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Abnormal timing of menarche in survivors of central nervous system tumors
A Report From the Childhood Cancer Survivor Study
Version of Record online: 23 MAR 2009
Copyright © 2009 American Cancer Society
Volume 115, Issue 11, pages 2562–2570, 1 June 2009
How to Cite
Armstrong, G. T., Whitton, J. A., Gajjar, A., Kun, L. E., Chow, E. J., Stovall, M., Leisenring, W., Robison, L. L. and Sklar, C. A. (2009), Abnormal timing of menarche in survivors of central nervous system tumors. Cancer, 115: 2562–2570. doi: 10.1002/cncr.24294
- Issue online: 20 MAY 2009
- Version of Record online: 23 MAR 2009
- Manuscript Accepted: 26 NOV 2008
- Manuscript Revised: 24 NOV 2008
- Manuscript Received: 22 OCT 2008
- National Cancer Institute. Grant Number: U24 CA55727
- American Lebanese Syrian Associated Charities
- late effects;
- brain tumor;
Children who receive high-dose radiotherapy to the hypothalamic-pituitary (H-P) axis may be at risk for both early and late puberty. To the authors' knowledge, data regarding the risk of altered timing of menarche after higher dose radiotherapy (RT), as used in the treatment of central nervous system (CNS) tumors, are limited.
The authors evaluated 235 female survivors of CNS tumors, diagnosed between 1970 and 1986, and >1000 sibling controls who were participants in the Childhood Cancer Survivor Study, and provided self-reported data concerning age at menarche.
Survivors of CNS tumors were more likely to have onset of menarche before age 10 years compared with their siblings (11.9% vs 1.0%) (odds ratio [OR], 14.1; 95% confidence interval [95% CI], 7.0-30.9). Of the 138 survivors who received RT to the H-P axis, 20 (14.5%) had onset of menarche before age 10 years, compared with 4.3% of those who did not receive RT (OR, 3.8; 95% CI, 1.2-16.5). Age ≤4 years at the time of diagnosis was associated with an increased risk (OR, 4.0; 95% CI, 1.7-10.0) of early menarche. In addition, survivors of CNS tumors were more likely than siblings to have onset of menarche after age 16 years (10.6% vs 1.9%) (OR, 6.6; 95% CI, 3.4-11.4). Doses of RT to the H-P axis >50 gray OR, 9.0; 95% CI, 2.3-59.5) and spinal RT conferred an increased risk of late menarche, as did older age (>10 years) at the time of diagnosis (OR, 3.0; 95% CI, 1.3-7.0).
Survivors of CNS tumors are at a significantly increased risk of both early and late menarche associated with RT exposure and age at treatment. Cancer 2009. © 2009 American Cancer Society.
The onset of puberty and menarche is a complex process, which is under the regulation of the hypothalamic-pituitary (H-P) axis. Damage to the H-P axis can alter the timing of both puberty and menarche in addition to the other hormonal systems regulated by the H-P axis. Children with central nervous system (CNS) tumors in proximity to the H-P axis, and/or children who undergo a surgical resection or receive radiotherapy (RT) in this region, are at particular risk for injury. Growth hormone deficiency is the most common outcome after hypothalamic injury; however, central hypothyroidism is common as well.
The strongest evidence that cranial radiation causes early sexual development and early menarche comes from extensive acute lymphoblastic leukemia (ALL) literature in which cranial RT in doses between 18 and 24 gray (Gy) were used for CNS prophylaxis of disease.1-8 However, to our knowledge few studies to date have addressed the effect of radiation on the timing of puberty or menarche in female survivors of CNS tumors. It appears that although lower doses of cranial radiation (18-24 Gy), such as those used in the treatment of childhood ALL, increase the incidence of early puberty and menarche, it is less clear whether higher doses of radiation, such as those used to treat children with CNS tumors, cause increased rates of early pubertal development.9-12 In addition, high-dose cranial RT may cause central hypogonadism, and patients who receive craniospinal RT are at risk for primary hypogonadism, both of which increase the risk for delayed or absent menarche.8, 13 Therefore, we conducted an analysis of the effect of RT on timing of menarche in survivors of pediatric CNS malignancies within the Childhood Cancer Survivor Study (CCSS) population to determine the incidence of both early and delayed menarche after CNS-directed RT among survivors of childhood CNS tumors.
MATERIALS AND METHODS
The CCSS Cohort
The CCSS is a retrospective cohort of children and adolescents treated for childhood cancer at 26 collaborating institutions in the US and Canada. Eligibility criteria for the cohort included diagnosis of childhood cancer with initial treatment received at 1 of the collaborating CCSS institutions between January 1, 1970 and December 31, 1986; a diagnosis of cancer before age 21 years; and survival for at least 5 years from the time of diagnosis of leukemia, CNS cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, renal tumor, neuroblastoma, soft tissue sarcoma, or bone tumor.
