Hypothalamic–Pituitary and Growth Disorders in Survivors of Childhood Cancer

An Endocrine Society Clinical Practice Guideline

Charles A. Sklar; Zoltan Antal; Wassim Chemaitilly; Laurie E. Cohen; Cecilia Follin; Lillian R. Meacham; M. Hassan Murad

Disclosures

J Clin Endocrinol Metab. 2018;103(8):2761-2784. 

In This Article

Central Precocious Puberty in Childhood Cancer Survivors

Epidemiology, Morbidity, and Mortality

The prevalence of CPP in childhood cancer survivors is estimated at 11.9% to 15.2%.[109,110] CPP in the context of a CNS insult may be associated with the accelerated fusion of the growth plates and potentially significant losses in AH.[109,111] Early sexual development may also result in challenges regarding the psychosocial adjustment of patients.[112]

Etiology and Clinical Manifestations

CPP is defined by the onset of pubertal development before the age of 8 years in girls and 9 years in boys as a result of the premature activation of the HP gonadal axis.[109,113] Table 1 summarizes the risk factors of CPP in childhood cancer survivors.

Diagnosis of Central Precocious Puberty in Childhood Cancer Survivors

   3.1 We recommend periodically assessing childhood cancer survivors for evidence of CPP if they have a history of hydrocephalus, tumors developing in or near the hypothalamic region, and/or have been exposed to HP radiation. (1∣⊕⊕⊕O)

   3.2 We recommend against using testicular volume as the primary or sole indicator of degree of sexual development in male childhood cancer survivors previously treated with gonadotoxic agents, such as alkylating agents or testicular radiotherapy. (1∣⊕⊕⊕O)

   3.3 We recommend measuring serum testosterone, preferably using liquid chromatography–tandem mass spectroscopy, and LH levels prior to 10:00 am to complement the clinical assessment of male childhood cancer survivors who are suspected of or are at risk for developing CPP and were exposed to gonadotoxic treatments. (1∣⊕⊕OO)

    Technical remark: Clinicians need to interpret plasma LH levels in patients exposed to gonadotoxic treatments in the context of their medical history and physical examination. Elevated LH levels in such patients may be due to primary gonadal injury rather than to the onset of central puberty.

Evidence. CPP is among the most common endocrine complications in children with tumors arising near the hypothalamus or optic pathways (such as low-grade gliomas), and it is often associated with neurofibromatosis type 1.[109,111,113–115] The prevalence of CPP in patients with these tumors is between 26% and 39%.[109,111,115] Exposure to HP axis radiation at a wide range of doses (20 to 50 Gy) has also been associated with CPP, albeit with a lower frequency (6.6%).[109] Additional risk factors for CPP include hydrocephalus,[113] young age at HP axis RT, and (in patients exposed to HP axis RT) female sex and increased body mass index.[110,116]

The clinical diagnosis of pubertal onset in female childhood cancer survivors primarily relies on the observation of breast development (as in the noncancer population). The diagnosis of pubertal onset in male childhood cancer survivors previously exposed to gonadotoxic treatments (e.g., alkylating agents, testicular radiation) requires a different approach than in males in the noncancer population, in whom increasing testicular volume is an early clinical indicator of the onset of puberty. Testicular volume is known to be affected by gonadotoxic cancer treatments because of germ cell and Sertoli cell injury.[117–119] Research has indicated that testicular size plots below the 10th percentile for chronologic age in up to 50% of male survivors of acute lymphoblastic leukemia treated with CRT and extended abdominal radiotherapy,[117] and it averages −2.0 SD in pediatric hematopoietic stem cell transplant recipients exposed to TBI.[119] Studies have shown that the testes of adult childhood cancer survivors are significantly smaller than controls[118] and correlate with impaired germ cell function.[120]

Given the limited reliability of testicular volume as a means of pubertal staging in male childhood cancer survivors treated with gonadotoxic modalities, laboratory markers such as am serum testosterone and LH plasma levels may allow an earlier and more accurate assessment in this subset of patients whose Leydig cell function is less frequently affected than their germ cell function.[117,119] Liquid chromatography–tandem mass spectroscopy should preferably be used to measure serum testosterone levels.[79] Medical providers should be aware that serum LH elevations could be due to primary gonadal injury rather than to the central onset of puberty in patients exposed to gonadotoxic treatments, and clinicians should interpret laboratory data in the context of the patient's cancer history and clinical presentation.[121] Measuring serum testosterone is especially helpful in boys exposed to gonadotoxic therapies and who are at risk for CPP given the challenges in the interpretation of clinical parameters (e.g., testicular volume) and LH values. In girls with elevated gonadotropins, the assessment of pubertal progression based on Tanner staging (breast development), the measurement of estradiol levels, and the assessment of uterine length and shape via ultrasound can help distinguish between CPP and primary gonadal insufficiency.[122]

As discussed in section 1 ("Short Stature/Impaired Linear Growth in Childhood Cancer Survivors"), the interpretation of growth velocity in childhood cancer survivors should be based not only on chronological age, but also on pubertal stage because of the frequent association between CPP and GHD.[109,111] Patients with genetic syndromes (such as neurofibromatosis type 1) and those exposed to craniospinal radiotherapy may also experience CPP.[26,123] GHD may compromise a patient's ability to experience linear growth acceleration during puberty in general and CPP in particular. Otherwise, the diagnostic work-up of childhood cancer survivors suspected of CPP follows the general steps followed in the general pediatric population (Table 2).[121,124–126]

Treatment of Central Precocious Puberty in Childhood Cancer Survivors

   3.4 We advise that the indications and the type of treatment regimens for CPP in childhood cancer survivors should be similar to those used for CPP in the noncancer population (Table 2). (Ungraded Good Practice Statement)

Evidence. Historical data on patients with tumor-related CPP who were not treated with pubertal suppression are scarce but suggest poor AH outcomes; although these patients may not have received treatment for other complications, including GHD.[127] Studies have shown that pubertal suppression with gonadotropin-releasing hormone agonist (GnRHa) improves the AH of patients with CPP (not necessarily childhood cancer survivors) in comparison with their predicted AH at baseline.[128–131] One study compared a cohort of 26 patients with CPP (31% related to a CNS insult) diagnosed at a young age (median 5 years) and treated with GnRHa to historical controls matched for demographic factors and etiology.[131] The report showed a significant improvement in final or near AH in the treated group (−0.9 ± 0.3 SD in females, −1.7 ± 1.6 in males) in comparison with nontreated historical controls (−1.9 ± 0.2 in females, −3.2 ± 6.4 SD in males; P = 0.01 for both).[131] These data allow speculation that childhood cancer survivors with CPP most likely benefit from pubertal suppression with GnRHa.[109,113] Available AH data have nevertheless indicated that patients may not experience a complete recovery of their growth, and patients and families should be informed of the multifactorial nature of growth impairment in childhood cancer survivors.[109,129] Children with a history of hydrocephalus, HP tumors, and/or radiotherapy may experience nonprecocious but early onset puberty (8 to 9 years in girls or 9 to 10 years in boys) or rapid tempo of puberty.[132,133] Data are limited regarding the benefits of treatment with GnRHa on these forms of puberty in childhood cancer survivors, except in patients who also have GHD and in whom pubertal suppression, in association with GH therapy, seems to result in improved height outcomes.[17,132] There are no data supporting the use of GnRHa to augment the AH prospects of childhood cancer survivors experiencing normal pubertal development. The overall course of treatment of CPP in childhood cancer survivors can follow the advice in place for noncancer populations.[121,134]

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