Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood

INTRODUCTION — Due to therapeutic advances, the survival rate for childhood cancer has significantly increased. Improved survival rates have led to increased recognition of long-term treatment-related morbidities, collectively known as "late effects," with 95 percent of childhood cancer survivors reported to have at least one chronic health condition by the age of 45 [1]. Endocrine-reproductive disturbances are among the most common late effects [1-5]. These often result in significant morbidity including poor growth, precocious or delayed puberty, thyroid dysfunction, infertility, and metabolic disease. Understanding how to improve the prevention, recognition, and treatment of endocrinopathies will improve the quality of life of childhood cancer survivors and others who are exposed to similar therapies.

An overview of the most common endocrinopathies observed in childhood cancer survivors and others treated with cytotoxic therapies during childhood will be provided here.

LONG-TERM FOLLOW-UP FOR SURVIVORS OF CANCER AND OTHERS TREATED WITH CYTOTOXIC THERAPIES DURING CHILDHOOD

Need for long-term follow-up — Endocrine-reproductive disturbances are among the most common late effects of cancer treatment, affecting up to 40 to 60 percent of childhood cancer survivors [1-3,6]. In a population-based study from Denmark, Finland, Iceland, Norway, and Sweden, the risk of an endocrine disorder in cancer survivors was 4.8 times greater than in the general population [6]. In this study, children with cancer diagnosed between five and nine years of age had the highest cumulative risk for an endocrinopathy, which reached 43 percent by the age of 60 years. More recently, an analysis of endocrine abnormalities in 14,290 five-year survivors from the Childhood Cancer Survivor Study (median age six years at diagnosis and 32 years at last follow-up) demonstrated that nearly one-half of childhood cancer survivors experienced at least one, 16.7 percent at least two, and 6.6 percent three or more endocrinopathies [4]. The cumulative incidence and prevalence of endocrinopathies among survivors in this study increased substantially over time, thus underscoring the need for lifelong screening for those at risk.

While this review focuses on risk of endocrinopathies among survivors of childhood cancer, the information applies to children treated with cytotoxic therapies (eg, hematopoietic cell transplantation [HCT]) for nonmalignant conditions as well. These disorders include bone marrow failure syndromes (eg, Fanconi anemia, amegakaryocytic thrombocytopenia [7-9]); primary immunodeficiencies (eg, severe combined immunodeficiency, Wiskott-Aldrich syndrome, hyper-immunoglobulin M syndrome); inherited hemoglobinopathies (eg, sickle cell disease, thalassemia [10,11]); and inherited metabolic disorders (eg, mucopolysaccharidoses, adrenoleukodystrophy [12-14]). Risk for endocrine dysfunction in these patients may be due to the underlying condition, the pretransplant conditioning regimen, or a combination of both. Patients with thalassemia are also at risk for a range of endocrinopathies due to potential iron overload arising from their need for multiple blood transfusions (see "Thalassemia: Management after hematopoietic cell transplantation", section on 'Endocrine dysfunction' and "Hematopoietic cell transplantation (HCT) for inherited bone marrow failure syndromes (IBMFS)", section on 'Post-HCT care'). Disease-related risks are beyond the scope of this topic.

Risk-based general screening for late effects — Detailed clinical guidelines related to childhood cancer survivors and potential therapy-related late effects are publicly available via the Children's Oncology Group (COG) Long-Term Follow-Up Guidelines [15]. These guidelines, initially published in 2003 and last updated in 2023, provide surveillance recommendations for risk-based follow-up care of childhood cancer survivors from the completion of therapy through adulthood. Patient education materials called "Health Links" complement the guidelines. At entry into a long-term follow-up program, all survivors should receive an individualized treatment summary, which outlines previous exposures, potential late effects, and recommended risk-based screening procedures in accord with COG guidelines. The COG guidelines may also be used to guide risk-based screening practices for individuals with noncancer diagnoses who were treated with similar cytotoxic therapies. Henceforth, we will use the term "survivors" to refer to individuals treated with chemotherapy, radiation therapy, and/or HCT during childhood or adolescence for a malignant or nonmalignant condition.

The Passport for Care (PFC), an online internet-based resource, utilizes the COG guidelines to provide individualized survivorship guidelines for survivors and their caregivers based on their treatment history. The PFC is in use in more than 150 survivor clinics and by more than 45,000 survivors [16].

A general overview of cancer survivorship is discussed separately (see "Overview of cancer survivorship care for primary care and oncology providers"). A review of survivorship issues specific to adult survivors of HCT is provided elsewhere. (See "Long-term care of the adult hematopoietic cell transplantation survivor".)

Risk factors and location of injury — Patients at risk for endocrine-reproductive disturbances are those who were treated with radiotherapy and/or high doses of alkylating agents, such as cyclophosphamide, ifosfamide, and busulfan [17-21]. Survivors at the highest risk of developing endocrine disorders post-treatment are those with the following conditions [6,18]:

●Central nervous system tumors

●Orbital/facial sarcomas

●Hodgkin lymphoma

●Conditions requiring treatment with HCT

Most causes of endocrinopathies in this population can be classified by location of injury either in the hypothalamic-pituitary axis or distal endocrine gland (table 1):

●Hypothalamus and pituitary gland – While tumors and surgery in the region of the hypothalamus and pituitary can cause damage to the hypothalamus and/or the pituitary gland, radiation-induced damage is usually due to injury at the level of the hypothalamus, which results in secondary deficiencies or dysregulation of the anterior pituitary hormones: growth hormone (GH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), and adrenocorticotropic hormone (ACTH).

•Linear growth and/or metabolic disturbance due to GH deficiency [22,23]. Other factors may also contribute to disordered growth. (See 'Growth hormone deficiency' below and 'Disordered growth' below.)

•Pubertal disorders including precocious and delayed puberty, and pubertal arrest due to disturbances in the production and secretion of LH and FSH. Menstrual disorders, sexual dysfunction, and infertility may also occur in sexually mature individuals. (See 'Disorders of luteinizing and follicle-stimulating hormones' below.)

•Central hypothyroidism. This is typically asymptomatic at presentation and detected on screening. (See 'Central hypothyroidism' below.)

•Fatigue, poor weight gain, or hypoglycemia, especially during periods of stress, due to ACTH deficiency [24]. (See 'Adrenocorticotropic hormone deficiency' below.)

