Endocrine late effects after bone marrow transplant
Article first published online: 3 JUL 2002
British Journal of Haematology
Volume 118, Issue 1, pages 58–66, July 2002
How to Cite
Brennan , B. M. D. and Shalet , S. M. (2002), Endocrine late effects after bone marrow transplant. British Journal of Haematology, 118: 58–66. doi: 10.1046/j.1365-2141.2002.03527.x
- Issue published online: 3 JUL 2002
- Article first published online: 3 JUL 2002
- bone marrow transplant;
- endocrine late effects;
- children and adults
Bone marrow transplantation (BMT) has increased significantly in the last decade and encompasses allogeneic and autologous transplantation of stem cells from bone marrow, peripheral blood and umbilical cord blood. Bone marrow transplantation is mainly used to treat patients with poor prognosis leukaemia but also other advanced or relapsed cancers and non-malignant disorders, so that now between 30 000 and 40 000 transplants are performed world-wide per year (Horowitz, 1998).
The success story in transplantation medicine, however, has resulted in significant endocrine late effects both in children and adults including thyroid, pituitary and gonadal dysfunction, with adverse effects on the growth of children. The relative risk of these adverse events is influenced by the underlying pathological condition, previous treatment for that condition, the use of total body irradiation (TBI) and the irradiation schedule, and the nature and quantity of the cytotoxic drugs used in the BMT preparative regimen.
The BMT preparative or conditioning regimen aims to totally ablate the bone marrow and its stem cells and, hence, the host immune system. Therefore, the occurrence of varying degrees of damage to normal tissues is not surprising. Single-agent chemotherapy conditioning regimens such as cyclophosphamide in children with severe aplastic anaemia (SAA) do not appear to adversely affect growth (Sullivan et al, 1984) or final height, although data are extremely limited (Cohen et al, 1996). The effect on growth, however, is significant in SAA if total lymphoid irradiation (TLI) is added (Bushhouse et al, 1989) and even more profound in leukaemic children if TBI is used (Sanders et al, 1986; Leiper et al, 1987; Bushhouse et al, 1989; Brauner et al, 1993; Thomas et al, 1993a; Michel et al, 1997).
The impact of the combination of high-dose cyclophosphamide (CY) in combination with high-dose busulphan (BU) is contentious. Wingard et al (1992) found no difference between the impairment of growth rates over the first two post-transplant years in patients treated with BU/CY and those treated with CY/TBI. Sanders (1994) reported similar findings, and Manenti et al, (1989) described reduced growth velocity in children aged between 10 and 12 years following a BMT for thalassaemia major with a BU/CY preparative regimen. The latter situation, however, must be complicated by the potential contribution of iron overload-induced gonadotrophin deficiency and pubertal delay. Sanders (1994), however, also reported a significant incidence of growth hormone (GH) deficiency in children transplanted for leukaemia following BU/CY alone.
In contrast to the above reports, Liesner et al (1994); Giorgiani et al (1995); Michel et al (1997) and Afify et al (2000) did not find any significant growth impairment in 80 children (combined series) for up to 5 years after BU/CY and a BMT. Furthermore, in a small group of 10 children studied by Cohen et al (1999) final height was not adversely affected. Firm conclusions about the impact of BU/CY on growth await more final height data. On the other hand, there is suggestive evidence that intensive pre-BMT chemotherapy may adversely affect growth, as demonstrated by Willi et al (1992) in a small cohort of patients with neuroblastoma who continued to grow poorly post BMT in contrast to a group treated for leukaemia. The major therapeutic differences between the two groups included the doses of local radiotherapy and type and number of cytotoxic drugs used pre-BMT (Willi et al, 1992).