Beginning in 1994, all participants (or parents of participants aged <18 years) completed a self-administered baseline questionnaire or telephone interview to collect demographic data and information regarding medication usage, physician-diagnosed medical conditions, and health-related behaviors, in addition to recurrence of the primary malignancy or the occurrence of a second malignant neoplasm. Since that time, a follow-up questionnaire was sent to all participants asking detailed information regarding menstrual history, including if they had ever had a menstrual period (yes/no/unsure), age at menarche, and ascertainment of medications required to induce menses. Medical records were abstracted for treatment information including surgical procedures, chemotherapy, and RT exposure. Details of this cohort and the study design have been previously described.14 The institutional review board at each participating center reviewed and approved the CCSS protocol and documents sent to participants.
Of the 20,691 participants eligible for the cohort, 2887 (14.0%) were survivors of CNS tumors. Of these, 491 (17.0%) could not be located and therefore were lost to follow-up, 511 (17.7%) refused to participate, and 9 (0.3%) were unable to participate because of language difficulties, resulting in 1876 participants with CNS tumors. Participants, nonparticipants, and those lost to follow-up were similar with regard to sex, cancer diagnosis, age at diagnosis, age when cohort was assembled, and type of cancer treatment.14, 15
A random sample of siblings of all CCSS participating cases was invited to participate to provide a comparison population that was neither diagnosed with nor treated for cancer. In the setting in which a case had multiple siblings, the sibling of closest age to the case was recruited. Of 6098 selected siblings, 3899 (63.9%) (of both sexes) participated in CCSS.
Ascertainment of Cases and Controls
Of the 1876 participants identified to have primary CNS tumors, 843 (44.9%) were female. Of these females, 557 (66.1%) completed both baseline and follow-up surveys, and had complete menarche and RT exposure data available. Of these, 136 experienced menarche before cancer diagnosis, resulting in 421 females being available for evaluation of early and late onset of menarche (Fig. 1).
Evaluation for Early Menarche
Early menarche was defined as menarche before 10 years of age. Of the 421 females available for evaluation, 92 participants were excluded because their cancer was diagnosed at or after age 10 years, 37 females were excluded because of recurrence/progression of the primary malignancy or the diagnosis of a second malignancy before age 10 years or at an unknown age, and 57 were excluded because medical therapy to induce menarche was used at an unknown age, resulting in 235 participants being eligible for evaluation of early menarche
Evaluation for Late Menarche
Late menarche was defined as onset of menarche at age ≥16 years. Of the 421 females available for evaluation, 48 were excluded because of recurrence/progression of the primary malignancy or a diagnosis of a second malignancy that occurred before age 16 years and predated the onset of menarche, or occurred at unknown age. An additional 138 females were excluded because medical therapy to induce menarche was used before the age of 16 years or at an unknown age, resulting in 235 participants being eligible for evaluation of late menarche. Participants with amenorrhea, who received medical therapy routinely used to induce menarche after the age of 16 years, were not excluded. Thus, the populations evaluable for both early and late menarche contained 235 participants, 158 (67%) of whom were mutually eligible for both evaluations.
The comparison group for the early menarche analysis comprised 1129 female siblings who reported their age at menarche and did not have medical therapy to induce menarche before age at menarche, or at an unknown age. One thousand fifty-one female siblings were used for comparison in the late menarche analysis who reported age at menarche and had received no menarche-inducing therapy before age 16 years.