•Polyuria, polydipsia, and hypernatremia due to arginine vasopressin deficiency (AVP-D, previously called central diabetes insipidus); this disorder is typically associated with surgical intervention and is rarely a sequela of either radiation or chemotherapy.

●Thyroid – Hypothyroidism may be due to direct damage to the thyroid gland, whereas hyperthyroidism (which is less common) can be caused by damage to or dysregulation of the thyroid. (See 'Thyroid disorders' below.)

●Gonads – Delayed puberty and infertility. Menstrual disturbances may also occur in postpubertal female patients.

Other complications may have multifactorial causes:

●Poor linear growth (see 'Disordered growth' below)

●Low bone mineral density (BMD) (see 'Low bone mineral density' below)

●Metabolic disorders, including diabetes mellitus and obesity [25] (see 'Overweight, obesity, and disorders of glucose homeostasis' below)

In the previously mentioned population study from Scandinavia, the most common endocrine disorders diagnosed in cancer survivors were due to pituitary hypofunction, primary hypothyroidism, and testicular and ovarian dysfunction [6].

HYPOTHALAMIC-PITUITARY DYSFUNCTION

Overview — Survivors at increased risk for hypothalamic-pituitary dysfunction are those treated with cranial irradiation, those with a central nervous system insult after surgery impacting the hypothalamic-pituitary area, or those requiring shunt placement due to hydrocephalus. This may result in abnormal levels of the following hormones that are regulated by or produced by these two areas of the brain. Hormonal abnormalities often occur concomitantly.

●Growth hormone (GH)

●Luteinizing hormone (LH)

●Follicle-stimulating hormone (FSH)

●Thyroid-stimulating hormone (TSH)

●Adrenocorticotropic hormone (ACTH)

●Arginine vasopressin (AVP), also known as antidiuretic hormone

Patients treated with radiation doses ≥18 Gy to the hypothalamic-pituitary axis are at risk for GH deficiency and central precocious puberty due to dysregulation of LH and FSH. Those treated with doses >30 to 40 Gy are at risk for deficiencies of LH, FSH, TSH, and ACTH. Those with histiocytosis, germinomas, or surgical trauma to the hypothalamus or posterior pituitary are at risk for AVP deficiency (AVP-D).

The risk of hypothalamic-pituitary dysfunction after cranial irradiation is both dose- and time-dependent and may not become apparent until many years after treatment. In a study of 748 survivors of childhood cancer exposed to cranial irradiation and observed for a mean of 27 years, systematic risk-based screening identified a substantial number of undiagnosed anterior pituitary deficiencies decades after exposure to radiation, especially GH and LH/FSH deficiencies [26]. A study of 3141 adult survivors of childhood cancer showed that hypothalamic-pituitary disorders were independently associated with impaired physical, sexual, and neurocognitive function [27]. It is thus imperative for at-risk survivors to have lifelong risk-based screening for hormonal abnormalities, with prompt initiation of hormone replacement therapies as clinically indicated.

Growth hormone deficiency

●Who is at risk – GH deficiency is associated with [20]:

•Brain tumors located near the hypothalamus or pituitary (eg, craniopharyngiomas, germinomas, and optic nerve gliomas) and their resection. Individuals with hydrocephalus requiring shunt placement also may be at risk [27].

•Cranial irradiation – GH deficiency is the most common endocrinopathy seen in survivors following cranial irradiation. GH deficiency occurs in a dose- and time-related fashion, with risk increasing as doses exceed 18 Gy of radiation and the time interval increases from treatment [28-30]. Children treated with total body irradiation with single fractions ≥10 Gy or fractionated doses ≥12 Gy are also at risk [31-33].

There is some evidence that children treated with intrathecal chemotherapy are also at risk, though the data are limited and require verification in future studies [27].

Children with precocious puberty may have concomitant GH deficiency, despite a seemingly normal height velocity. (See 'Precocious puberty' below and 'Disordered growth' below.)

●Testing and diagnosis – For survivors with suspected GH deficiency, prompt referral to an endocrinologist is recommended. After reviewing the child's growth curves and treatment-related risk factors, the endocrinologist will order GH stimulation testing if indicated based on documentation of poor growth (see 'Tracking linear growth in the cancer survivor' below). Failure of two GH stimulation tests, using two different pharmacologic agents known to increase GH secretion, is required for the diagnosis of GH deficiency. An exception is that individuals with three other confirmed anterior pituitary defects do not require provocative testing to make the additional diagnosis of GH deficiency [5]. (See "Diagnosis of growth hormone deficiency in children".)

In patients who received radiation impacting the brain, insulin-induced hypoglycemia may be the most sensitive and reliable pharmacologic test of GH status. Insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP-3), which are commonly used as surrogate markers of GH secretion in children assessed for short stature, are not reliable indicators of GH status following cranial irradiation or documented hypothalamic-pituitary injury, due to tumoral expansion [5,34-36].

Adults with GH deficiency may develop visceral adiposity, low muscle mass, muscle weakness, and poor exercise tolerance (see "Growth hormone deficiency in adults"). It is unclear to what degree long-term GH supplementation can ameliorate these adverse outcomes in adult survivors. Referral to an experienced endocrinologist is indicated for any adult survivor considering GH replacement therapy.

●Management – We suggest GH therapy for most children with established GH deficiency [5]. A preponderance of evidence suggests that GH therapy is generally safe and efficacious in this population [37]. Guidelines recommend waiting for at least one year after completion of cancer-directed therapy before initiating GH treatment [5]. The clinician should engage the family in a comprehensive consultation regarding the benefits and risks of GH therapy in survivors prior to making a decision about initiation of therapy. Although several studies have reported no evidence of increased risk of tumor recurrence associated with GH therapy [38,39], there are data showing a small risk of second neoplasms, particularly solid tumors, in childhood cancer survivors treated with GH [39,40]. However, a study of 12,098 childhood cancer survivors (338 treated with GH and 11,760 not treated with GH) showed that GH treatment was not associated with increased risk of second neoplasms of the central nervous system, which are the most common type of second neoplasm [41]. (See "Treatment of growth hormone deficiency in children", section on 'Adverse effects of growth hormone therapy'.)