Total body irradiation
Several reports have intimated that growth impairment is worse if TBI is administered in single rather than multiple fractions (Brauner et al, 1993; Thomas et al, 1993a). Curiously, Brauner et al (1993) described a marked difference in the growth outcome in children receiving a single TBI dose of 8 Gy rather than 10 Gy, suggesting a critical threshold; alternatively, the variation in post-BMT growth between their two groups of children might be explained by differences in underlying pathologies and pre-BMT treatment schedules (Brauner et al, 1993). In contrast, Clement-De Boers et al (1996) reported final height data which indicate that a substantial height loss, approximately 2 standard deviations (SD) for boys and one SD for girls, does occur following 7 to 8 Gy single-dose TBI and that much of this height loss is late, taking place during puberty. In final height studies, which include patients in whom fractionated TBI had been administered, the loss of final height is not as substantial (Cohen et al, 1996; Holm et al, 1996). Cohen et al (1996) demonstrated a loss in height from BMT to final height of 0·9 SD, but as all patients spontaneously achieved a normal height, i.e. above −2 SDS, they counselled against growth hormone treatment. However, the median age at transplant of the 28 patients studied by Cohen et al (1996) was 10·8 years. Sanders (1999) observed a greater impact on final height in 15 children who had not received GH therapy and who were less than 6-years of age at the time of transplantation, the mean final adult height was −3·49 (± 1·77). In 67 children transplanted between 6 and 12 years old, the mean final height was −1·92 (± 1·43) and, finally, −0·37 (± 1·38) in 93 children 12–15 years old (P = 0·0001). Holm et al (1996) demonstrated that the loss at final height amounted to 7·9 cm in females and 8·6 cm in males and these estimates were based on a mixed cohort who had received single- and fractionated-dose TBI. No difference was found between final height and target height (Holm et al, 1996). Growth data following fractionated TBI in larger series, however, although devoid of information about final height, do not appear to support a beneficial effect of fractionating TBI with regard to growth (Brauner et al, 1997).
Cranial irradiation prior to BMT caused the greater loss in height compared with TBI alone (Cohen et al, 1996; Holm et al, 1996). At final height this amounted to a loss of 1·46 SD (Cohen et al, 1996).
In addition to the significant reduction in standing height SD after TBI, altered body proportions with a relatively short spine have been described (Thomas et al, 1993a; Holm et al, 1996). The skeletal disproportion has been seen as early as 1 year after TBI for acute lymphoblastic leukaemia (ALL), irrespective of the schedule of radiation, either single or fractionated. Furthermore, GH deficiency, per se, is associated with normal skeletal proportions, implying that the skeletal disproportion seen after TBI results from radiation-induced skeletal dysplasia.
Graft-versus-host disease and post-transplant complications
Graft-versus-host disease (GVHD) complicating BMT may be associated with considerable impairment of growth (Sanders et al, 1986). The acute growth-suppressive effects of glucocorticoids would explain the deceleration of linear growth in most chronic GVHD patients. In some patients, however, once chronic GVHD is controlled, growth rates may return to normal and catch-up growth may be seen (Sanders, 1994). Other children fail to achieve catch-up growth after completion of treatment and, equally, decreased growth rates of the patients with chronic GVHD who did not receive treatment suggest that factors other than steroids contributed to their decreased growth (Sanders et al, 1986), i.e. the disease process itself. The effect of post-transplant complications has been further explored by Adan et al (1997). In this series, the group with no complications 4 years post BMT showed a mean height of 0·5 ± 0·3 SD, while the group with complications had a mean height of − 1·6 ± 0·3 SD. All patients had been conditioned with chemotherapy alone.
