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 average IQ (with vocational limitations), whereas if a child starting at low‐average might drop to borderline and subsequently be suited for manual labor or have no job options. Cranial boost irradiation amplifies the risk for cognitive impairment. Hearing loss can contribute to cognitive impairment and is associated with cranial radiation doses ≥30 Gy. Platinum therapy used pretransplant or for HCT conditioning (e.g. high‐risk neuroblastoma) can cause hearing loss accompanied by tinnitus and vertigo (see Table 8.1).
Glucocorticoids can cause a variety of cognitive effects including mood disturbances that can be problematic for patients. Infection with HHV6, HSV, VZV, CMV toxoplasmosis and JC virus generally needs exclusion in cases of post‐HCT cognitive decline. Underlying diseases like FA, DC, Hurler syndrome, ALD, SCID and SCD may have pretransplant neurologic deficits that may stabilize or progress after HCT (see Table 8.1 for screening advice).
Peripheral neuropathy can be a chief complaint for some survivors and etiologies frequently include pre‐HCT neurotoxic chemotherapies like vincristine, platinum agents, or brentuximab, and posttransplant CNI therapy can exacerbate. Management of painful dysesthesias can be difficult but use of gabapentin or pregabalin is often considered.
Psychological and quality of life
Pediatric HCT survivors are at risk for depression, fatigue, pain, social withdrawal, educational problems, vocational problems including unemployment and dependent living (see Table 8.1). They are less likely to report risky health behaviors (alcohol and smoking). Among autologous recipients younger age and current chronic pan were independently associated with greater depression and fatigue and among allogeneic recipients, cGVHD severity, being female, and with current pain were associated with both depression and fatigue [112].
Subsequent neoplasms (SMN)