Once the risks and benefits have been carefully weighed, exogenous GH therapy can be provided to patients with GH deficiency. In a report of 183 childhood cancer survivors treated with GH, greater final height was associated with a younger bone age at the time of initiation of GH and higher doses of GH, while a higher dose of spinal irradiation was negatively associated with final height [23]. Dosing and management of GH therapy is similar to that for children with GH deficiency who are not cancer survivors. (See "Treatment of growth hormone deficiency in children", section on 'Growth hormone treatment'.)

For cancer survivors who are not GH-deficient and who have short stature or poor linear growth due to spinal irradiation, treatment with GH is not recommended [5].

Disorders of luteinizing and follicle-stimulating hormones — Puberty refers to the phase of development that occurs when a child's body progresses into adulthood and reaches sexual maturity. Secondary sexual characteristics that herald the onset of puberty include breast development in girls and increased testicular volume and penile enlargement in males. These changes should appear in a predictable fashion and may be tracked over time via the sexual maturity rating (Tanner staging) system [42,43]. However, testicular volume may not be a reliable indicator of pubertal status in male survivors, since gonadotoxic therapy can damage the seminiferous tubules and result in inappropriately small testicular volume for pubertal stage [5,44,45]. (See "Normal puberty".)

Survivors are at risk for pubertal derangements including precocious puberty, pubertal delay, and pubertal arrest (hypogonadotropic hypogonadism) [46]. As a result, follow-up care with tracking and recording the onset of secondary sexual characteristics and pubertal height velocity can identify children with pubertal derangements due to luteinizing hormone (LH) and follicle-stimulating hormone (FSH) disorders [46].

Adult survivors with LH/FSH deficiency may present with sexual dysfunction, unexplained infertility, and secondary amenorrhea in women and nonspecific symptoms such as fatigue in men.

Precocious puberty — While there is significant variation in age at onset of normal puberty, abnormally early puberty, referred to as precocious puberty, is historically defined as any sign of secondary sexual maturity before age eight years in girls and age nine years in boys (see "Definition, etiology, and evaluation of precocious puberty"). Select survivors are at risk for central precocious puberty, which is caused by premature activation of the hypothalamic-pituitary-gonadal axis and subsequent early elevation of LH and FSH levels. In girls, this may lead to early menarche, defined by the onset of menstrual cycles prior to the age of 10 years. Advancement of bone age more than 2 standard deviations for chronologic age is also a consistent finding in children with precocious puberty [20]. In survivors of central nervous system malignancies, or those treated with cranial radiotherapy, puberty may progress at a rapid tempo with similar advancement of bone age and risk of short stature [46].

●Who is at risk – Survivors treated with cranial irradiation (≥18 Gy) are at risk for the development of central precocious puberty [46-48]. Other risk factors include a history of hydrocephalus or tumors in the region of the hypothalamus-pituitary (eg, optic-chiasmal gliomas). Among patients treated with radiation to the hypothalamus, the risk is further increased with younger age at diagnosis, female sex, and increased body mass index [47].

●When to suspect a problem and refer – Any survivor previously treated with hypothalamic radiation noted to have secondary sexual characteristics prior to age eight in girls and age nine in boys should have a more complete evaluation by a pediatric endocrinologist. Survivors of a central nervous system malignancy, or those treated with brain radiation, who are noted to have a rapid tempo of pubertal development, should be referred to an endocrinologist as well. In these patients, the primary care provider can assess skeletal maturity via standard bone age and measure LH and FSH levels. For affected boys, early morning testosterone levels should also be assessed [5]. In girls, plasma estradiol should be measured, and pelvic ultrasound, which assesses size of the ovaries and uterus, also may be obtained. If any abnormalities are noted or the primary care provider is not comfortable performing the evaluation, patients should be promptly referred to an endocrinologist for further testing and diagnosis.

●Treatment options – Since central precocious puberty may cause rapid bone age advancement with resultant reduction in final height potential, it may be beneficial to temporarily suppress the hypothalamic-pituitary-gonadal axis by employing long-acting formulations of gonadotropin-releasing hormone (GnRH) agonists, similar to treatment for children with idiopathic central precocious puberty [5]. Such therapy may prevent further advancement in skeletal maturity, resulting in a modest improvement in final height. (See "Treatment of precocious puberty", section on 'Treatment for central precocious puberty'.)

Delayed or arrested puberty — While some survivors are at risk for early or precocious puberty, others remain at risk for pubertal delay or arrest (hypogonadotropic hypogonadism due to LH and FSH deficiency). Delayed puberty is defined by lack of breast development in girls and lack of testicular enlargement in boys by an age that is 2 to 2.5 standard deviations later than average, typically 13 years in girls and 14 years in boys [49,50].

●Who is at risk – Survivors treated with doses of radiation >30 to 40 Gy to the hypothalamic-pituitary axis are at risk for deficits of LH and FSH [30].

●When to suspect a problem and refer – Any survivor who has not demonstrated any pubertal development by age 13 in girls and age 14 in boys should be referred to an endocrinologist for further evaluation. A prior history of high-dose radiation to the hypothalamic-pituitary axis with low testosterone and estradiol levels, and low or sometimes normal gonadotropin levels is concerning for gonadotropin (LH and FSH) deficiency. Screening to rule out nonspecific organ dysfunction includes a complete blood count, erythrocyte sedimentation rate (ESR), comprehensive metabolic panel, thyroid function studies, prolactin, and urinalysis.

Hypogonadotropic hypogonadism in adulthood — Survivors who have reached sexual maturity can also develop treatment-related LH/FSH deficiency. Presentation in females includes secondary amenorrhea, and in males, loss of libido, erectile dysfunction, and reduced energy or stamina. A diagnosis of hypogonadotropic hypogonadism should be suspected in at-risk males with low morning testosterone levels (<200 ng/dL) and low or normal LH and FSH levels, or amenorrheic females with low estradiol and low or normal FSH levels. Survivors treated with high-dose hypothalamic radiation (>30 Gy) should have lifelong screening. For males, we suggest including annual measurements of morning testosterone, regardless of symptoms. For females, we suggest baseline LH/FSH and estradiol levels if symptoms such as irregular menstrual periods or amenorrhea are present.

●Treatment options – After a comprehensive history, physical examination, and laboratory evaluation are complete, treatment with estrogen therapy in females and testosterone in males may be indicated to induce pubertal development. Adult-dose sex steroid replacement therapy is indicated in affected postpubertal patients. (See "Approach to the patient with delayed puberty".)