Growth hormone status
There are now many studies which have shown a significant incidence of GH deficiency (20–70%) following TBI and high-dose CY (Borgstrom & Bolme, 1988; Sanders et al, 1988a; Hovi et al, 1990; Papadimitriou et al, 1991; Ogilvy-Stuart et al, 1992; Olshan et al, 1993; Huma et al, 1995; Brauner et al, 1997). The majority of these studies have reported impaired GH responses to provocative stimuli, although a few groups have described reduced spontaneous GH secretion (Borgstrom, 1988; Hovi et al, 1990). If TBI is fractionated, GH status is not spared (Thomas et al, 1993a; Huma et al, 1995) and there is also a clearer picture with regard to the radiation threshold dose required to induce GH deficiency. On the basis of GH provocative tests and insulin-like growth factor-1 (IGF-1) estimations, Clement-De Boers et al (1996) found no evidence of GH deficiency in eight children growing poorly after a single TBI dose of 7–8 Gy, whereas a single TBI dose of 10 Gy or fractionated doses of 12 Gy clearly do induce GH deficiency (Ogilvy-Stuart et al, 1992; Brauner et al, 1997). Holm et al (1996), with repeated assessment of GH status over time, showed improvement in GH secretion in nine individuals. This implies that caution is required in interpreting GH status in studies in which it has only been assessed on a single occasion. Couto-Silva et al (2000) have tried to analyse factors other than GH deficiency causing poor growth following BMT. Significant numbers of patients who had received TBI had GH deficiency defined by responses to pharmacological tests. This was complicated by persistently low body mass index (BMI) and low leptin levels, leading the authors to imply that poor nutrition may be a factor and that nutritional support in addition to GH replacement may optimize the growth rate of these patients (Couto-Silva et al, 2000). Taskinen & Saarinen-Pihkala (1998) also suggested that nutritional status, in particular pretransplant, had an impact on height velocity in the post-transplant period, with those patients with the poorest nutritional status having the worst post-transplant growth.
In contrast to most of the paediatric series, GH secretion does not appear to be influenced by TBI administered in adult life. Littley et al (1991) studied 18 adults who had received TBI and a BMT between 17 and 55 months earlier. They all had a normal peak GH response to a GH provocation test, which supports the hypothesis that the GH status of adults compared with that of children is less vulnerable to irradiation damage. Kauppila et al (1998) suggested that a minority of adult patients may show an impaired GH response to a provocative test following TBI for a BMT; all of their patients, however, had a normal IGF-1 level and the provocative test (growth hormone-releasing hormone, GHRH) chosen to assess GH status was a poor one (Shalet et al, 1998).
A remaining unanswered question concerns the GH status of adults who were considered to be and treated for GH deficiency in childhood following a conditioning regimen for a BMT.
In general, adults with GH deficiency only receive GH replacement if the degree of deficiency is considered to be severe (Shalet et al, 1998). Typically the GH status of a child considered for GH replacement following TBI is only moderately impaired; therefore it is unlikely that in adult life the biochemical criteria required to justify GH replacement would be satisfied in such an individual. Of course this is not the case for the patient who had received both cranial irradiation and TBI in childhood; under these circumstances the probability of severe GH deficiency in adult life is considerable.
Growth hormone therapy
The literature contains no data on pubertal growth and relatively little information on final height achieved in response to GH replacement in children with TBI-induced GH deficiency (Cohen et al, 1999). The majority of the therapeutic results are short-term, usually 1 year, with occasional studies extending to 3 years (Papadimitriou et al, 1991). Furthermore, most series contain relatively small numbers of children and the growth data are documented in insufficient detail, although there is general agreement that there is a significant improvement in height velocity during the first year of GH treatment compared with pretreatment velocity, with responses which range between a modest improvement in growth velocity and frank catch-up growth (Borgstrom & Bolme, 1988; Papadimitriou et al, 1991; Olshan et al, 1993; Giorgiani et al, 1995; Huma et al, 1995; Brauner et al, 1997).
In a subset of patients transplanted for thalassaemia, good responders to GH therapy over the first 2 years appeared to be those in whom the normal hepatic synthesis of IGF-1 was conserved, and liver damage was not irreversible (De Simone et al, 1997); the latter study was short-term and contained very small numbers of patients.
Without randomized controlled studies running through to final height, it remains impossible to predict the gain in stature from GH replacement in children with GH deficiency associated with TBI. Children will continue to be treated on an ad hoc individual basis.
It has been recognized for many years that external irradiation to the neck may lead to thyroid dysfunction and predispose to thyroid tumours. After a TBI dose of 10–12 Gy, the typical biochemical finding is a mildly elevated basal thyroid-stimulating hormone (TSH) level and a normal serum thyroxine concentration (Katsanis et al, 1990; Sanders, 1991; Ogilvy-Stuart et al, 1992; Borgstrom & Bolme, 1994). Frank biochemical hypothyroidism with a more elevated TSH level and low thyroxine concentration is rare. The thyroid dysfunction occurs both in children (Katsanis et al, 1990; Ogilvy-Stuart et al, 1992; Borgstrom & Bolme, 1994) and adults (Littley et al, 1991) following TBI and may be transient (Katsanis et al, 1990).
