Endocrine Late Effects of Cancer Treatment

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Growth

Many childhood cancer survivors have growth disturbance, but the cause often is multifactorial. The lack of GH production or secretion may result directly from GH deficiency or indirectly from hypothyroidism or sex steroid deficiency. There is a negative association between the presence of concomitant endocrinopathies and final height [4]. There also is a negative association between spinal irradiation and final height [4], [5]. Spinal irradiation causes a deficit in sitting height [6], [7].

Hypothalamic-pituitary dysfunction

Radiation therapy (RT) for CNS, orbit, facial, or nasopharyngeal, or for ALL or administered as part of TBI before BMT may result in pituitary hormone deficiencies. The hypothalamus rather than the pituitary appears to be the site of damage because there are delayed anterior pituitary hormone responses to hypothalamic releasing hormones in patients with anterior pituitary hormone deficiencies [18], [19].

The likelihood of the development of deficiencies and the speed of onset are related to the

Growth hormone deficiency

GH secretion is the pathway that is most vulnerable to external radiation. The development and severity of GH deficiency are dependent on the dose [25]. Merchant et al [26] found that the peak GH response within 12 months after conformal RT, which allows for a better assessment of the dose of RT to the hypothalamus, depends on hypothalamic dose-volume affects and may be predicted on the basis of a linear model that sums the effects of the entire distribution of dose. Large volumes of radiation

Hypogonadotropic hypogonadism

Radiation doses to the hypothalamus-pituitary greater than 50 Gy typically result in gonadotropin deficiency [17], whereas doses greater than 35 Gy also may do so [18], [34]. Adult male survivors of childhood brain tumors treated with RT but not chemotherapy have significantly lower basal luteinizing hormone (LH) and total testosterone levels compared with controls. In addition, the peak follicle-stimulating hormone (FSH) response to gonadotropin releasing hormone is blunted [35].

Central hypothyroidism

Prophylactic cranial RT doses of 15 to 24 Gy for ALL do not have an adverse effect on hypothalamic-pituitary-thyroidal function within a median follow-up time of 8 years, based on the response of TSH to thyrotropin-releasing hormone (TRH) [36]. The incidence of central hypothyroidism after RT for pediatric brain tumors is highly variable among reports. In a study by Livesey et al [22], a median calculated hypothalamic dose of 48 Gy led to 3.4% of patients developing central hypothyroidism, as

Central adrenal insufficiency

Among patients with pituitary or hypothalamic space-occupying lesions, adrenal insufficiency resulting from a cranial tumor or RT has been described previously as rare [22], [38]. At lower doses of CIR, such as 18 to 24 Gy for ALL, there is no suppression of the hypothalamic-pituitary-adrenal (HPA) axis [39]. After patients received CIR for brain tumors, Oberfield et al [40] showed that the mean integrated values for cortisol and ACTH responses to corticotropin-releasing hormone were not

Hyperprolactinemia

Hyperprolactinemia can result from high-dose cranial RT, especially with doses of greater than 50 Gy to the hypothalamus. Elevated prolactin levels can cause galactorrhea in females and may suppress the hypothalamic-pituitary-gonadal axis, resulting in hypogonadism in either gender [1].

Precocious puberty

CNS tumors, specifically optic gliomas, astrocytomas, and hamartomas, may present with central precocious puberty (CPP) [49]. Rarely, craniopharyngioma can present with precocious puberty [50]. β-human chorionic gonadotropin-secreting tumors (mixed germ cell tumors) in boys can present with pubic hair development and phallus enlargement, but these tumors are not associated with precocious puberty in girls.

The cause of organic CPP appears to be multifactorial and is directly related to the

Thyroid disorders

Children who received mantle radiation for Hodgkin's disease, CSI for brain tumors, or TBI as conditioning for BMT are at risk of developing thyroid disease because of the radiosensitivity of the thyroid gland [20].

Primary gonadal failure

Both external radiation and chemotherapy can cause gonadal dysfunction. Toxic chemotherapeutic agents include alkylating agents such as the nitrogen mustard compounds (cyclophosphamide, ifosfamide, and mephalan), nitrosureas (carmustine [systematic name 1,3-bis(2-chloroethyl)-l-nitrosourea [BCNU] and CCNU), busulfan, thiotepa, and cisplatin; the monoamine oxidase inhibitor procarbazine; and the mitotic inhibitor etoposide. Alkylating agents act as inhibitors of DNA synthesis and damage those

Bone density

The level of bone mineral density (BMD) has been investigated mostly in survivors of ALL and BMT. Most studies used dual energy x-ray absorptiometry (DEXA) of the lumbar vertebrae to assess BMD. DEXA does not measure true volumetric density because there is no information about the depth of the bone; therefore, it underestimates the bone density of short people. Skeletal maturity and the stage of sexual development also are key determinants of BMD. Quantitative (q)CT describes authentic

Obesity

Obesity is a sequela of tumors of the hypothalamic region and the treatment of these tumors with surgery or radiation. Parameters that predict more rapid weight gain include younger age at diagnosis, a radiation dose to the hypothalamus of greater than 51 Gy, the presence of any endocrinopathy, tumor located in the hypothalamus, tumor histology (craniopharyngioma, pilocytic astrocytoma, and medulloblastoma), and the extent of surgery [110]. Weight gain results from damage to the ventromedial

Summary

Endocrine sequelae are common in cancer survivors. Incidence and prevalence rates over time remain difficult to interpret because of small study sizes and variable treatment regimens. Nevertheless, patients at risk of developing endocrinologic sequelae can be identified and followed carefully so that treatment, when necessary, is provided in a timely manner and morbidity is minimized or prevented.

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