Central hypothyroidism — Thyroid hormone is important for normal development and metabolism in children and young adults (see "Thyroid hormone action" and "Clinical manifestations of hypothyroidism"). Select survivors are at risk for central hypothyroidism. (See "Central hypothyroidism".)

●Who is at risk – Survivors treated with surgery and/or high-dose radiation to the hypothalamic-pituitary area are at risk for central hypothyroidism (ie, deficient production of thyroid-stimulating hormone [TSH]) [30,51-53]. Approximately 3 to 9 percent of patients treated with radiation doses >30 to 40 Gy to the hypothalamic-pituitary axis will develop central hypothyroidism [54]. Lower doses of radiation and treatment with chemotherapy do not appear to be associated with central hypothyroidism [55-57].

●Screening and diagnosis – Childhood cancer survivors treated with high doses of radiation to the hypothalamic-pituitary region should have annual screening thyroid function studies, continuing through adulthood [5]. In treating survivors with other hormone deficiencies, such as LH/FSH and/or adrenocorticotropic hormone (ACTH) deficiency, providers should have a high index of suspicion for the development of central hypothyroidism.

Central hypothyroidism is usually diagnosed by an abnormally low free T4 level with low or normal basal TSH concentrations. In rare instances, the TSH level may be mildly elevated in those with central hypothyroidism. For individuals who receive radiation to both the brain and neck (eg, individuals with medulloblastoma who are exposed to craniospinal radiation), a mixed form of hypothyroidism may occur wherein the free T4 level is low and TSH modestly elevated. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Diagnosis'.)

●Treatment – Levothyroxine is indicated for patients with TSH deficiency. Dose should be titrated to maintain normal free T4 levels. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Treatment and prognosis'.)

Adrenocorticotropic hormone deficiency — In healthy individuals, the hypothalamus releases corticotrophin-releasing hormone and vasopressin, which stimulate the pituitary gland to secrete ACTH. ACTH prompts secretion of cortisol from the adrenal cortex. Cortisol is a regulatory hormone in gluconeogenesis, the body's response to stress, and has a major role in maintaining homeostasis.

●Who is at risk – ACTH deficiency is relatively uncommon in childhood cancer survivors [53,58] but may result from direct damage to the hypothalamic-pituitary region (from the presence of tumor or surgical intervention) or following high-dose irradiation >30 Gy to the area [24,59,60]. Transient ACTH deficiency may also result from prolonged use of pharmacologic doses of glucocorticoids. (See "Causes of central adrenal insufficiency in children".)

●When to suspect a problem – Patients with ACTH deficiency may present with fatigue, poor weight gain, and/or hypoglycemia. In times of stress or illness, unrecognized ACTH deficiency can be life-threatening. (See "Causes of central adrenal insufficiency in children".)

●Screening – At-risk survivors should be screened annually for ACTH deficiency, even if they are asymptomatic [5]. While some groups recommend screening with an annual ACTH stimulation test (low-dose corticotropin test) [59], the Children's Oncology Group (COG) Long-Term Follow-Up Guidelines recommend annual screening with a morning (8 AM) cortisol level for at least 15 years after treatment or as long as clinically indicated [15]. Due to diurnal variation of cortisol secretion, 8 AM is the optimal time to assess peak serum cortisol concentration for annual testing.

●When to refer – At-risk patients with screening basal cortisol levels <10 mcg/dL (276 nmol/L), or those who are symptomatic, should be referred to an endocrinologist for dynamic testing of adrenal function. Tests for appropriate central regulation of adrenal function include the insulin tolerance test, glucagon stimulation test, ACTH stimulation and metyrapone tests. The laboratory evaluation to confirm the diagnosis for ACTH deficiency is discussed separately. (See "Clinical manifestations and diagnosis of adrenal insufficiency in children" and "Diagnostic testing for hypopituitarism" and "Clinical manifestations and diagnosis of adrenal insufficiency in children", section on 'Diagnostic approach'.)

●Treatment – Patients with ACTH deficiency require glucocorticoid replacement therapy (eg, hydrocortisone, prednisone, or prednisolone) at physiologic doses based on a daily production rate of hydrocortisone of 7 mg/m² per day. Under stress conditions, such as illness or surgery, glucocorticoid dosing should be increased to three times the normal replacement dose. If the patient is unable to tolerate oral therapy, an intramuscular injection of approximately 50 mg/m² of hydrocortisone sodium succinate (Solu-Cortef) should be administered. Every patient with ACTH deficiency should wear a medical identification bracelet, indicating the diagnosis of adrenal insufficiency, at all times. (See "Treatment of adrenal insufficiency in children".)

Arginine vasopressin deficiency — AVP-D, previously called central diabetes insipidus, is a rare endocrinopathy in the childhood cancer survivor. It is generally associated with surgical intervention and not due to injury from either radiation therapy or chemotherapy. (See "Evaluation of patients with polyuria".)

●Who is at risk – AVP-D may result from direct damage to the hypothalamic region, typically due to the presence of tumors, infiltrative lesions, or neurosurgical trauma to the hypothalamus and posterior pituitary [61]. AVP-D does not typically result from treatment with irradiation or chemotherapy. However, it has been reported as a rare but reversible side effect of treatment with temozolomide [62]. (See "Arginine vasopressin deficiency (central diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation".)

●When to suspect a problem – Patients with AVP-D may present with sudden polyuria, nocturia, and/or enuresis, as well as polydipsia. If unrecognized, severe dehydration may result. (See "Arginine vasopressin deficiency (central diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation".)

●Screening – The COG Long-Term Follow-Up Guidelines do not recommend routine screening tests for AVP-D in asymptomatic childhood cancer survivors. However, any at-risk patient who presents with polyuria and/or polydipsia should have further diagnostic testing performed including plasma sodium concentration, serum osmolality, and urine osmolality. Patients who present with polyuria and/or polydipsia should be tested for diabetes mellitus and AVP-D. Patients with AVP-D may have normal laboratory studies if net water losses have been minimized by compensatory thirst mechanisms. (See "Evaluation of patients with polyuria", section on 'Evaluation of suspected polyuria'.)

●When to refer – Any symptomatic at-risk patient, particularly one with a high-normal plasma sodium concentration (greater than 142 mEq/L) and urine osmolality less than plasma osmolality, should be referred to a pediatric endocrinologist for further evaluation. A water deprivation test may be ordered to confirm the diagnosis. (See "Evaluation of patients with polyuria".)