In a large series of 270 adults post BMT, Al-Fiar et al (1997) demonstrated a lower prevalence of abnormalities of thyroid function than observed in most other series, particularly for children. A trend was observed with an increase in the incidence of thyroid dysfunction associated with increasing TBI doses. In addition, chemotherapy-only conditioning regimens (BU/CY) were also implicated, with an 11% incidence of thyroid dysfunction compared with 16·7% for 12 Gy TBI.
The incidence of thyroid dysfunction following fractionated TBI (15–16%) (Sanders, 1991; Ogilvy-Stuart et al, 1992; Boulad et al, 1995) appears significantly less than that following single-dose TBI (46–48%) (Sanders, 1991; Thomas et al, 1993b; Borgstrom & Bolme, 1994); however, the long-term natural history of irradiation-induced thyroid dysfunction is unknown and, thus, the timing of the peak incidence of biochemical thyroid abnormalities has not been established for TBI schedules.
The risk of thyroid tumours following neck irradiation is real and dose-related (Sklar et al, 2000). The latency period between thyroid irradiation and clinical presentation with a thyroid tumour may be many years. Thus far, the number of reports of thyroid cancer following TBI are few (Sanders et al, 1988a; Uderzo et al, 1994; Rovelli et al, 1997) and the incidence low; Sanders et al (1988a) reported 2 out of 116 children with thyroid papillary carcinoma following TBI. In a recent report of second malignancies following BMT for acute leukaemia, five thyroid carcinomas occurred among 3182 children with a strong relationship between age of transplant and the occurrence of thyroid cancer (Socie et al, 2000). This suggests that the thyroid gland is highly sensitive to the effects of irradiation at a very young age. In the light of the latter risk, the majority of endocrinologists would treat a patient with an elevated TSH level with thyroxine replacement, as there are a considerable number of animal studies to suggest that lowering a previously raised TSH level into the normal range in a child, who has received irradiation to the thyroid gland, is likely to reduce the risk of thyroid malignancy. However, there are no follow-up data to support this strategy in patients treated for long periods with thyroxine.
Finally, there is an eightfold increase in the incidence of hyperthyroidism following neck irradiation for Hodgkin's disease (Sklar et al, 2000); it is a little surprising that this endocrine complication has not been reported following TBI, although the incidence is dose-related and affected by latency period.
Initially there was some concern that a significant proportion of children might require glucocorticoid replacement therapy following TBI & BMT. Sanders et al (1986) had reported a high incidence of adrenocortical dysfunction but subsequent studies have found little evidence of cortisol deficiency post BMT (Ogilvy-Stuart et al, 1992).
The adrenal gland is relatively radio-resistant and impairment of adrenocorticotropic hormone (ACTH) secretion is not seen in children receiving 18–24 Gy cranial irradiation prophylactically for ALL (Crowne et al, 1993). If the patient receives glucocorticoid therapy for GVHD, then suppression of the pituitary–adrenal axis will occur; once glucorticoid therapy is stopped then persistence of pituitary–adrenal axis suppression is related to the duration and intensity of the previous glucocorticoid exposure.
