Introduction

High-dose chemotherapy or chemoradiotherapy followed by hematopoietic cell transplantation (HCT) for children and young adults with malignant or nonmalignant disorders has resulted in an ever-increasing number of long-term survivors. An understanding of the impact of the preparative regimen is important to appreciate and anticipate the effect on growth and development in children after HCT. The most common regimens utilize high-dose CY given alone or in combination with BU or other chemotherapy agents such as carmustine (BCNU), melphalan, etoposide (VP-16), fludarabine or thiotepa and given with or without TBI thorocoabdominal irradiation or TLI. Both high-dose chemotherapy and irradiation therapy are known to affect the function of the neuroendocrine system, and therefore, growth and development. Endocrine gland secretions act as stimulants to promote normal growth, and normal growth and development require balanced endocrine gland function. This article discusses the effects observed to date of the agents used in HCT preparative regimens on the endocrine function and subsequent effects on growth and development in children and young adults.

Thyroid function

Normal thyroid hormone production is important for normal height growth in children. Thus, subnormal thyroid hormone production contributes to decreased height growth. Irradiation of the thyroid gland has been associated with development of compensated hypothyroidism, overt hypothyroidism, thyroiditis and thyroid neoplasms.¹ After irradiation the onset of thyroid dysfunction often begins as compensated hypothyroidism with elevated thyroid-stimulating hormone (TSH) and normal thyroid hormone production, but then may progress to overt hypothyroidism over the next several decades. Hypothyroidism contributes to decreased height growth in children.

Thyroid dysfunction and an increased incidence of benign and malignant thyroid nodules may follow neck irradiation. Thyroid function is usually evaluated with thyrotropin-stimulating hormone (TSH), thyroxine (T4) and triiodothyronine (T3) and free T4. Physical examination is an unreliable way to detect thyroid nodules, and a change in thyroid hormone levels does not distinguish between benign and malignant diseases. Ultrasound detected thyroid abnormalities in 44% of survivors of childhood cancer who received irradiation to the head and neck compared to 14% with palpable lesions. Radionuclide scans confirmed the ultrasound findings in 87% of cases.² Some report thyroid malignancy occurring between 1.5 and 6.0 years after irradiation therapy, whereas others suggest a latency period for up to 40 years with a peak incidence occurring 15–25 years after irradiation exposure of 2–5 Gy.³ Studies from the Chernobyl accident indicate that children are much more susceptible to the carcinogenic effects of irradiation of the thyroid than older individuals.⁴ Thus, children who have received TBI or TLI in their HCT preparative regimens are at risk for development of thyroid neoplasms.

Results from reported studies (Table 1) demonstrate that the majority of patients prepared with chemotherapy-only preparative regimens have normal thyroid function. Compensated hypothyroidism and overt hypothyroidism often occur after TBI or TLI regimens (Table 1).^{5, 6, 7} A recent report⁵ found that factors associated with hypothyroidism were patient age <9 years, single-dose TBI and HCT in second complete remission. Fractionated TBI appears to result in a lower incidence of thyroid abnormalities, but follow-up is shorter for this group of children and development of thyroid dysfunction, and thyroid malignancies may be delayed several decades.

Table 1 - Thyroid function after hematopoietic cell transplant.

Full table

All patients who develop overt hypothyroidism should receive therapy with thyroxine managed by a pediatric endocrinologist. The benefit of thyroid replacement therapy in patients with compensated hypothyroidism remains controversial. Papillary carcinoma, toxic goiter and an adenoma have been observed between 4 and 14 years in six children after 10.0 Gy single-exposure TBI and in at least five others after exposure to fractionated TBI.⁸ All patients had abnormal thyroid function and none were treated with thyroid hormone. The adenoma was found at autopsy, but the others were treated successfully with thyroidectomy or radioactive iodine thyroid ablation. All patients who have received TBI or TLI should be examined annually with tests of thyroid function and perhaps ultrasound.

Growth

Linear growth is a finely regulated phenomenon that results from interaction of genetics, nutrition, hormones, metabolism and cerebrocortical influences. In infancy growth is largely determined by nutrition and metabolic factors, but in childhood growth is largely influenced by growth hormone (GH) and in puberty by the synergistic action of GH and sex steroids. Thus, GH has a major role in the height growth process.

