Endocrine and Metabolic Complications
Thyroid Dysfunction
New‐onset thyroid disease is one of the most common non‐malignant late effects after AHSCT, with a cumulative incidence of 14.2% [3]. The median time to diagnosis from transplant is approximately 1 year [3]. A Spanish study on 169 AHSCT survivors has identified thyroid dysfunction in 62 (37%) patients, with subclinical hypothyroidism, overt primary hypothyroidism, and subclinical hyperthyroidism in 54, 6, and 2 patients respectively [35]. Transient subclinical hypothyroidism can be seen in 16% of patients at 3 months posttransplant, which typically disappears at 12 months [36]. A Swedish study on 111 AHSCT survivors showed thyroid dysfunction in 20 patients, 16 of whom had received prior TBI. Notably, in patients who developed thyroid dysfunction, pretransplant thyroid stimulating hormone (TSH) level was significantly higher compared to those who did not. All patients should have at least yearly thyroid function screening after transplant 17,18]. Patients should also be educated regarding signs and symptoms of hypo‐ and hyperthyroidism.
Bone Complications
Bone disease is an important non‐malignant late effect after AHSCT [3]. Common bone complications are osteopenia, osteoporosis, and avascular necrosis. Osteopenia and osteoporosis are measured clinically by the T‐score on dual‐energy X‐ray absorptiometry (DEXA) scan [7]. Osteopenia is diagnosed by a T‐score of ‐1.0 to ‐2.5 and osteoporosis is diagnosed by a T‐score of less than ‐2.5 or presence of fragility fractures [37]. Common risk‐factors for bone density loss from broader osteoporosis literature are glucocorticoid use, exposure to radiation, vitamin D deficiency, and hypogonadism. Notably, a prednisone equivalent dose of more than 7.5 mg/day and a cumulative dose of more than 5 grams is associated with an increased risk of osteoporosis [38], which is clinically relevant in myeloma and lymphoma AHSCT recipients who may have exposure to corticosteroids as a part of pre‐ and/or posttransplant therapy, and will be discussed further below.
In a single‐institution study of 493 auto‐transplant survivors, the cumulative incidence of avascular necrosis was 4.3% at a median follow‐up of 3 years from transplant [3]. This further translated into an increased need for joint replacement surgery, with an incidence of 4.2% posttransplant compared to a pretransplant prevalence of 1.8%. Notably, the median time‐to‐diagnosis of avascular necrosis was around 1 year, and the median time‐to‐joint replacement surgery was 3 years from AHSCT. The cumulative incidence of osteoporosis was also higher at 9.7% after transplant compared to a pretransplant prevalence of 2.4% [3]. Risk‐factors for development of osteoporosis in the entire cohort of auto‐ and allogeneic‐transplant survivors were diabetes mellitus, lung disease, chronic graft‐versus‐host‐disease (cGVHD), and avascular necrosis/joint replacement. Another large study of approximately 600 AHSCT survivors showed a 2.9% cumulative incidence of avascular necrosis at 10 years [39]. A prospective study from Roswell Park measured bone mineral density (BMD) at pretransplant baseline and day 100 in both auto‐ and allogeneic transplant recipients to characterize the trajectory and risk‐factors of bone loss [40]. Interestingly, the magnitude of accelerated bone loss in the immediate posttransplant period was similar in auto‐ and allogeneic‐transplant recipients and was comparable to bone loss from 7–17 years’ worth of aging. Furthermore, a primary lymphoma diagnosis was the only risk factor for accelerated bone loss in AHSCT recipients.