Following BMT, disturbances of insulin related metabolism are less frequently reported compared with other endocrine disturbances (Smedmyr et al, 1990; Lorini et al, 1995; Taskinen et al, 2000). Lorini et al (1995) studied pancreatic function in 34 patients undergoing BMT for haematological malignancy, of whom 24 had received a combination of TBI and cytotoxic drugs. All 34 patients showed normal glucose levels during an intravenous glucose tolerance test (GTT) and a normal haemoglobin A1C concentration. Hirayama et al (1998) reported a child who, following BMT including TBI and splenic irradiation, went on to develop type II non-insulin-dependent diabetes mellitus 8 years post transplant; a causal relationship, however, between TBI and the development of diabetes mellitus has never been established. Taskinen et al (2000) assessed glucose and lipid metabolism after BMT in 23 long-term survivors (median age 20 years). Twelve (52%) of the 23 BMT patients had insulin resistance, including impaired glucose tolerance in six and type II diabetes in four patients. The frequency of insulin resistance increased with the time since BMT. Abdominal obesity, but not overweight, was common among the patients with insulin resistance. The core signs of the metabolic syndrome were found in nine (39%) of the BMT patients compared with none of the healthy controls. As there are striking similarities between the metabolic syndrome and GH deficiency in adults, the latter may be an important explanation for these findings of Taskinen et al (2000). GH status, however, was not routinely assessed in this study.
There is a high prevalence of gonadal toxicity in both children and adults and this is well-recognized in the literature. The reproductive dysfunction is dose-related and may prove reversible in both males and females (Sanders et al, 1988a; Sklar et al, 2000). In a large retrospective review of 270 patients who underwent BMT from 1974 to 1988 including children and adults, 92% of the males and 99% of the females developed gonadal dysfunction (Mertens et al, 1998). Gonadal toxicity, however, is dependent on age, sex, type of transplantation conditioning regime and previous therapy. The gonadal toxicity may result in failure to undergo or progress in pubertal development, infertility, sexual dysfunction and the need to take hormone replacement therapy in adult life.
In women, high doses of alkylating agents, irradiation and older age at time of transplantation increases the risk of ovarian damage (Apperley & Reddy, 1995). The LD50 (the radiation dose causing the death of 50% of cells) for the human oocyte has been estimated to be < 4 Gy (Wallace et al, 1989a). Therefore, it is not surprising that a high prevalence of primary ovarian failure is found after TBI. Sanders et al (1988b) studied 144 women transplanted for leukaemia following cyclophosphamide and TBI, and reported that amenorrhea, decreased oestradiol levels and elevated gonadotrophin levels were present for the first 3 years after BMT in all 144 women, nine of whom showed recovery of ovarian function eventually.
With increasing age at transplant, the probability of restoration of ovarian function decreases by a factor of 0·8 per year of age (Sanders et al, 1988b). Patients who received 12 Gy fractionated TBI are 4·8 times more likely to recovery ovarian function than those receiving 10 Gy single dose or 15·75 Gy fractionated TBI (Sanders et al, 1988b). After TBI, ovarian failure occurs quickly usually within 3 months (Littley et al, 1991) and the majority of women are symptomatic within 6 months (Cust et al, 1989).
In women receiving chemotherapy-only conditioning, recovery of ovarian failure occurs when single-agent cyclophosphamide (200 mg/kg) (Sanders et al, 1988b) is used or following single-agent melphalan (Singhal et al, 1996). The recovery following CY only, however, is age dependent with only 5 out of 16 women over 26 years of age recovering normal ovarian function but full recovery in all 27 women < 26 years (Sanders et al, 1988b). The addition of busulphan, however, to cyclophosphamide in either ‘little’ BU/CY (busulphan 16 mg/kg, cyclophosphamide 120 mg/kg) or ‘big’ BU/CY (busulphan 16 mg/kg, cyclophosphamide 200 mg/kg) regimens causes permanent ovarian failure in all but the occasional patient (Sanders et al, 1996; Grigg et al, 2000).
Chatterjee et al (1994a) studied the acute effects of high-dose multiagent chemotherapy ± TBI on ovarian function. There was no difference between patients conditioned with or without TBI. The severity of the acute ovarian dysfunction, however, could not predict the long-term prospects for recovery of ovarian function.
In recent years there have been several reports of pregnancies following BMT either following chemotherapy alone (Borgna-Pignatti et al, 1996; Singhal et al, 1996; Jackson et al, 1997) or conditioning including TBI (Maruta et al, 1995; Milpied et al, 1996; Wang et al, 1998). In a large multicentre European survey, Salooja et al (2001) assessed outcome of conception in women and the partners of men previously treated by stem cell transplantation. The crude birth rate for the whole cohort at 1·7 per 1000 patients was significantly lower than the crude birth rate of 12·5 per 1000 patients for England and Wales. They also noticed a significantly higher than normal rate of preterm deliveries and low birth weight. Although pregnancies occurred in 20 women who had received TBI, the numbers were significantly smaller than following non-TBI regimens. The conclusions of the European survey concur with the North American experience (Sanders et al, 1996).
