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

Hypogonadotropic Hypogonadism in Childhood Cancer Survivors

Epidemiology, Morbidity, and Mortality

The estimated prevalence of LH/FSH deficiency (LH/FSHD) in childhood cancer survivors is 10.8%.[47] Depending on the age of onset, LH/FSHD may manifest as delayed puberty (absence of signs of puberty after the ages of 13 years in girls and 14 years in boys)[135] or interrupted puberty, or LH/FSHD may manifest during adulthood as amenorrhea (females) or symptoms related to low testosterone (males). Untreated LH/FSHD in older childhood cancer survivors may be associated with adverse cardiovascular and bone health outcomes.[47] Confounders related to the interpretation of low testosterone levels in obese men have complicated the understanding of the true impact of this problem.[47,136]

Etiology

LH/FSHD may occur within the context of panhypopituitarism following the direct anatomical injury of the HP area due to tumor growth or surgery. LH/FSHD may also occur as a late effect of HP axis radiation, especially at doses ≥30 Gy.[47,65,137]

Diagnosis of LH/FSHD in Childhood Cancer Survivors

   4.1 We recommend screening for LH/FSHD in childhood cancer survivors exposed to HP axis radiation at doses ≥30 Gy and in those with a history of tumors or surgery affecting the HP axis region. (1∣⊕⊕⊕O)

   4.2 We advise using the same strategies to diagnose LH/FSHD in childhood cancer survivors as are used in the noncancer population (Table 2). (Ungraded Good Practice Statement)

Evidence. Childhood cancer survivors who are at risk for developing LH/FSHD because of their tumor or treatment history require periodic evaluation of their HP gonadal function.[47,65,137–139] These assessments are important given the potential occurrence of LH/FSHD as a late effect and the rather nonspecific symptoms associated with this deficiency, especially in males.[47,79,136]

The diagnosis of LH/FSHD in the general pediatric and adolescent population is complicated by the high prevalence of constitutional delay of growth in boys and by the presence of several congenital causes for LH/FSHD such as Kallmann syndrome, pituitary stalk interruption, and midline defects.[140] Although such considerations may pertain to childhood cancer survivors experiencing pubertal delay, exposure to HP axis radiation and the presence of other pituitary deficiencies are generally robust indicators of LH/FSHD.[135] Undetectable, low, or declining serum testosterone levels (males) or undetectable or low estradiol levels (females) in the setting of low or inappropriately normal levels of gonadotropins past 13 years of age in girls and 14 years of age in boys are suggestive of LH/FSHD during adolescence.[135,140] The diagnosis of LH/FSHD in adult childhood cancer survivors follows the same steps as those outlined by the Endocrine Society for the general population.[79] Medical providers should cautiously interpret gonadotropin and sex hormone levels in obese or underweight individuals. It is important to note that childhood cancer survivors exposed to high-dose HP axis radiation, especially in the range ≥50 Gy, are at risk for developing hyperprolactinemia,[65] which may also occur as a side effect of various drugs, especially antipsychotics. Hyperprolactinemia should be ruled out in patients with suspected LH/FSHD, as is the case in the general population.[79]

Treatment of LH/FSHD in Childhood Cancer Survivors

   4.3 We advise following the same treatment approach to LH/FSHD in childhood cancer survivors as is appropriate in the noncancer population (Table 2). (Ungraded Good Practice Statement)

Evidence. Pubertal induction in adolescent female childhood cancer survivors with LH/FSHD can follow guidelines available for the general pediatric population.[135,140] The use of testosterone to induce puberty in boys during adolescence does not seem to adversely impact future fertility prospects in patients with LH/FSHD;[141] however, data specific to childhood cancer survivors are limited.[142]

Clinicians can use the same guidelines for the diagnosis and management of LH/FSHD in adult childhood cancer survivors as they do for adults with LH/FSHD (Table 2). Other measures potentially improving bone health, such as adequate dietary calcium intake and vitamin D supplementation, should be offered, along with sex hormone replacement.[79] The benefits of estrogen replacement have been deemed to outweigh the risk of breast cancer in women 40 to 49 years in the general population.[79] There are no data to support the need for a different approach in female childhood cancer survivors requiring estrogen/progesterone replacement for LH/FSHD. Preliminary studies do not support an increased risk of secondary breast cancer following spinal radiotherapy.[143] In a recent study of hormone replacement therapy in women with premature ovarian insufficiency and a history of exposure to chest RT, the risk of breast cancer remained significantly lower than in childhood cancer survivors who retained normal ovarian function.[144] Those with premature ovarian insufficiency who received hormone replacement therapy had a modestly increased risk of breast cancer, but not to the same degree as those with endogenous hormone production.

Medical providers should be aware of known drug interactions between antiepileptic medications and estrogen replacement, with potential repercussions on the efficacy of either treatment when the other is added or doses are changed.[79] Antiepileptic drugs with enzyme-inducing properties (such as carbamazepine, oxcarbazepine, phenobarbital, phenytoin, and topiramate) may decrease the efficacy of sex hormones by interfering with their metabolism or by increasing the secretion of sex hormone–binding globulin. Other, nonenzyme-inducing, antiepileptic drugs such as lamotrigine, valproate, and levetiracetam have been shown to cause changes in plasma sex hormone concentrations but the mechanisms are unknown. Conversely, estrogen replacement may increase seizure risk in patients treated for epilepsy because of increased neuron excitability and/or interference with drug metabolism (as with lamotrigine).[145] Estrogen replacement therapy increases the production of thyroid-binding globulin and may decrease the production of IGF-I; these interactions may require increasing the doses of levothyroxine and human recombinant GH in patients on treatment of hypothyroidism and GHD, respectively.[79] The effect of estrogen replacement on circulating IGF-I may be avoided if transdermal formulations are used in lieu of oral forms.[79] Clinicians should discuss the risks and benefits of estrogen replacement with patients and base treatment decisions on relevant guidelines and patient preferences.

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