Survivor treatment exposures were categorized into surgery alone, surgery with cranial RT, surgery with cranial RT and chemotherapy, surgery with cranial and spinal RT, and all modalities combined. Absorbed radiation doses to the H-P axis were calculated for each participant who received CNS RT based on measurements in a tissue-equivalent phantom and a 3-dimensional computer model of the patient. To quantify radiation exposure, the brain was partitioned into 4 anatomic segments (frontal cortex, temporal lobes including H-P axis, posterior fossa, and the parietal and occipital cortex), and maximum RT doses were estimated for each region. For this study, it was assumed that the H-P axis received the full-beam dose if at least half of the total temporal lobe/H-P axis region was included in the beam; otherwise, this segment was considered to have received scatter dose. Treatment diagrams and photographs taken in the treatment position were reviewed to make the determination of which brain segments were irradiated. If diagrams were not available, a written description of the medical record was used to estimate the regions included and the dose administered. Further details of the dosimetry method have been previously reported.16, 17
Logistic regression was used to investigate the univariate and multivariate associations between early or late menarche and potential risk factors. Models were first fit to compare menarche outcomes between survivors and siblings using generalized estimating equations with robust variance estimates to adjust for case-sibling pairings within the same family.18 Additional sets of models were fit within the survivor population to evaluate diagnosis-related and treatment-related risk factors. Covariates were selected for inclusion in final multivariate models by examining combinations of risk factors and determining the factors that best fit the data using the Akaike information criterion.19
To further explore the dose-response relation between CNS RT and both early and late menarche, we combined the current population of CNS tumor survivors at risk for early menarche (n = 235) and late menarche (n = 235) with a previously published cohort of 949 patients treated for ALL and evaluated by the CCSS. Eight hundred seventy-four met the eligibility criteria outlined above for the evaluation of early menarche and 678 for late menarche.20 Combining these cohorts provided a wider dose distribution with increased power to detect a dose-response relation between RT and the risk of early or late menarche. Logistic regression was used to investigate the multivariate associations in this combined analysis of CNS tumor and leukemia survivors.
The mean age at the time of survey completion was 26 years (standard deviation [SD], 5.0 years) for the early menarche cohort, 29 years (SD, 5.1 years) for the late menarche cohort, and 32 years (SD, 8.2 years for the early menarche cohort and 8.1 years for the late menarche cohort) for each of the sibling comparison groups. Survivors and their siblings shared similar distributions in ethnicity (Table 1). Among the survivors of childhood CNS malignancies, the mean age at diagnosis was 5 years (SD, 2.6 years) for the early menarche cohort and 7 years (SD, 3.6 years) for the late menarche cohort; however, a significant proportion (43% in the early menarche group and 23% in the late menarche group) were diagnosed and treated by 4 years of age. Gliomas were the most common histologic subtype among both early and late cohorts of 5-year survivors. Although a significant proportion of this population received surgery alone, most participants received some form of RT, resulting in 44.9% of the population (46.5% in the late menarche cohort) receiving >40 Gy to the H-P axis.
|Characteristic||Survivors: Early Menarche, n=235 (%)||Siblings: Early Menarche, n=1129 (%)||Survivors: Late Menarche, n=235 (%)||Siblings: Late Menarche, n=1051 (%)|
|Age at cancer diagnosis, y|
|<2||25 (10.8)||14 (6.0)|
|2-4||75 (31.9)||41 (17.4)|
|5-9||135 (51.4)||103 (43.8)|
|Glioma||152 (64.7)||147 (62.6)|
|Medulloblastoma/PNET||52 (22.1)||65 (27.7)|
|Other||31 (13.2)||23 (9.8)|
|Caucasian, non-Hispanic||206 (87.7)||993 (88.0)||207 (88.1)||924 (87.9)|
|Black, non-Hispanic||10 (4.3)||27 (2.4)||9 (3.8)||25 (2.4)|
|Hispanic/Latino||8 (3.4)||39 (3.5)||7 (3.0)||37 (3.5)|
|Asian/Native American/Pacific Islander||1 (0.4)||12 (1.1)||1 (0.4)||12 (1.1)|
|Other||10 (4.3)||18 (1.6)||11 (4.7)||18 (1.7)|
|Unknown||0||40 (3.5)||0||35 (3.3)|
|Surgery only||66 (28.1)||61 (26.0)|
|Surgery+brain RT||66 (28.1)||67 (26.5)|
|Surgery+brain RT+spine RT||29 (12.3)||35 (14.9)|
|Surgery+brain RT+chemotherapy||21 (8.9)||15 (6.4)|
|All 4 treatment modalities||21 (8.9)||25 (10.6)|
|Chemotherapy only||2 (0.9)||0|
|Unknown||30 (12.8)||32 (13.6)|
|Dose to H-P axis, Gy*|
|None||82 (41.8)||72 (38.5)|
|20.01-30||3 (1.5)||4 (2.1)|
|30.01-40||23 (11.7)||24 (12.8)|
|40.01-50||47 (24.0)||30 (16.0)|
|>50||41 (20.1)||57 (30.5)|
|Timing of menarche|
|Early (aged <10 y)||28 (11.9)||10 (1.0)|
|Late (aged >16 y)||25 (10.6)||20 (1.9)|
Early Menarche Risk Profile
The mean age at onset of menarche among survivors was 11.9 years (SD, 2.1 years), whereas siblings experienced menarche at a mean of 12.7 years (SD, 1.5 years) (P < .0001). Survivors of CNS tumors were more likely to have onset of menarche before age 10 years (11.9%) than their siblings (1%) (odds ratio [OR], 14.1; 95% confidence interval [95% CI], 6.9-30.9).