Based on the trajectory and risk‐factors of bone complications after AHSCT, DEXA scan should be performed to assess bone density at one year and subsequently as clinically indicated. Diagnostic MRI should be performed when avascular necrosis is suspected, and orthopedic oncology should be consulted. The Fracture Risk Assessment Tool (FRAX) is widely used to risk‐stratify patients with osteoporosis. In patients with calcium or vitamin D deficiency, supplementation with 800–1200 mg of calcium and at least 50 nmol/l of 25‐hydroxyvitamin‐D can be beneficial in preventing fragility fractures [41]. Lifestyle interventions, including regular physical activity, good nutrition, and avoiding smoking or excessive alcohol intake should be implemented in AHSCT survivors for preserving bone health. Patients at a high risk of fragility fracture should initiate pharmacologic therapy with bisphosphonates or monoclonal antibodies directed against receptor activator of nuclear factor‐κB ligand (RANKL) [41]. Though most clinical trials in osteoporosis have limited the duration to around 3 years, optimal duration of bone strengthening agents remains controversial. Novel bone modifying agents, including RANKL inhibitor (Denosumab) is currently being evaluated in transplant survivors.
Gonadal Dysfunction
Hypogonadism is common in both males and females after AHSCT. In males, cytotoxic chemotherapy and irradiation can damage the germinal epithelium of testes and Leydig cells [42], leading to hypogonadism. At 3 months post‐AHSCT, 85% of men have high follicle stimulating hormone (FSH) level and about one‐third have low testosterone levels, indicating inhibition of the reproductive axis [36]. Though testosterone level in most men normalizes at 1 year, FSH level remains elevated, along with azoospermia in around 90% [36]. Prior exposure to pelvic or abdominal radiotherapy is associated with high FSH level. A small prospective study on male sexual function in AHSCT survivors who were disease free for at least 6 months after transplant demonstrated normal patient‐reported interest in sexual activities and erectile function in more than three‐quarters of survivors, despite high FSH, high luteinizing hormone (LH), and low testosterone level in 88%, 47%, and 38% of patients respectively [43]. Notably, decreased testosterone level correlated with loss of libido and a diagnosis of Hodgkin disease. A study from the Center for International Blood and Marrow Transplant Research (CIBMTR) database identified 13 male AHSCT survivors whose female partners had successful pregnancy [44]. Notably, in these males, the median age at AHSCT was 28 years, with the most common primary diagnosis being lymphoma. Furthermore, only one out of 13 had received TBI as a part of the conditioning regimen and approximately one‐quarter had received radiation prior to transplant. Gonadal function in males should be monitored with serum FSH, LH, and testosterone levels [17]. In pre‐pubertal boys, annual FSH and LH monitoring should be considered from the age of nine. Testosterone level should also be monitored to ensure normal progression of puberty. Semen banking or cryopreservation of testicular tissue should be discussed prior to transplant.
Ovarian suppression, due to damage to follicles by gonadotoxic chemotherapy and/or radiation, is common in females. A Canadian study investigated ovarian function in 17 AHSCT survivors less than 50 years of age who were alive and disease‐free for at least 18 months after transplant [45]. Notably, the median age at transplant was 27 years in this study. All patients became menopausal immediately after AHSCT, with approximately one‐third recovering ovarian function at a median of 24 months after AHSCT [45]. The median age at transplant for patients who recovered ovarian function versus those who did not was 19 and 30 years respectively (p = 0.03). Furthermore, exposure to TBI as a part of conditioning regimen demonstrated a trend towards sustained loss of ovarian function. Another study on 21 auto‐transplant recipients aged 11–21 years showed clinical and hormonal evidence of ovarian failure in approximately 60% at a median of 7 years posttransplant [46]. Notably, exposure to high‐dose busulfan in conditioning regimen was associated with severe and persistent ovarian failure. A study from the CIBMTR database identified 20 women who reported successful pregnancy after AHSCT [44]. The median age at AHSCT was 22 years and none of these women had received TBI as a part of the conditioning regimen. Another study from the European Society for Blood and Marrow Transplantation identified 39 female patients who successfully conceived after transplant [47]. The median age at transplant of these 39 women was 24 years, with the median time from AHSCT to pregnancy being 2.5 years. Only 5% of these patients had received TBI as a part of conditioning [47]. Prepubertal girls undergoing AHSCT should be referred to endocrinology for full evaluation if there is a delay in puberty onset. Monitoring