The impact of GH deficiency on subsequent growth in the HCT population is difficult to determine since GH studies have not been performed consistently. Data are therefore difficult to interpret as to whether intensive chemotherapy regimens with or without CNS irradiation are associated with persistent growth impairment because only growth rates are usually reported.⁹ These and other studies suggest that recipients of chemotherapy HCT preparative regimens only without cranial irradiation have height losses that are less than observed after HCT using TBI-containing preparative regimens.^{10, 11, 12}

Irradiation to the central nervous system (CNS) has been associated with GH deficiency, which appears to be related to the child's age at the time of irradiation, the irradiation dose received, and the length of time lapsed after completion of irradiation.¹³ When children referred for HCT have received 18–24 Gy CNS irradiation prior to referral and TBI is included in their preparative regimen, their total CNS irradiation dose exceeds the estimated threshold of 30 Gy for development of GH deficiency.¹⁴ GH deficiency may develop within 2–3 years after receiving this total dose of CNS irradiation, whereas GH deficiency may not develop in patients who receive lower doses of CNS irradiation for up to 5–10 years. Thus, it may be anticipated that nearly all children who have received CNS irradiation in addition to TBI or as TBI are likely to develop GH deficiency, but for some who receive only TBI, the GH deficiency may not develop until after their growth period, depending on their age at TBI.

Following a preparative regimen with high-dose CY-only, normal growth rates and height s.d. have been observed.^{15, 16} BU, an alkylating agent frequently combined with CY in preparative regimens, is an agent that affects dividing cells as well as nondividing cells and crosses the blood–brain barrier. The effect of BU on growth appears to depend on patient age at the time of transplant with younger children (<8 years) having normal growth and those older (8 years) not appearing to achieve their genetic height potential.^{16, 17, 18} The European Group for Blood and Marrow Transplantation reported final height to be -0.391.16,¹⁶ and we have observed the final height s.d. score to be -0.3 to -0.4 (1) s.d. or height at a mean of the 30th percentile.

Growth impairment after TBI preparative regimens has been well documented.^{15, 19, 20} Children given single-exposure TBI usually have been the group with the greatest incidence of growth rate impairment which often has been associated with decreased GH production. Fractionated TBI is also associated with decreased growth rates and decreased height s.d. scores.^{21, 22, 23} Patients who received CNS irradiation prior to TBI had height s.d. scores that were less than those who had not received CNS irradiation.^{24, 25, 26} Patient age at transplant has been noted to be a significant factor in predicting final height since children less than 10 years of age at transplant have the greatest risk for growth failure and significantly decreased adult height. Boys also appear to be at greatest risk of growth failure compared with girls.

GH stimulates growth of epiphyseal cartilage and subsequent bone growth directly by action of insulin-like growth factor I (IGF-1). When insufficient GH is produced, growth velocity and bone maturation are delayed and the divergence of the growth rate from normal increases with age unless replacement therapy is administered. The total height gained from GH therapy is inversely related to patient age at the start of GH treatment and positively related to the duration of therapy. Treatment with GH before the child's height has decreased to below the third percentile (-1.8 s.d.) results in the greatest final height response to treatment. Growth before puberty is the major determinant of final height, therefore treatment with GH during the prepubertal period needs to be optimized.

GH has additional beneficial effects for the growing child in addition to height growth. Studies in children with GH deficiency have shown that GH deficiency-associated reduced bone turnover is reversed with GH therapy.²⁷ Because the foundation for skeletal health is established in childhood, prevention of decreased bone mineral density begins by optimizing gains in bone mineral acquisition throughout childhood. Although bone health among children after HCT has not been well studied, one report shows that the effect of GH and bisphosphonate therapy on bone mineral density resulted in an improvement in bone mineral density among those treated with GH and bisphosphonate compared to those who received GH without bisphosphonate.²⁸

The incidence of GH deficiency after TBI and HCT varies from 20 to 85% depending upon differences in time of testing after HCT, differences in preparative regimen received, inclusion of patients with and without cranial irradiation and use of different methods of GH testing.^{20, 29, 30, 31} Even though GH deficiency has been observed, less than half have received GH therapy. Many investigators felt, based on small numbers treated, short treatment durations, and treatment of older age children, that GH therapy did not benefit the children. Recent data suggests that improvements in final height can be achieved with contemporary dosing regimens that utilize daily GH doses of 0.04 mg/kg, increasing to 0.06 mg/kg at puberty.³² One recent study shows that when a group of GH deficient children transplanted with fractionated TBI either received or did not receive GH therapy, final height was a function of the age at treatment and patient gender.²³ Male patients had the poorest growth. Figure 1 shows the final height for 42 children with GH deficiency treated with GH and 48 children with GH deficiency who were not treated with GH is influenced by age at the time of TBI and at time of treatment with GH.²³ This study demonstrated that children 2–10 years of age who were treated with GH had significantly better final height than children in the same age group not treated with GH. In contrast little benefit in height growth was present among GH-treated children who were older than 10 years at transplant. This study also showed no untoward or unexpected side effects related to GH therapy (Figure 1).