Despite the reports of pregnancy post BMT, the majority of adult women experience ovarian failure and, hence, infertility is inevitable. As a result, options to preserve fertility have been pursued. They include cryopreservation of embryos conceived by in vitro fertilization (IVF), which requires controlled stimulation of the ovary for several weeks, regular monitoring by ultrasonography and aspiration of follicles (Tan et al, 1994). Oocyte banking can be considered in the absence of a male partner but is still regarded as experimental (Fabbri et al, 2001). Animal studies have shown that re-implantation of frozen and thawed ovarian tissue can restore ovulatory cycles and natural fertility in animals (Parrott, 1960; Gosden et al, 1994). This led to Radford et al (2001) exploring this technique in adult women prior to high-dose chemotherapy. To date, one woman treated for Hodgkin's disease has had restoration of ovarian function, albeit for a short time post re-implantation of ovarian cortical strips. Despite these encouraging preliminary results, further patients need to be investigated to determine whether ovarian function can be restored for sufficient lengths of time in order to restore fertility. Furthermore, the risk of transmission of malignant cells via the ovarian tissue re-implanted will vary depending on the cancer type. Further information about the safety of the procedure is mandatory before such manoeuvres could enter clinical practice.
In view of the age dependency of cytotoxic induced damage, it might be predicted that the prospects of recovery of ovarian function following conditioning regimens for BMT would be better in girls than in adult women. Recent reports have now supported this hypothesis, with a significant number of girls achieving menarche, 21 out of 32 (Sarafoglou et al, 1997; Matsumoto et al, 1999), all of whom had been transplanted prepubertally and had received TBI or thoraco-abdominal irradiation; none had received busulphan. Interestingly, even a small difference in age at BMT had a profound impact on the prognosis for ovarian function. Female patients with ovarian failure had a BMT at a median age of 8·6 years compared with 6·1 years for those entering puberty spontaneously (Sarafoglou et al, 1997). Busulphan may also induce ovarian failure in prepubertal girls but, unlike TBI, the age dependency is less well-established (Teinturier et al, 1998; Afify et al, 2000).
Despite the potential for normal ovarian function, the reproductive outcome might be less good. In a young girl, the uterus and uterine blood supply are vulnerable to radiation-induced damage, leading subsequently in adult life to a greatly increased risk of miscarriage and low-birth-weight babies (Li et al, 1987; Wallace et al, 1989b; Critchley et al, 1992). Holm et al (1999) found a severe impact of TBI and BMT on the internal female genitalia, causing reduced uterine and ovarian volumes despite hormone replacement therapy (HRT) or spontaneous pubertal development. During normal puberty, uterine growth continues for several years after the menarche (Holm et al, 1995) and it is likely that the growing uterus is more vulnerable to irradiation than the adult uterus. They suggest (Holm et al, 1999) that incremental doses of HRT should be tried in order to effect normal uterine growth and that longitudinal ultrasound studies are useful tools in assessing the effects on uterine development, including endometrial response.
The findings of Holm et al (1999) were confirmed by Bath et al (1999), who showed that following TBI in childhood the adult uterus is small, with poor blood flow and an absent endometrium. Bath et al (1999) went on to give this cohort of eight women physiological sex steroid replacement for 3 months and found an improvement in all measures of uterine function, to such an extent that there was no difference in uterine blood flow and endometrial thickness from the comparison group of women who had not been irradiated. Uterine volume, however, remained small and correlated with age at irradiation; the younger the age, the smaller the uterus (Bath et al, 1999). These findings mean that, following TBI, both uterine and ovarian functional status need to be considered before choosing the optimal assisted reproductive technique for an individual woman.
