The potential for linear growth can be eroded by various endocrine and non-endocrine factors, leading to adult short stature. Growth hormone (GH) deficiency is among the main endocrine factors associated with short stature and most frequently occurs as a complication of cranial radiotherapy.

Tumors developing close to the hypothalamus and/or pituitary gland such as craniopharyngiomas, germinomas, and optic nerve gliomas can cause GH deficiency as a direct anatomical insult or because of the surgery required to remove or reduce the size of these tumors. The other hypothalamic–pituitary functions are generally affected in these situations.

Growth hormone deficiency is the most frequently observed and often the only hypothalamic–pituitary deficit in individuals treated with cranial radiotherapy [4, 5]. The deficit occurs in a time- and dose-dependent fashion. The higher the dose of radiation and the longer the time interval from treatment, the greater the risk [6]. Growth hormone deficiency can be observed within 5 years when doses exceed 30 Gy [5]. Following lower doses, such as 18 to 24 Gy, growth hormone deficiency may not become evident for 10 or more years [7]. The effects of chemotherapy alone on GH secretion are not as well established as those of radiotherapy. Growth hormone deficiency has been reported in relatively small numbers of individuals treated with chemotherapy alone [8–11].

The diagnosis of GH deficiency can be difficult to establish except in situations where direct anatomical insults to the hypothalamus and/or the pituitary are documented (e.g., sellar tumors, surgical removal). Given the kinetics of GH secretion, the hormone being released mostly through nocturnal pulses, deficiencies can be difficult to capture and the diagnosis has to be based on the convergence of clinical features and laboratory results. A decreased growth velocity, observed over a 6-month time interval, should raise the suspicion of GH deficiency [12]. It is important to note that other endocrine and non-endocrine factors can contribute to growth deceleration and that the elements obtained during the clinical evaluation can help in elucidating the contribution of each additional factor. For instance, high dose radiotherapy to the spine, such as following total body irradiation (TBI), can directly damage the vertebral growth plates and cause a skeletal dysplasia where the sitting height is more affected than the standing height [13–16]. It is therefore important in individuals who received such treatments to measure and plot on dedicated growth charts the sitting height of the individual and compare this to the standing height. Body weight and body mass index (BMI) are important markers of nutritional status which can influence linear growth. In addition, excessive weight gain contrasting with linear growth deceleration can reflect thyroid dysfunction. Pubertal staging is an important part of any endocrine evaluation, but is essential in this context as concurrent central precocious puberty—a fairly common endocrine complication observed in individuals treated with cranial radiotherapy—can mask the clinical signs of growth hormone deficiency with seemingly normal growth rates owing to the inappropriate secretion of sex steroids.

Given the pulsatile and circadian nature of GH secretion patterns, GH plasma measurements require dynamic testing, often referred to as GH stimulation testing. A pharmacologic agent known to increase GH secretion (or secretagogue) is injected and GH levels are measured serially over a 2-hour period. Stimulation tests are non-physiologic and can yield non-reproducible results. In children, the interpretation of the GH peak values varies with the GH assay and the standard used by the different laboratories; a normal GH peak response hence varies between 5 and 10 ng/mL depending on all these factors. In adults, different cut off values have been defined depending on the secretagogue used during the test and according to BMI [17]. The diagnosis of GH deficiency generally requires failing two stimulation tests using two different secretagogues. In patients who received irradiation to the hypothalamus and/or pituitary, however, failing one stimulation test was considered enough in the consensus guidelines published by the Growth Hormone Research Society [18]. Plasma Insulin like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) which are more stable than GH levels, are widely used as surrogate markers of GH secretion. They are used by many clinicians as screening tools before offering GH stimulation testing. This approach is problematic by several aspects. The interpretation of the IGF-1 and IGFBP-3 levels requires factoring in patient age, pubertal stage, and skeletal maturation data. Plasma IGF-1 levels are also affected by changes in liver function and by the nutritional status. Additionally, IGF-1 and IGFBP-3 levels can be inappropriately normal in children with GH deficiency following hypothalamic/pituitary irradiation or local tumoral expansion and hence cannot be used to screen for GH deficiency in this population [19, 20]. Hence, when clinical suspicion is present, GH stimulation testing should be offered even if IGF-1 and/or IGFBP-3 levels were within the normal range. A left-hand X-ray obtained to assess the degree of skeletal maturation, referred to as the “Bone Age” is an important part of the investigation of a child with growth deceleration. Differences between the bone age and the chronological age are helpful in assessing the potential for catch-up growth [21].