●Treatment – Patients with AVP-D require hormone replacement with desmopressin acetate (also referred to as DDAVP), which may be administered orally, via nasal insufflation, or, less often, via subcutaneous injection. Initiation of hormone replacement requires close monitoring of urine volume status and symptom control. (See "Arginine vasopressin deficiency (central diabetes insipidus): Treatment", section on 'Children'.)

DISORDERED GROWTH

Risk factors for poor growth — Linear growth in childhood cancer survivors may be negatively impacted by both endocrine and nonendocrine factors.

●Nonendocrine factors include radiation-induced direct damage to the growth plate, usually of the vertebrae, and suboptimal nutritional status. Patients treated with abdominal, spinal, and/or total body irradiation often manifest stunted spinal growth, which becomes most apparent during puberty [63-65]. Patients with a history of radiation impacting the spine are at risk for growth impairment that disproportionately affects the spine (causing skeletal dysplasia) [66,67].

●Endocrine etiologies of short stature include growth hormone (GH) deficiency, untreated central precocious puberty, and primary and central hypothyroidism. GH deficiency and central precocious puberty are typically seen in patients treated with radiation doses ≥18 Gy to the hypothalamic-pituitary axis [68]. Primary hypothyroidism may result from exposure of the thyroid gland to radiation, radioactive iodine-labeled agents, or surgical removal of the thyroid gland. (See 'Growth hormone deficiency' above and 'Precocious puberty' above and 'Primary hypothyroidism' below.)

Adjuvant chemotherapy does not appear to be an independent risk factor for short stature [68,69], although chemotherapy alone did result in a small statistically significant reduction in final height in a study of acute lymphoblastic leukemia survivors [70]. However, the long-term use of glucocorticoids that may be given to children with chronic graft versus host disease is associated with poor growth. (See "Causes of short stature", section on 'Glucocorticoid therapy'.)

Individuals with certain nonmalignant conditions may be at increased risk for poor growth independent of therapeutic exposures. As examples:

●Fanconi anemia is often associated with short stature [71]; final height may be further impacted by treatment-related endocrinopathies such as growth hormone deficiency and primary hypothyroidism. Additionally, androgens used to treat Fanconi anemia may accelerate epiphyseal maturation and thereby further impair final height [7]. (See "Clinical manifestations and diagnosis of Fanconi anemia".)

●Mucopolysaccharidoses, such as Hurler or Hunter syndrome, are also at high risk for growth failure, which may be due to skeletal dysplasia and/or growth hormone resistance [12,13]. (See "Mucopolysaccharidoses: Clinical features and diagnosis" and "Mucopolysaccharidoses: Complications".)

●Thalassemia major is typically characterized by ineffective erythropoiesis, which can lead to extramedullary sites of hematopoiesis, iron overload, and poor growth. (See "Diagnosis of thalassemia (adults and children)".)

Tracking linear growth in the cancer survivor — For all survivors who have not completed their linear growth and are at risk for disordered growth, height and weight should be tracked every six months on age-appropriate normative growth curves. (See "Normal growth patterns in infants and prepubertal children".)

Growth should be tracked using the standard growth charts from the World Health Organization or Centers for Disease Control, depending on the child's age, as recommended by the American Academy of Pediatrics. (See "Measurement of growth in children", section on 'Recommended growth charts with calculators'.)

For all survivors treated with radiation impacting the spine (ie, total body irradiation; craniospinal irradiation; or radiation to the chest, abdomen, or pelvis), we recommend serial measurements of sitting height to monitor for growth impairment that disproportionately affects the spine (causing skeletal dysplasia) [5].

Evaluation — Further investigation is warranted for any child noted to have a decreased height velocity over a six-month period or a drop in two major height percentile curves (eg, 50^th to 10^th percentiles) on standardized growth curves [19]. The following should be included in the evaluation of a survivor who manifests signs of poor linear growth:

●Nutritional status, as measured by body weight and body mass index, should be assessed, as it can influence linear growth.

●Thyroid function should be measured since hypothyroidism may lead to declining height velocity. (See 'Primary hypothyroidism' below.)

●Long-term use of glucocorticoids, which is associated with poor growth.

●GH deficiency should be suspected in any child treated with cranial and/or total body irradiation who manifests a decreased height velocity over a six-month period of time. (See 'Growth hormone deficiency' above.)

●Pubertal staging also must be considered, as precocious puberty can mask the signs of GH deficiency with seemingly normal height velocity due to the inappropriate secretion of sex steroids. (See 'Precocious puberty' above.)

THYROID DISORDERS — In addition to deficits in thyroid-stimulating hormone (TSH) production due to hypopituitarism, survivors may develop thyroid dysfunction related to direct treatment-related insults to the thyroid gland.

Primary hypothyroidism

●Who is at risk – Primary hypothyroidism frequently occurs after treatment for childhood cancer [1,72-74]. It may also occur after hematopoietic cell transplantation for malignant and nonmalignant diseases. (See "Acquired hypothyroidism in childhood and adolescence".)

Besides complete or partial thyroidectomy, the main treatment-related risk factor is radiation to the thyroid due to mantle or neck, craniospinal, or total body irradiation [28,52,55,75,76]. The risk increases with higher doses of radiation and the longer the time interval of follow-up from the initial intervention. Adult survivors previously treated with radiation impacting the neck are thus at high risk for the development of primary hypothyroidism.

Other risk factors include:

•Tyrosine kinase inhibitor therapy [77]

•Radiolabeled agents (eg, 131-I-metaiodobenzylguanidine [78,79] or 131-I-labeled monoclonal antibody [80,81])

•Hematopoietic cell transplantation (HCT) following treatment with high-dose chemotherapy (eg, busulfan and cyclophosphamide) [73,82]

•Other reported associations include female sex, White race, and older age at diagnosis [28,83]

●Screening and diagnosis – Since hypothyroidism can occur more than 25 years after therapy, the need for continued lifelong surveillance must be emphasized [20]. Serial monitoring of TSH levels is recommended for all at-risk survivors. Serum free T4 levels should be obtained in patients with elevated TSH levels.

The diagnosis of primary hypothyroidism is based on high serum TSH levels and low serum free T4 values. (See "Laboratory assessment of thyroid function" and "Acquired hypothyroidism in childhood and adolescence", section on 'Diagnosis'.)