Figure 1.

Final height for 42 children with growth hormone deficiency (GHD) treated with growth hormone (GH) and 48 children with GHD not treated with GH.

Full figure and legend (35K)

Evaluation of the child with decreased height growth includes an accurate measurement of height using the Harpenden stadiometer, a measurement of bone age and two measurements of GH secretion (Table 2). The determination of who should be treated and management of treatment with GH is best done by a pediatric endocrinologist for it involves monitoring not only of growth but also the toxicities associated with GH administration, including management of other endocrine hormone functions. Who to treat with GH is also complex and involves considerations of height growth per interval of time (for example, every 6 months), genetics and results of bone age, GH testing. Treatment of the appropriate patients with GH is beneficial, however, because of improvements in final height.²³

Table 2 - Post transplant endocrine evaluations.

Full table

Puberty

The transitional stage when the individual matures from a sexually immature individual to a sexually mature individual is known as puberty. This stage is accompanied by substantial changes in gonadal and GH activity, development of secondary sexual characteristics and increased growth velocity. The timing and sequence of these pubertal events varies between individuals, which makes it not possible to assess a child's pubertal development based only on chronological age. Normally, pubertal development is closely related with osseous maturation measured by bone age. The initiation and completion of puberty requires an intact hypothalamic–pituitary–gonadal axis. The normal pubertal growth rate is approximately 1.5–2 times greater than the prepubertal growth rate.³³ When the pubertal sex hormone secretion is absent, the increased growth velocity associated with the pubertal growth spurt is substantially blunted and the development of secondary sexual characteristics is delayed or absent.

Sex hormones indirectly stimulate linear growth by increasing endogenous GH secretion.³⁴ This leads to increasing circulating and tissue levels of IGF-1, which activates growth at the level of bone and cartilage. Thus, treatment with low-to-moderate doses of sex hormones may promote increased height growth, while physiological adult doses of sex hormones will likely result in a greater influence on skeletal maturation with compromise in final adult height. Children with hypogonadotropic hypogonadism have an absence of sex hormone production, delayed puberty, delayed pubertal growth spurt and a decrease in final adult height.³⁵

As shown in Table 3, the pubertal development of those children who received CY-only preparative regimen is essentially normal, whereas those who received BUCY preparative regimen have delayed development. Table 3 also shows the pubertal development of children who received either 10 Gy single-exposure TBI or 12–15.75 Gy fractionated exposure TBI. As can be seen, approximately half of the children developed normally through puberty after fractionated TBI, whereas substantially less developed normally through puberty after single-exposure TBI.

Table 3 - Pubertal development after transplant.

Full table

It is recommended that the pubertal development of children who have received a hematopoietic cell transplant be monitored carefully after patients reach a chronological age of 10–11 years. Tanner Developmental Scores should be determined annually. Children with evidence of gonadal failure and delayed pubertal development will likely benefit from the use of supplemental hormones administered with the guidance of a pediatric endocrinologist. Doses of sex hormone therapy should begin low with gradual increase to simulate natural hormone production and to prevent premature advancement of bone age and to promote the pubertal growth spurt. Patients with normal pubertal development, normal gonadotropins and sex hormone production should receive appropriate sexual behavior counseling as pregnancy could occur.

Conclusions

Endocrine function evaluations following HCT demonstrate that the occurrence of abnormalities may influence the child's growth and development and are related to the type of HCT preparative regimen received. Children who receive CY-only preparative regimen usually do not have endocrine function abnormalities, but individuals who receive BUCY preparative regimens are likely to have pubertal developmental problems. Children who have received TBI-based preparative regimens may have thyroid function abnormalities, growth and GH abnormalities as well as delayed pubertal development.

