childhood, hGH predominates and, in puberty, the synergistic interplay of hGH and sex steroids is critical for attainment of final adult height. During all stages, any prolonged disturbance of physical or psychosocial well‐being may adversely impact growth and development [93,94]. For the child with cGVHD such disturbances may include delayed hormonal and direct skeletal effects of pretransplant TBI ± cranial irradiation, chronic glucocorticoid therapy >5mg/m2/day [95,96] and phases when GVHD activity is inadequately controlled. Excessive glucocorticoid doses may cause pubertal delay by inhibiting release of gonadotropins or directly inhibiting secretion of sex steroids, but primary gonadal failure can also occur secondary to conditioning.
The monitoring approach is to, at least annually, plot height, height‐velocity, weight annually on age/gender‐appropriate (and sometimes disease‐specific) growth charts, along with Tanner staging to assess pubertal status. Bone age is followed in growing children to assess skeletal maturity and growth potential while children progress towards final adult height. Referral to pediatric endocrinology is advised if a child is falling off their height percentile channel and/or not entering puberty at the usual time. Coordination of testosterone or estrogen therapy for pubertal delay must be carefully coordinated with hGH therapy so that premature closure of epiphyses and compromise of final adult height is avoided. Issues to note are that there is no threshold dose of glucorticoids above which response to hGH clearly and predictably declines. However, the best growth responses to hGH appear to occur when prednisone is dosed at ≤0.5 mg/kg/once daily on alternate‐days [97,98]. A reasonable approach is to wait until prednisone therapy is at every‐other‐day dosing or at least <5 mg/m2/day before hGH testing and/or replacement therapy are undertaken. HCT survivors who received TBI ± CNS radiation showed an unfavorable profile of inflammation (higher IL‐6), adipokines (higher leptin and lower adiponectin), and sarcopenic obesity (higher percent fat mass and lower lean body mass per DEXA scan) compared to sibling controls despite having similar BMI [99,100]. Increasing lean body mass may represent a tangible target for mitigating high cardiometabolic risks of HCT survivors. Interestingly, obese prepubertal boys who received 6 months of hGH, without additional dietary or exercise modifications, experienced a 5% increase in lean body mass which lends support to the hypothesis that hGH may provide other benefits in addition to promoting height growth [101].
Hypogonadism, pubertal delay and infertility
Exposure‐related gonadal toxicity may cause infertility in children and adults. However, whereas gonadal hormonal insufficiency causes premature menopause and, less commonly, early andropause, children can experience delayed puberty, failure to develop secondary sexual characteristics, and failure to achieve normal adult bone mass. Underlying diagnoses like thalassemia, sickle cell disease, FA, DBA, DC are at greater risk due to endocrinopathies associated with iron‐overload. In boys, Leydig cells are less sensitive to damage than spermatogonia. In prepubertal girls, hormonal function and fertility are equally impaired, and primary ovarian insufficiency is very common after myeloablative busulfan in post‐pubertal girls. Age‐appropriate monitoring of gonadotropin and gonadal hormone levels is usual and some endocrinologists find the anti‐Mullerian hormone level to be a helpful indicator of ovarian reserve.
Thyroid dysfunction
Abnormal thyroid function is most often associated with conditioning that includes irradiation which results in compensated or overt hypothyroidism [102]. Transient sick euthyroid syndrome (SES) is a well‐recognized, possibly adaptive response to severe systemic nonthyroidal illness and after HCT is more common in adults compared to children. SES is characterized by reduced free T3 or T4, reduced‐total thyroxine and a normal thyroid stimulating hormone (TSH). Compared to patients with a normal thyroid function panel, patients with SES were receiving higher glucocorticoid doses when thyroid function was tested but it is unclear to what extent high‐dose glucocorticoid therapy and acute GVHD were interdependent [103]. Thyroid hormone‐replacement is not indicated for SES. Isolated case reports and small case series have documented “auto”‐immune hyperthyroidism and hypothyroidism after allogeneic HCT and, in many of these cases, adoptive transfer of abnormal donor lymphocyte clones has been suggested as a possible mechanism but immune dysregulation associated with concomitant cGVHD might be a contributing factor [104,105]. Treatment of overt hypothyroidism or hyperthyroidism is identical to nontransplant situations. Though the clinical significance of antithyroid microsomal antibodies is unclear, it is of interest that these have been detected in 5%–40% of patients with cGVHD [106,107].