Replacement therapy using recombined human GH is proven to improve final height prospects in survivors with childhood onset GH deficiency [22, 23]. Initiation of replacement therapy at a younger bone age—and hence longer duration of replacement therapy—and higher doses of therapy positively correlated with a greater final height outcome [24]. Safety concerns pertaining to the use of GH in individuals with a history of malignancy are related to the known pro-mitogenic and proliferative effects of GH and IGF-1. Growth hormone replacement is generally deferred until 1 year after the successful completion of all cancer therapies and initiated only if there are no changes in the patient’s remission status. The treatment is also interrupted when a patient is diagnosed with a recurrence or a second neoplasm. In order to more systematically address these ongoing safety concerns, many large-scale studies pertaining to the long term risks associated with the use of GH in childhood cancer survivors have been published over the years. These studies did not show an increase in the risk of brain tumor recurrence, disease recurrence, or death following GH replacement therapy [25–27]. However, there was a slight increase in the risk of a secondary solid tumor, the most commonly observed being meningiomas [27, 28]. Cancer survivors treated with GH may also be at a higher risk of developing slipped epiphyses compared with children treated with GH for idiopathic GH deficiency [29]. As an entity, adult GH deficiency is increasingly being recognized given its association with increased body fat, raised plasma lipids, and decreased bone density and reduced quality of life [10, 11, 30]. Treatment with GH in adult survivors of childhood cancer seems to have a greater impact on quality of life, and to result in improvements in the metabolic parameters [11, 31–33].

The thyroid gland is particularly vulnerable to radiation, and primary hypothyroidism is by far the most common thyroid disorder observed in childhood cancer survivors. Individuals treated with neck/mantle irradiation for Hodgkin lymphoma, craniospinal irradiation for brain tumors, or TBI for cytoreduction before HSCT are therefore at a significant risk of becoming hypothyroid in the years that follow the exposure [5, 7, 52–56]. Treatments with radio-labeled agents such as Iodine-131-metaiodobenzylguanidine (I131-MIBG) [57] and I131-labeled monoclonal antibody for neuroblastoma [58] have also been associated with hypothyroidism. Chemotherapy alone does not seem to cause hypothyroidism [56, 59]. The prevalence of hypothyroidism is primarily determined by the total dose of radiation to the thyroid and by the duration of follow-up. Additional risk factors for developing hypothyroidism include female gender, white race, and being older than 15 years of age at the time of diagnosis [54, 59]. As hypothyroidism can occur more than 25 years following the completion of cancer treatments, it is imperative that individuals at risk undergo lifelong surveillance.

Clinical signs suggestive of hypothyroidism include fatigue, cold intolerance, abnormal weight gain, hair loss, low energy levels, depression, and menstrual irregularities. In children who have not completed growth, hypothyroidism is associated with a decreased growth velocity contrasting with an abnormal weight gain. Given the relatively non-specific nature of many of these symptoms and knowing that many individuals would become profoundly hypothyroid before developing any of these symptoms, it is recommended to screen for abnormal thyroid functions in individuals at risk by obtaining labs at least yearly. These include plasma Free T4 and TSH levels. Elevated TSH levels contrasting with normal or low Free T4 levels are suggestive of primary hypothyroidism. The treatment consists of replacement with levothyroxine at substitutive doses.

Therapy-induced hyperthyroidism is a relatively uncommon complication in childhood cancer survivors; it occurs most often following external beam radiation to the neck for Hodgkin lymphoma. The main risk factor is the exposure of the thyroid to doses >35 Gy [54, 56]. Medical treatment is determined individually depending on the severity of the presentation.