References

1. Fleming ID, Black TL, Thompson EI, Pratt C, Rao B, Hustu O. Thyroid dysfunction and neoplasia in children receiving neck irradiation for cancer. Cancer 1985; 55: 1190–1194. | Article | PubMed | ISI | ChemPort |
2. Crom DB, Kaste SC, Tubergen DG, Greenwald CA, Sharp GB, Hudson MM. Ultrasonography for thyroid screening after head and neck irradiation in childhood cancer survivors. Med Pediatr Oncol 1997; 28: 15–21. | Article | PubMed | ISI | ChemPort |
3. Shore RE, Woodard E, Hildreth N, Dvoretsky P, Hempelmann L, Pasternack B. Thyroid tumors following thymus irradiation. J Natl Cancer Inst 1985; 74: 1177–1184. | PubMed | ChemPort |
4. Antonelli A, Miccoli P, Derzhitski VE, Panasiuk G, Solovieva N, Baschieri L. Epidemiologic and clinical evaluation of thyroid cancer in children from the Gomel region (Belarus). World J Surg 1996; 20: 867–871. | Article | PubMed | ISI | ChemPort |
5. Berger C, Le-Gallo B, Donadieu J, Richard O, Devergie A, Galambrun C et al. Late thyroid toxicity in 153 long-term survivors of allogeneic bone marrow transplantation for acute lymphoblastic leukaemia. Bone Marrow Transplant 2005; 35: 991–995. | Article | PubMed | ISI | ChemPort |
6. Katsanis E, Shapiro RS, Robison LL, Haake RJ, Kim T, Pescovitz OH. Thyroid dysfunction following bone marrow transplantation: long-term follow-up of 80 pediatric patients. Bone Marrow Transplant 1990; 5: 335–340. | PubMed | ISI | ChemPort |
7. Boulad F, Bromley M, Black P, Heller G, Sarafoglou K, Gillio A et al. Thyroid dysfunction following bone marrow transplantation using hyperfractionated radiation. Bone Marrow Transplant 1995; 15: 71–76. | PubMed | ISI | ChemPort |
8. Sanders JE, The Long-Term Follow-Up Team. Endocrine problems in children after bone marrow transplant for hematologic malignancies. Bone Marrow Transplant 1991; 8: 2–4. | PubMed | ISI |
9. Robinson LL, Nesbit Jr ME, Sather HN, Meadows AT, Ortega JA, Hammond GD. Height of children successfully treated for acute lymphoblastic leukemia: a report from the late effects study committee of children's cancer study group. Med Pediatr Oncol 1985; 13: 14–21. | Article | PubMed |
10. Leahey AM, Teunissen H, Friedman DL, Moshang T, Lange BJ, Meadows AT. Late effects of chemotherapy compared to bone marrow transplantation in the treatment of pediatric acute myeloid leukemia and myelodysplasia. Med Pediatr Oncol 1999; 32: 163–169. | Article | PubMed | ISI | ChemPort |
11. Leung W, Hudson MM, Strickland DK, Phipps S, Srivastava DK, Ribeiro RC et al. Late effects of treatment in survivors of childhood acute myeloid leukemia. J Clin Oncol 2000; 18: 3273–3279. | PubMed | ISI | ChemPort |
12. Leung W, Hudson M, Zhu Y, Rivera GK, Ribeiro RC, Sandlund JT et al. Late effects in survivors of infant leukemia. Leukemia 2000; 14: 1185–1190. | Article | PubMed | ISI | ChemPort |
13. Shalet SM. Irradiation-induced growth failure. Clin Endocrinol Metab 1986; 15: 591–606. | Article | PubMed | ISI | ChemPort |
14. Shalet SM, Clayton PE, Price DA. Growth and pituitary function in children treated for brain tumours or acute lymphoblastic leukaemia. Horm Res 1988; 30: 53–61. | PubMed | ISI | ChemPort |
15. Sanders JE, Buckner CD, Sullivan KM, Doney K, Appelbaum F, Witherspoon R et al. Growth and development in children after bone marrow transplantation. Horm Res 1988; 30: 92–97. | PubMed | ISI | ChemPort |
16. Cohen A, Rovelli A, Bakker B, Uderzo C, Van Lint MT, Esperou H et al. Final height of patients who underwent bone marrow transplantation for hematological disorders during childhood: a study by the working party for late effects-EBMT. Blood 1999; 93: 4109–4115. | PubMed | ISI | ChemPort |
17. De Simone M, Verrotti A, Lughetti L, Palumbo M, Di Bartolomeo P, Olioso P et al. Final height of thalassemic patients who underwent bone marrow transplantation during childhood. Bone Marrow Transplant 2001; 28: 201–205. | Article | PubMed | ISI | ChemPort |