There is evidence to show that the germinal epithelium of the testis is more vulnerable to the effects of both cytotoxic chemotherapy and irradiation than either the ovary or the Leydig cell (Shalet, 1994). Therefore, the universal finding of damage to the germinal epithelium would be anticipated following both gonadotoxic chemotherapy and irradiation. Occasionally, germ cell dysfunction induced by high-dose chemotherapy and single-fraction TBI of 7·5 Gy appears to be amenable to recovery, as demonstrated by the return tonormal of a previously elevated follicular-stimulating hormone (FSH) level with time (Sklar et al, 1984). More recently, however, there have been rare reports of successful pregnancies in partners of men who had undergone BMT with chemotherapy and single-fraction TBI conditioning (Jacob et al, 1995). Rarely, however, recovery of spermatogenesis has been described in adults even after fractionated TBI (Littley et al, 1991). Further adult studies from Molassiotis et al (1995) showed that the majority of males transplanted with and without TBI have persistently elevated FSH and luteinizing hormone (LH) levels post BMT, but normal testosterone levels. Marked elevation of the FSH level is associated with testicular germinal aplasia and azoospermia (van Thiel et al, 1972). Littley et al (1991) also demonstrated normal testosterone levels in the vast majority of men following BMT. Although subtle Leydig cell dysfunction may be observed in the transplanted male (Chatterjee et al, 1994b), testosterone replacement is rarely required. Chatterjee et al (2000) have reported loss of libido and erectile dysfunction in men who received high-dose chemotherapy and TBI conditioning for a BMT for myeloma; they attributed the sexual dysfunction to cavernosal arterial insufficiency. Van Basten et al (2000) published data which indicate that such vascular changes are unlikely to follow chemotherapy.
Sanders (1991) reported abnormalities in pubertal development and impaired Leydig cell function in approximately half the boys who underwent BMT before puberty at their centre. This has not been the experience of other workers nor would it be anticipated from the known relationship between radiation dose and Leydig cell function. Leiper et al (1987) and Ogilvy-Stuart et al (1992) observed normal puberty and normal testosterone levels in essentially all boys undergoing BMT with TBI conditioning. Sarafoglou et al (1997) observed similar findings in boys following BMT with high-dose chemotherapy and hyperfractionated TBI, with the exception of one boy who had received an additional testicular irradiation dose of 12 Gy. The radiation dose, however, utilized in TBI schedules, means that permanent infertility is likely for the majority of boys treated with this modality.
In the long term, decreased bone mineral density (BMD) might be expected following BMT due to the use of steroids and methotrexate during and after transplant plus the known association of BMT with growth hormone deficiency (Ogilvy-Stuart et al, 1992) and hypogonadism. Cross-sectional studies assessing BMD post BMT demonstrated reduction in BMD in children, i.e. age < 18 years at transplant, but not in adults (Bhatia et al, 1998). The reduction in BMD in patients transplanted in childhood was not confirmed, however, by Nysom et al (2000). In this study, reduced height and therefore reduced bone size was controlled for and, hence, size-adjusted bone mass was normal. In a large study of adults post BMT, Kauppila et al (1999) found 68% had significantly reduced BMD with increased collagen and bone turnover. The different results obtained by Kauppila et al (1999) may reflect the conditioning regimens their patients received, being of greater intensity (TBI/CY or BU/CY) than those received by the patients reported by Bhatia et al (1998). In order to understand the mechanisms of reduced BMD, Valimaki et al (1999) prospectively measured bone mass and turnover following BMT. Significant bone loss occurred in the 6 months following BMT, resulting from an imbalance between bone formation and resorption, hallmarked by a reduction in the former and an increase in the latter. In the first 6 weeks post BMT there was a significant decline in serum testosterone in the males, which returned to normal at 6 months; thus, the acute hypogonadism may have played a part in the decreased BMD. The bone loss could not be prevented by calcium with or without calcitonin. Four of 25 patients experienced vertebral compression fractures. The findings of Kashyap et al (2000), demonstrating that BMD prior to BMT was normal in the majority, supported the study of Valimaki et al (1999) in pointing out that the bone loss occurred post BMT, with the sharpest decline in the first 6 months. Stern et al (2001), in a prospective study of 104 adults undergoing an allogeneic haematopoietic stem cell transplant, confirmed that significant bone loss was common over the first 12 months.