●Treatment – Lifelong replacement therapy with levothyroxine is indicated for patients with primary hypothyroidism. Serum TSH should be monitored to assess dosing adequacy and medication compliance. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Treatment and prognosis'.)

Hyperthyroidism — Treatment-related hyperthyroidism occurs much less often than primary hypothyroidism after cytotoxic therapy. It most often results after exposure of the thyroid gland to radiation [84]. In survivors of Hodgkin lymphoma, a radiation dose >35 Gy to the thyroid has been identified as a risk factor for the development of hyperthyroidism [28]. Hyperthyroidism has also been reported in survivors of acute lymphoblastic leukemia treated with a radiation dose >15 Gy [55] and in HCT recipients due to immune-mediated disease caused by adoptive transfer of abnormal clones of T or B cells from donor to recipient [85-88]. (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents".)

Thyroid neoplasms

●Who is at risk – Survivors are at risk for both benign and malignant thyroid neoplasms after exposure of the thyroid gland to radiation [73,89,90]. Patients at risk include those treated with head, neck, chest, mantle, craniospinal, or total body irradiation. Treatment prior to 10 years of age, and/or total doses of radiation between 20 and 29 Gy appear to confer the greatest risk for the development of thyroid cancer [90-92]. The association between radiation dose and thyroid cancer is curvilinear, with risk increasing at low to moderate doses and decreasing at doses >30 Gy due to cell-killing effect [91]. Among patients treated with radiation doses to the thyroid of ≤20 Gy, treatment with alkylating agents appears to increase thyroid cancer risk [73,93]. The risk of thyroid cancer persists throughout the adult life of at-risk survivors. (See "Thyroid nodules and cancer in children" and "Radiation-induced thyroid disease".)

●How to screen – Survivors treated with radiation potentially impacting the thyroid gland should have lifelong annual screening examinations for thyroid abnormalities. While some have advocated the use of thyroid ultrasonography as a means of screening for thyroid carcinoma in previously irradiated patients [94,95], the Children's Oncology Group (COG) recommends annual examination of the thyroid gland via careful palpation [15]. The International Guideline Harmonization Group for Late Effects of Childhood Cancer recommends shared decision-making regarding whether to undergo surveillance for thyroid cancer as well as the choice of surveillance modality [96].

Given the indolent course of second primary thyroid cancer, harm related to unnecessary procedures following the detection of abnormalities on ultrasonography remains an area of controversy [96,97]. Routine use of screening thyroid ultrasonography in survivors increases detection of small nodules of uncertain clinical significance and may result in unnecessary and excessive invasive procedures. This was illustrated in a study of pediatric Hodgkin lymphoma survivors who underwent routine screening thyroid ultrasonography [98]. Although thyroid nodules were a common finding, only one case of malignant thyroid cancer was detected by ultrasound screening. Another six cases of thyroid cancer developed in the cohort, which were detected after clinical findings prompted further evaluation. All seven patients with thyroid cancer were alive at the time of data analysis.

GONADAL DYSFUNCTION — In addition to impaired gonadal function related to perturbations of gonadotropin secretion from the pituitary gland (see 'Disorders of luteinizing and follicle-stimulating hormones' above), survivors are at risk for primary gonadal dysfunction due to direct damage to the ovaries or testes.

Males — The human testis has two primary functions: sperm production and testosterone production. One or both of these functions may be negatively impacted by cytotoxic treatment (see "Causes of primary hypogonadism in males"). Germ cells and Sertoli cells form the seminiferous tubules where spermatogenesis occurs; Leydig cells are responsible for the production of testosterone.

Germ cell dysfunction

●Who is at risk – Exposure of the sperm-producing cells to radiation and/or certain types of chemotherapy may result in oligo/azoospermia [99]. Impaired sperm production at doses as low as 0.15 Gy [20,100] may result from direct testicular radiation or scatter from other treatment fields, such as the pelvis, bladder, or inguinal/femoral area. Germ cell dysfunction is present in virtually all males treated with total body irradiation.

Chemotherapeutic agents associated with impaired spermatogenesis include mechlorethamine, cyclophosphamide, ifosfamide, procarbazine, busulfan, melphalan, and cisplatin. The impairment of spermatogenesis depends on the cumulative dose [101-106]. Alkylating agents used in concert have additive gonadotoxic effects. Although earlier studies suggested that younger age at treatment was associated with a lower risk of germ cell loss, data are inconclusive.

●How to test – The only definitive test available to determine a survivor's ability to produce semen is a sperm analysis [97,107]. Although a variety of clinical (eg, decreased testicular volume) and biochemical findings (eg, raised plasma concentrations of follicle-stimulating hormone [FSH] and reduced plasma concentrations of inhibin-B) have been associated with impaired sperm production in population studies, none is ideal as a diagnostic for oligospermia due to poor sensitivity and/or specificity [97,107,108].

Leydig cell dysfunction

●Who is at risk – Leydig cells are susceptible to radiation-induced damage at higher doses than those associated with germ cell dysfunction; risk is directly related to testicular radiation dose and inversely related to age at treatment [109]. While individuals treated with ≥20 Gy of fractionated radiation to the testes are known to be at highest risk, other data have shown that radiation doses <20 Gy also represent a significant risk factor for the development of Leydig cell dysfunction in adult survivors [110]. Most prepubertal males who receive radiation doses ≥24 Gy to the testis will develop Leydig cell failure [107]. Chemotherapy alone rarely results in Leydig cell failure, although subclinical Leydig cell dysfunction has been reported following treatment with alkylating agents [108,109,111]. However, one study with long-term follow-up revealed that risk is associated with older attained age and exposure to higher doses of alkylating agents [110].

●When to suspect a problem – Leydig cell failure will result in failed entry into puberty if it occurs before pubertal onset or pubertal plateauing if it occurs after the start of puberty. Affected males who have completed normal puberty may present with reduced libido, erectile dysfunction, decreased bone mineral density (BMD), and decreased muscle mass. Patients who have any of these symptoms after gonadotoxic therapy should be assessed for Leydig cell failure. (See "Clinical features and diagnosis of male hypogonadism".)