18. Afify Z, Shaw PJ, Clavano-Harding A, Cowell CT. Growth and endocrine function in children with acute myeloid leukaemia after bone marrow transplantation using busulfan/cyclophosphamide. Bone Marrow Transplant 2000; 25: 1087–1092. | Article | PubMed | ISI | ChemPort |
19. Sanders JE, Pritchard S, Mahoney P, Amos D, Buckner CD, Witherspoon RP et al. Growth and development following marrow transplantation for leukemia. Blood 1986; 68: 1129–1135. | PubMed | ISI | ChemPort |
20. Brauner R, Adan L, Souberbielle JC, Esperou H, Michon J, Devergie A et al. Contribution of growth hormone deficiency to the growth failure that follows bone marrow transplantation. J Pediatr 1997; 130: 785–792. | Article | PubMed | ISI | ChemPort |
21. Brauner R, Fontoura M, Zucker JM, Devergie A, Souberbielle JC, Prevot-Saucet C et al. Growth and growth hormone secretion after bone marrow transplantation. Arch Dis Child 1993; 68: 458–463. | PubMed | ISI | ChemPort |
22. Thomas BC, Stanhope R, Plowman PN, Leiper AD. Growth following single fraction and fractionated total body irradiation for bone marrow transplantation. Eur J Pediatr 1993; 152: 888–892. | Article | PubMed | ISI | ChemPort |
23. Sanders JE, Guthrie KA, Hoffmeister PA, Woolfrey AE, Carpenter PA, Appelbaum FR. Final adult heights of patients who received hematopoietic cell transplantation in childhood. Blood 2005; 105: 1348–1354. | Article | PubMed | ISI | ChemPort |
24. Giorgiani G, Bozzola M, Locatelli F, Picco P, Zecca M, Cisternino M et al. Role of busulfan and total body irradiation on growth of prepubertal children receiving bone marrow transplantation and results of treatment with recombinant human growth hormone. Blood 1995; 86: 825–831. | PubMed | ISI | ChemPort |
25. Holm K, Nysom K, Rasmussen MH, Hertz H, Jacobsen N, Skakkebaek NE et al. Growth, growth hormone and final height after BMT. Possible recovery of irradiation-induced growth hormone insufficiency. Bone Marrow Transplant 1996; 18: 163–170. | PubMed | ISI | ChemPort |
26. Cohen A, Rovelli A, Van-Lint MT, Uderzo C, Morchio A, Pezzini C et al. Final height of patients who underwent bone marrow transplantation during childhood. Arch Dis Child 1996; 74: 437–440. | PubMed | ISI | ChemPort |
27. Baroncelli GI, Bertelloni S, Ceccarelli C, Cupelli D, Saggese G. Dynamics of bone turnover in children with GH deficiency treated with GH until final height. Eur J Endocrinol 2000; 142: 549–556. | Article | PubMed | ISI | ChemPort |
28. Carpenter PA, Hoffmeister P, Chesnut III CH, Storer B, Charuhas PM, Woolfrey AE et al. Bisphosphonate therapy for reduced bone mineral density in children with chronic graft-versus-host disease. Biol Blood Marrow Transplant 2007; 13: 683–690. | Article | PubMed | ISI | ChemPort |
29. Huma Z, Boulad F, Black P, Heller G, Sklar CA. Growth in children after bone marrow transplantation for acute leukemia. Blood 1995; 86: 819–824. | PubMed | ISI | ChemPort |
30. Ogilvy-Stuart AL, Clark DJ, Wallace WH, Gibson BE, Stevens RF, Shalet SM et al. Endocrine deficit after fractionated total body irradiation. Arch Dis Child 1992; 67: 1107–1110. | PubMed | ChemPort |
31. Shalet SM, Toogood A, Rahim A, Brennan BM. The diagnosis of growth hormone deficiency in children and adults (Review). Endocr Rev 1998; 19: 203–223. | Article | PubMed | ISI | ChemPort |
32. MacGillivray MH, Baptista J, Johanson A. Outcome of a four-year randomized study of daily versus three times weekly somatropin treatment in prepubertal naive growth hormone-deficient children. Genentech study group. J Clin Endocrinol Metab 1996; 81: 1806–1809. | Article | PubMed | ISI | ChemPort |
33. Cutter GB, Cassosta FG, Ross JR. Pubertal growth: physiology and pathophysiology. Recent Prog Horm Res 1986; 42: 443–470. | PubMed |
34. Pescovitz OH. The endocrinology of the pubertal growth spurt. Acta Paediatr Scand Suppl 1990; 367: 119–125. | Article | PubMed | ChemPort |
35. Bourguignon J-P. Linear growth as a function of age at onset of puberty and sex steroid dosage: therapeutic implications. Endocr Rev 1988; 9: 467–488. | PubMed | ISI | ChemPort |