The risk of early menarche was strongly associated with radiation exposure to the H-P axis. Among the 138 patients with radiation exposure to this location, 14.5% (n = 20) had onset of menarche before age 10 years, compared with only 4.3% of those who did not receive RT to the H-P axis (OR, 3.8; 95% CI, 1.2-16.5). Notably, 17% of participants receiving >50 Gy to the H-P axis experienced menarche before age 10 years (OR vs no H-P axis RT, 4.6; 95% CI, 1.2-22.4). In addition, among all eligible patients, those diagnosed and treated before age 5 years had 4-fold odds (OR, 4.0; 95% CI, 1.7-10.0) of early menarche. There were no observed associations between histologic diagnosis, use of chemotherapy, or ethnicity with early age at onset of menarche. Multivariate analysis demonstrated RT dose >50 Gy (OR, 3.7; 95% CI, 1.1-13.7) and young age (≤4 years) (OR, 3.9; 95% CI, 1.5-11.9) as significant independent risk factors for early menarche (Table 2). RT strata <50 Gy (1-40 Gy: OR, 2.6 [95% CI, 0.5-12.0]; and 40.01-50 Gy: OR, 1.9 [95% CI, 0.5-7.2]) demonstrated increased odds of early menarche, but did not reach statistical significance.
|Odds Ratio||95% CI|
|RT dose H-P axis, Gy*|
|No RT (referent)||1.00||—|
|Age at diagnosis, y|
|RT to H-P axis ± spine RT|
|H-P axis ≤50 Gy, no spine RT||1.84||0.21-16.07|
|H-P axis ≤50 Gy, plus spine RT||4.73||0.86-36.0|
|H-P axis >50 Gy, no spine RT||6.90†||1.46-49.57|
|H-P axis >50 Gy, plus spine RT||12.40†||2.66-89.64|
|No RT (referent)||1.00||—|
|Age at diagnosis, y|
Late Menarche Risk Profile
The mean age of onset of menarche among survivors was 12.4 years (SD, 2.3 years) compared with 12.7 years (SD, 1.5 years) in the sibling cohort. The survivor cohort eligible for evaluation of late menarche was more likely to have onset of menarche after age 16 years (10.6%) than their siblings (1.9%) (OR, 6.1; 95% CI, 3.4-11.4). The risk of late menarche was associated with radiation exposure to both the H-P axis (OR, 4.7; 95% CI, 1.3-22.9) and to the spine (OR, 3.0; 95% CI, 1.2-7.5). The greatest risk for late menarche was associated with a dose of >50 Gy RT to the H-P axis (OR vs no H-P axis RT, 9.0; 95% CI, 2.3-59.5). In addition, children diagnosed with cancer at an older age (age ≥10 years) were at increased risk for late menarche (OR, 3.0; 95% CI, 1.3-7.0) compared with those aged <10 years at the time of diagnosis. Risk for late menarche was also greater for those diagnosed with medulloblastoma (OR, 3.3; 95% CI, 1.4-7.8) than for other diagnostic groups, presumably because of the use of both cranial and spinal RT in this population. There was no association with race, ethnicity, or the use of alkylating chemotherapy reported, although it is interesting to note that few participants (n = 33) received alkylating agents during this era.
Multivariate analysis was used to further assess the independent effects of RT to both the H-P axis and the spine on the development of late menarche (Table 2). Increasing risk for late menarche was observed across combinations of RT exposure, with participants receiving >50 Gy RT to the H-P axis without spine RT (OR, 6.9; 95% CI, 1.5-49.6) and participants receiving >50 Gy RT to the H-P axis with additional spine RT (OR, 12.4; 95% CI, 2.7-89.6) found to have the greatest risk for late onset of menarche.
Evaluation of Timing of Menarche Across a Broad Range of Radiation Doses by Combining CNS Tumor and Leukemia Survivors
We performed additional analysis combining this CNS tumor population with a population treated for ALL with CNS-directed RT and therefore at risk for the abnormal timing of menarche, to identify whether a dose-response relation between RT and the timing of menarche existed. In multivariate analysis (Table 3) when controlling for diagnosis (CNS tumor vs leukemia), H-P axis exposure to RT at any dose was found to be significantly associated with an increased risk for early menarche, with an H-P axis dose >50 Gy conferring the highest risk (OR, 5.7; 95% CI, 1.6-22.1). Age ≤4 years at the time of diagnosis remained a significant independent risk factor for early menarche (OR, 4.2; 95% CI, 2.1-8.6) after controlling for RT exposure. A test for trend across RT dose to the H-P axis was statistically significant (P < .001).