●Screening – Males treated with ≥20 Gy radiation to areas that may impact the testes (flank/hemiabdomen, whole abdomen, inverted Y, pelvic, prostate, bladder, iliac, inguinal, femoral, testicular, total lymphoid, or total body) should have periodic screening with measurements of luteinizing hormone (LH) and early-morning testosterone levels beginning at age 14 and careful monitoring of pubertal progression [15]. Elevated serum levels of LH with low levels of testosterone are consistent with the diagnosis of Leydig cell failure. The clinical features and diagnosis of male hypogonadism are discussed separately. (See "Clinical features and diagnosis of male hypogonadism".)

●Treatment – Males with evidence of Leydig cell failure should be referred to an endocrinologist for initiation of testosterone replacement therapy. BMD should be assessed in those with testosterone deficiency. (See "Testosterone treatment of male hypogonadism".)

Females — Due to the interdependence of the sex steroid-producing cells and oocytes within the ovarian follicle, ovarian failure results in impairment of both sex hormone production and fertility.

Premature ovarian insufficiency

●Who is at risk – Premature ovarian insufficiency may result from treatment with gonadotoxic chemotherapy, radiation impacting the ovaries, or surgical removal of the ovaries [112].

Chemotherapy-induced acute ovarian failure, which is the permanent loss of ovarian function within five years of cancer diagnosis, typically results from treatment with high doses of alkylating agents [113,114], particularly when administered in preparation for stem cell transplantation [115,116]. Risk is directly correlated with cumulative dose and older age at exposure. A risk calculator has been developed for the prediction of acute ovarian failure among female childhood cancer survivors [116,117].

Females treated with radiation impacting the ovaries (irradiation of the spine, flank, hemiabdomen below the iliac crest, whole abdomen, inverted Y, pelvis, vagina, bladder, iliac lymph nodes, total lymphoid system, or total body) are at increased risk for premature ovarian insufficiency [112-114,118-120]. Doses to the ovary exceeding 1000 cGy are associated with a very high risk of premature ovarian insufficiency [121]. When ovarian transposition is performed prior to radiotherapy, however, many girls retain ovarian function [109]. Irradiation at older age confers a greater risk.

Women who have normal ovarian function at the end of treatment with potentially gonadotoxic therapy remain at risk for premature ovarian insufficiency later in life and should be counseled accordingly [113,122].

●When to suspect a problem – If ovarian function is lost in girls prior to pubertal onset, delayed puberty and primary amenorrhea will result. In those in whom ovarian function is lost during or after puberty, pubertal arrest, secondary amenorrhea, and menopausal symptoms will occur (see "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)"). If these symptoms are noted along with elevated gonadotropins, referral should be made to an endocrinologist or gynecologist for initiation of hormone replacement therapy. (See "Management of primary ovarian insufficiency (premature ovarian failure)".)

●Screening – All females treated with gonadotoxic therapies should have periodic Tanner staging to monitor pubertal progression, along with concomitant serum FSH measurements. The Children's Oncology Group (COG) guidelines recommend FSH and estradiol levels (and/or endocrinology referral) for females with no signs of puberty by age 13, pubertal arrest, and/or menstrual irregularity or menopausal symptoms [15]. Elevated gonadotropin levels are consistent with premature ovarian insufficiency.

●Treatment – Girls with pubertal delay or arrest should be referred to an endocrinologist or gynecologist for initiation of hormone replacement therapy.

Pregnancy and measures to preserve fertility in survivors of childhood cancer and hematopoietic cell transplantation are discussed in detail elsewhere. (See "Overview of infertility and pregnancy outcome in cancer survivors".)

LOW BONE MINERAL DENSITY

●Who is at risk – Survivors of childhood cancer and/or hematopoietic cell transplantation are at increased risk for low bone mineral density (BMD) due to the following risk factors [123]:

•Malignant infiltration of bone

•Exposure to cranial or craniospinal irradiation

•Chemotherapeutic agents that interfere with bone metabolism such as glucocorticoids [88,124-126] (see "Clinical features and evaluation of glucocorticoid-induced osteoporosis")

•Sex hormone deficiency and growth hormone (GH) deficiency due to secondary effects of treatment [88,127]

•Sedentary lifestyle and suboptimal nutrition, which is often problematic in childhood cancer survivors [128,129]

Methotrexate was previously thought to be a risk factor for low bone mineral density, but there is a lack of evidence supporting this association [130,131].

For many patients, low BMD will normalize over time without specific interventions [132]. One report showed that the prevalence of fractures among adult survivors of childhood cancer was not increased compared with sibling controls [133].

Although quite rare, childhood cancer survivors have also been reported to have an increased risk of osteonecrosis when compared with normal siblings [134]. (See "Bone problems in childhood cancer patients", section on 'Avascular necrosis (Osteonecrosis)'.)

●Screening and diagnosis – Subjects at high risk for low BMD and those who experience fractures should undergo screening with bone density studies at entry into a long-term follow-up program [123] (see "Screening for osteoporosis in postmenopausal women and men"). Dual-energy x-ray absorptiometry (DXA) has traditionally been used to determine BMD but results in children and adolescents must be interpreted according to age, height, and pubertal stage using normative Z-scores rather than T-scores. (See "Osteoporotic fracture risk assessment" and "Overview of dual-energy x-ray absorptiometry".)

Quantitative computed tomography (QCT), which assesses both trabecular and cortical BMD with adjustments for age, sex, and height, is also available in some centers to track survivors' longitudinal bone health [132,135]. However, due to its considerable expense and higher radiation dose, QCT is primarily used as a research tool at this time.

●Treatment – Calcium and vitamin D supplementation, and regular weight-bearing exercise, should be encouraged in all survivors with borderline or low BMD [136]. Sex hormone and GH replacement therapy may be useful in improving BMD in patients with known deficiencies [20]. Survivors with severe BMD deficits or a history of multiple fractures should be referred to an endocrinologist for consideration of further treatment.

OVERWEIGHT, OBESITY, AND DISORDERS OF GLUCOSE HOMEOSTASIS — In addition to the adverse effects associated with obesity in the general population, obesity has been linked to an increased risk of cancer recurrence and mortality in cancer survivors. (See "The roles of diet, physical activity, and body weight in cancer survivors", section on 'Weight'.)

