylating agents is known to increase the risk of gonadal damage, no such association was noted in this study, likely due to the small number of participants who received alkylators for treatment of CNS tumors in this era32
The self-report nature of data collection may be a limitation of this study, although previous work suggests women's recall of age at menarche is generally quite accurate.33
Additionally, recall of menarche is better than that of other pubertal milestones.34
However, lack of data on other pubertal milestones prevented assessment of tempo of female puberty. Also, 17% of the eligible population was lost to follow-up and an additional 18% refused participation creating the potential for bias within this analysis. However, previous analysis has determined few differences between participants in the CCSS cohort, non-participants, and those lost to follow-up reducing the potential for participation bias14
. An additional limitation was our inability to define the precise location of tumor in relation to the H-P axis, and the extent of surgical intervention in this cohort. Thus, it is unclear to what extent tumor location and surgical resection may have independently affected timing of menarche. Finally, this analysis is unable to determine the contribution of chemotherapy, most significantly alkylating agents, to altered timing of menarche, due to the relatively few number of survivors who received chemotherapy during this treatment era (1970-1986). We are currently expanding the CCSS cohort to include patients diagnosed between 1987-1999, a period in which chemotherapy was used increasingly for treatment of CNS tumors. Future investigations of this cohort will be needed to determine independent risk for altered timing of menarche associated with these agents.
In summary, radiation used for treatment of CNS tumors confers a significant risk for both early and delayed timing of menarche. Thus, it is imperative that clinicians following these patients anticipate this increased propensity for altered pubertal timing in those at greatest risk. Advances in the delivery of RT to the CNS over the last decade, with the use of techniques such as conformal RT and proton beam RT, may limit the dose exposure to the H-P axis and reduce the subsequent risk for some of these abnormalities. Future investigation of large cohorts of survivors of childhood CNS tumors will be necessary to confirm these expectations.