Iatrogenic Cushing’s Syndrome and Adrenal insufficiency
Cushingoid appearance most often results from prolonged prednisone therapy; cosmetic changes are troubling for patients, and especially for teenagers who are often already dealing with major changes of body image. Counseling may be helpful that these changes are mostly reversible, given enough time off steroids. Divided‐dose prednisone regimens should be avoided for cGVHD due to greater adrenal suppression than daily or alternating‐day regimens. Abrupt withdrawal of steroids may provoke symptoms of secondary adrenal insufficiency, which should be anticipated in any patient treated for more than 3 weeks with daily doses exceeding 7.5 mg of prednisone or equivalent. Blunted cortisol response may be life threatening when stress responses are needed. Because mineralocorticoid deficiency is not present hyperkalemia does not usually occur. Symptoms of adrenal insufficiency are usually dominated by fatigue and weakness but may be difficult to distinguish from a flare of GVHD or, steroid withdrawal syndrome; the latter is dominated by arthralgias and myalgias and tends to stabilize if taper decrements are smaller. Adrenal insufficiency may be confirmed by showing that serum cortisol at 07:00–09:00 hours is <3.6 mcg/dL or the serum cortisol at 30 or 60 minutes after a standard cosyntropin test dose (250 mcg IV) does not increase >19 mcg/dL [108–110]. Hydrocortisone 8 mg/m2 to 12 mg/m2 per day is the preferred adrenal cortisol replacement therapy. The total dose is usually divided into two to three daily doses, with half to two‐thirds of the daily dose administered at 08:00h to mimic the physiologic cortisol secretion pattern and lower doses at either 12:00h and 17:00h (or just 17:00h). The exact dose regimen is adjusted according to symptoms and signs suggestive of over‐ or under‐replacement. Though prednisone is recommended for the treatment of primary adrenal insufficiency, the longer biologic half‐life of prednisone compared to hydrocortisone makes it more likely to suppress the HPA axis. Therefore, hydrocortisone is preferable for replacement therapy in secondary adrenal insufficiency. Stress‐dose steroids should be considered for illnesses that include fever, vomiting, diarrhea, major surgery, or trauma. Recovery of the HPA axis varies from days to several months which must be considered when a taper of replacement therapy is attempted.
Insulin Resistance and Diabetes Mellitus
Two large studies suggest that the prevalence of Type II diabetes after HCT is 6–8%, which is higher than in the general population [47,111]. Reported risk factors include a diagnosis of leukemia, non‐Hispanic white ethnicity, family history of diabetes and asparaginase toxicity [111]. In one study, the risk factors of allogeneic HCT and total‐body irradiation were somewhat interrelated [47]. Patients at risk should be educated and monitored accordingly.
Neurocognitive
In this domain, the two key late effects to consider in practice are cognitive deficits with or without leukoencephalopathy, and peripheral neuropathies. The former can manifest as concentration difficulties with delayed developmental milestones and learning difficulties. Risk factors include high‐dose TBI ± additional cranial irradiation, CNS‐penetrant chemotherapies including busulfan, fludarabine, cytarabine, methotrexate, thiotepa, intrathecal agents as well as calcineurin inhibitor (CNI) therapy for GVHD. As a rule of thumb, full‐dose TBI (≥12 Gy) in a child <4 years old will drop IQ by approximately 10 points. In practical terms, if this child had average IQ before HCT, they could drop to low