|Odds Ratio||95% CI|
|RT dose to H-P axis, Gy*|
|No RT (referent)||1.00||—|
|Age at diagnosis, y|
|CNS tumors (referent)||1.00||—|
In the assessment of dose response for development of late menarche (Table 4), when controlling for diagnosis and spinal RT exposure, only RT exposure >50 Gy (OR, 13.2; 95% CI, 1.81-142.7) was found to be significantly associated with late menarche; however, evidence of a dose-response relation with RT exposure to the H-P axis may exist (P < .008, test for trend). Older age at the time of RT exposure (OR, 3.1; 95% CI, 1.31-7.7) was found to retain statistical significance in this model.
|Odds Ratio||95% CI|
|Age at diagnosis, y|
|RT dose to H-P axis, Gy‡|
|>20 to ≤30||3.17||0.96-14.39|
|>30 to ≤50||6.34||0.81-60.51|
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 the release of pituitary gonadotropins, resulting in stimulation of gonadal end organs (testis/ovaries).21 The diagnosis and treatment of a childhood CNS malignancies before the onset of puberty have the potential to profoundly impact the timing and the tempo of both puberty and menarche. The clinical impact is particularly important, because patients experiencing the 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 puberty.24 In addition, girls with true precocious puberty are at increased risk for several 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
The early identification of the association between CNS-directed RT and the early onset of puberty occurred in populations treated for childhood ALL. However, to our knowledge, 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 and Rappaport identified the risk for precocious puberty in patients with CNS tumors after cranial RT doses of 24 to 45 Gy delivered to the hypothalamic-pituitary region in a case series of 6 patients.27 In addition, 5 of these 6 children 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 with population norms.9 Similarly, in a retrospective cohort of 36 patients, Oberfield et al reported that females but not males experienced the early onset of puberty after treatment for CNS tumors.29 Thus, to the best of our knowledge, the current study represents the largest population of CNS tumor survivors evaluated for the early onset of menarche published to date and includes a large sibling cohort for comparison. Our data demonstrate that female survivors of CNS tumors have a >14-fold risk of developing menarche before the age of 10 years, compared with 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 RT (dose-response effect) on the risk of early menarche. Our combined analysis of both ALL and CNS tumor populations provided data regarding >1000 patients who received a broad spectrum of RT 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, although the test for trend suggests a statistically significant dose-response relation exists, the small increase in risk across these dose ranges may be clinically insignificant.
Whole brain and/or focal RT to the H-P axis places patients at risk not only for early puberty, but also for the gradual onset of H-P 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 to 45 Gy compared with those who received only 20 Gy.31 In addition, females who receive spinal RT may have the added risk of delayed puberty or menarche because of direct gonadal damage.20 In addition to quantifying this risk for delayed menarche among survivors of CNS tumors at >6-fold, the findings of the current study document that cranial RT doses >50 Gy confer the greatest risk for delayed menarche. The addition of spinal RT augments this risk, such that patients who received both >50 Gy to the H-P axis and spinal RT have a 12-fold increase in their risk of delayed menarche, compared with patients with CNS tumors who did not receive RT. Although exposure to alkylating agents is known to increase the risk of gonadal damage, no such association was noted in the current study, most likely because of the small number of participants who received alkylators for treatment of CNS tumors in this era.32
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 In addition, recall of menarche is better than that of other pubertal milestones.34 However, lack of data regarding other pubertal milestones prevented the assessment of tempo of female puberty. In addition, 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, nonparticipants, and those lost to follow-up, thereby reducing the potential for participation bias.14 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 the timing of menarche. Finally, this analysis was unable to determine the contribution of chemotherapy, most significantly alkylating agents, to the altered timing of menarche, because of the relatively low 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 and 1999, a period during which chemotherapy was used increasingly for the treatment of CNS tumors. Future investigations of this cohort will be needed to determine independent risk for the altered timing of menarche associated with these agents.
In conclusion, RT used for the 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 thereby 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.
Conflict of Interest Disclosures
The Childhood Cancer Survivor Study is supported by a grant from the National Cancer Institute (U24 CA55727, L.L. Robison, Principal Investigator) and the American Lebanese Syrian Associated Charities (ALSAC-St. Jude Children's Research Hospital).
- 21Puberty: ontogeny, neuroendocrinology, physiology, and disorders. In: KronenbergH, ed. Williams Textbook of Endocrinology. 11th ed. Philadelphia, Penn: Saunders Elsevier; 2008: 969-1166., .