Autoimmune thyroid disease, most likely a result of the adoptive transfer of abnormal clones of T or B cells from donor to recipient, has been reported in allogeneic HSCT recipients. Both hyperthyroidism and hypothyroidism have been described in the presence of TSH receptor auto-antibodies and thyroglobulin auto-antibody respectively [60, 61].

The exposure of the thyroid to either direct radiation or scatter radiation (for example after prophylactic CNS irradiation in patients treated for ALL) is a significant risk factor for thyroid neoplasms, benign and malignant. Treatment before 10 years of age and/or with doses in the range of 20–29 Gy are significant risk factors. The association between thyroid irradiation and thyroid neoplasms is linear at low doses of radiation, but shows a downward turn at doses above 20–25 Gy, with a risk that remains, nevertheless, elevated compared to the general population [62, 63]. The majority of the observed cancers were differentiated carcinoma (ie, papillary and follicular) with a median latency around 20 years [54, 62, 64]. An increased risk of thyroid cancer in association with chemotherapy (independent of radiotherapy) was recently reported but remains relatively minor compared to the effect of radiation [63].

In general, post-irradiation thyroid cancers behave in a non-aggressive fashion, similar to what is observed in de novo thyroid cancers among the young [65]. The pathogenesis of radiation-induced thyroid neoplasms is felt to be be related to rearrangements of RET-PTC induced by the exposure to radiation [66, 67]. Thyroid neoplasms following radiotherapy may not become evident for many years after exposure to radiation; therefore, all individuals at risk require lifelong clinical follow-up by an expert endocrinologist [54, 56, 65]. Periodically screening individuals at risk for the presence of clinically non-palpable thyroid neoplasms using thyroid ultrasound has been recommended by some groups [68]. This strategy remains controversial, as it may result in more frequent biopsies and has not, so far, been shown to reduce morbidity or mortality in this population [59].

The human testis harbors two functional compartments: A sex steroid-producing compartment, and a sperm-producing compartment. The former consists of testosterone-producing Leydig cells while the latter consists of the seminiferous tubules, which include germ cells as well as the Sertoli cells that support and nurture them. The two compartments are interrelated given that adequate testosterone production is necessary for normal spermatogenesis, but their functions otherwise remain relatively distinct [69]. The two functional compartments are affected in different ways by cancer treatments.

In females, the estrogen producing cells and oocytes are functionally and structurally interdependent within the ovarian follicle. As a result, when ovarian failure occurs, both sex hormone production and fertility are disrupted [71]. Given the progressive decline in oocyte reserve with increasing age, older age is an important risk factor for ovarian failure following childhood cancer and its treatments [71]. Owing to a greater follicular reserve, the ovaries of prepubertal girls are more resistant to chemotherapy-induced damage when compared to the ovaries of adults [89, 93, 94]. Nevertheless, certain chemotherapeutic agents, especially alkylating agents, given at high doses can cause ovarian failure, even in younger subjects [94–97]. Older age at treatment, exposure to procarbazine at any age, and exposure to cyclophosphamide between the ages of 13–20 years old were independent risk factors for acute ovarian failure (AOF) [94]. Females who receive high-dose myeloablative therapy with alkylating agents such as busulfan, melphalan, and thiotepa in preparation for HSCT are at high risk of developing ovarian failure [98]. The majority of prepubertal girls and adolescents receiving standard chemotherapy will fortunately maintain or recover ovarian function during the immediate post-treatment period [71, 99, 100]. In women who do retain or recover function following treatment with standard doses of alkylating agents, a subset will experience premature menopause when they reach their twenties and thirties [71, 76, 95, 101, 102]. Female survivors with a history of exposure to high doses of alkylating agents, to lomustine or cyclophosphamide, were less likely to experience a pregnancy when compared to sibling controls [44]. When female childhood cancer survivors treated with chemotherapy do get pregnant, no adverse pregnancy outcomes were identified [103].