●Who is at risk – In a study of a large cohort of adult childhood cancer survivors, the prevalence of obesity was greater than 40 percent [1]. Risk factors include exposure to cranial irradiation, female sex, younger age at treatment, and exposure to dexamethasone [137]. Survivors of acute leukemia and certain brain tumors, and pediatric stem cell transplantation recipients are at particular risk for obesity [138-140]. (See "Acute lymphoblastic leukemia/lymphoblastic lymphoma: Outcomes and late effects of treatment in children and adolescents", section on 'Obesity' and "Obesity in adults: Etiologies and risk factors", section on 'Hypothalamic obesity'.)

Exposure to abdominal radiation or total body irradiation appears to predispose survivors to metabolic syndrome (constellation of hypertension, dyslipidemia, and central or visceral adiposity), which is associated with an increased risk of type 2 diabetes mellitus and atherosclerotic disease [141-146]. Patients with growth hormone (GH) deficiency are also at risk for metabolic syndrome. In addition, abdominal or total body irradiation is a risk factor for diabetes mellitus in young adulthood [147-149], with higher risk noted among those treated at younger ages [150]. The Children's Oncology Group (COG) Long-Term Follow-Up Guidelines recommend that all patients treated with abdominal or total body irradiation should have a fasting blood glucose (or hemoglobin A1c) drawn every two years, or more frequently if clinically indicated.

●Treatment – Survivors who are overweight or obese should be counseled about the importance of lifestyle changes such as smoking cessation, increased physical activity, and dietary modification (see "Pediatric prevention of adult cardiovascular disease: Promoting a healthy lifestyle and identifying at-risk children"). Drug therapy may be initiated for those with insulin resistance or diabetes mellitus not responsive to lifestyle modifications. (See "Dyslipidemia in children and adolescents: Management" and "Management of type 2 diabetes mellitus in children and adolescents".)

OUR APPROACH — Long-term surveillance is needed for all survivors at risk for endocrinopathies. Our approach, which is consistent with the Children's Oncology Group (COG) Long-Term Follow-Up Guidelines, includes the following:

●For all survivors who have not completed their linear growth, height and weight should be tracked every six months on age-appropriate normative growth curves. (See 'Disordered growth' above.)

Evaluation of patients with poor linear growth includes assessment of growth hormone (GH) and thyroid function and nonendocrinologic factors (eg, nutrition).

●For prepubertal patients, the onset of secondary sexual characteristics and height velocity should be tracked and recorded. For patients who have completed normal puberty, screening is focused on a risk-based assessment of damage to either the hypothalamic-pituitary axis or gonads and the presence of related symptoms. Screening entails measurement of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone in males and LH and FSH in females. (See 'Gonadal dysfunction' above.)

●Screening for other endocrinopathies is based on treatment-related risk assessment (eg, radiation fields and doses and chemotherapeutic agents) and symptomatology including:

•Thyroid dysfunction (see 'Central hypothyroidism' above and 'Thyroid disorders' above)

•Adrenocorticotropic hormone (ACTH) (see 'Adrenocorticotropic hormone deficiency' above)

•Low bone mineral density (BMD) (see 'Low bone mineral density' above)

•Diabetes mellitus

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Endocrine-reproductive disturbances are among the most common late effects after treatment with cytotoxic therapy, affecting up to 40 to 60 percent of childhood cancer survivors, and may occur many years after completion of therapy. The primary risk factors are radiotherapy and/or high doses of alkylating agents, especially prior to hematopoietic cell transplantation (HCT). (See 'Need for long-term follow-up' above and 'Risk factors and location of injury' above.)

●Overview of long-term surveillance – To promote early identification and treatment of endocrine problems, lifelong surveillance and follow-up care should be provided for at-risk survivors, as outlined in the table (table 1). Health care providers must identify those at risk by screening for potential late effects and treat or refer to appropriate specialists when indicated. (See 'Our approach' above.)

●Endocrinopathies

•Hypothalamic-pituitary dysfunction – Childhood cancer survivors treated with cranial irradiation or those who have had surgery impacting the hypothalamic-pituitary area are at increased risk for hypothalamic-pituitary dysfunction. (See 'Hypothalamic-pituitary dysfunction' above.)

Those treated with radiation doses ≥18 Gy to the hypothalamic-pituitary axis are at risk for growth hormone (GH) deficiency and central precocious puberty, while those treated with >30 to 40 Gy are at risk for pubertal absence/arrest due to deficiencies of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), central hypothyroidism due to thyroid-stimulating hormone (TSH) deficiency, and central adrenal insufficiency due to adrenocorticotropic hormone (ACTH) deficiency. Survivors treated with cranial radiation remain at lifelong risk for hormonal abnormalities and thus should receive annual risk-based screening for hormonal dysfunction. (See 'Growth hormone deficiency' above and 'Hypogonadotropic hypogonadism in adulthood' above and 'Central hypothyroidism' above.)

•Thyroid dysfunction – Patients treated with radiation impacting the thyroid gland are at risk for primary hypothyroidism, hyperthyroidism, thyroid nodules, or secondary thyroid cancer. Primary hypothyroidism also may develop in survivors treated with partial or total thyroidectomy, radiolabeled agents, and tyrosine kinase inhibitors. (See 'Thyroid disorders' above.)

•Gonadal dysfunction – Primary gonadal dysfunction may occur due to direct injury by alkylating agents and/or radiation to the gonads. It can result in failure to enter or complete puberty and infertility. (See 'Gonadal dysfunction' above.)

Other endocrinologic complications may be multifactorial including:

•Poor linear growth and/or short stature – Factors that may contribute to poor linear growth include direct radiation injury to growth plates and vertebrae, GH deficiency, untreated precocious puberty, hypothyroidism, poor nutritional status, and excessive doses of exogenous glucocorticoids. Nonmalignant disorders, such as Fanconi anemia, mucopolysaccharidoses, and thalassemia, are independently associated with poor linear growth. (See 'Disordered growth' above.)

•Low bone mineral density (BMD) – Factors that contribute to low BMD include chemotherapeutic agents that interfere with bone metabolism (eg, glucocorticoids), sex hormone and/or GH deficiency, sedentary lifestyle, and suboptimal nutrition. (See 'Low bone mineral density' above.)

•Obesity and diabetes mellitus – Survivors of childhood leukemia and certain brain tumors are at increased risk for overweight and obesity. Those treated with abdominal or total body irradiation are at increased risk for diabetes mellitus and metabolic syndrome. (See 'Overweight, obesity, and disorders of glucose homeostasis' above.)