The most worrying of the bone studies is that of Kauppila et al (1999) in that the degree of reduction in BMD was substantial in at least 20% of patients (z-score < −2·5 SD). Information regarding the long-term risk of osteoporosis and fractures is badly needed.
In conclusion, the increasingly successful use of BMT for a wide variety of pathological processes has given rise to a mixture of endocrine problems in the survivors. Most but not all of these endocrine problems are a consequence of BMT conditioning regimens with TBI and/or chemotherapy.
Potential problems in children include poor growth, hypothyroidism, thyroid tumours and delayed or absent puberty. In the absence of detailed knowledge of the natural history of growth patterns in untreated BMT children through to final height, it remains unclear how much benefit can be obtained from GH replacement therapy; nor is the correct replacement dose of GH defined for a child with irradiation- and chemotherapy-induced skeletal dysplasia in addition to GH insufficiency. Furthermore, in a child with GH deficiency on GH replacement therapy who also has severe gonadal damage, the relative needs of the child in terms of growth and virilization or feminization need careful consideration. For the majority of these children infertility will be an issue in adulthood and, therefore, in the future we may need to consider prior to transplant whether there is a requirement to collect, store and manipulate the germ cells and/or gonadal tissue with the ultimate aim of enabling an individual to become a parent of a child who is genetically related to them. This, in turn, presents an enormous challenge to many professionals in relation to the ethics and the associated practicalities of harvesting and storing germ cells and/or gonadal tissue. Clearly these multiple endocrine sequelae mean that such children must be assessed and reviewed by a paediatric endocrinologist.
In the adult patient the risk of hypothyroidism will require regular monitoring, but at present the major needs of the patient are in the field of reproductive medicine. The reproductive endocrinologists/gynaecologists will need to consider fertility counselling, including the possibility of donor oocyte and IVF and HRT requirements, and the pretransplant storage of germ cells and/or gonadal tissue. All of these adult survivors deserve regular endocrine input into their long-term management.
- 1997) Growth after bone marrow transplantation in young children conditioned with chemotherapy alone. Bone Marrow Transplantation, 19, 253–256. , , , , & (
- 2000) Growth and endocrine function in children with acute myeloid leukaemia after bone marrow transplantation using busulfan/cyclophosphamide. Bone Marrow Transplantation, 25, 1087–1092. , , & (
- 1997) Abnormal thyroid stimulating hormone (TSH) levels in adults following allogeneic bone marrow transplants. Bone Marrow Transplantation, 19, 1019–1022. , , , , & (
- 1995) Mechanism and management of treatment related gonadal failure in recipients of high-dose chemoradiotherapy. Blood Review, 9, 93–116. & (
- 1999) Ovarian and uterine characteristics after total body irradiation in childhood and adolescence: response to sex steroid replacement. British Journal of Obstetrics and Gynaecology, 106, 1265–1272. , , , , & (
- 1998) Bone mineral density in patients undergoing bone marrow transplantation for myeloid malignancies. Bone Marrow Transplantation, 22, 87–90. , , , & (
- 1996) Successful pregnancy after bone marrow transplantationfor thalassaemia. Bone Marrow Transplantation, 18, 235–236. , , & (
- 1988) Growth and growth hormone in children after bone marrow transplantation. Hormone Research, 30, 98–100. & (
- 1994) Thyroid function in children after allogeneic bone marrow transplantation. Bone Marrow Transplantation, 13, 59–64. & (
- 1995) Thyroid dysfunction following bone marrow transplantation using hyperfractionated radiation. Bone Marrow Transplantation, 15, 71–76. , , , , , , & (
- 1993) Growth and growth hormone secretion after bone marrow transplantation. Archives of Diseases of the Child, 68, 458–463. , , , , , , , , , & (
- 1997) Contribution of growth hormone deficiency to the growth failure that follows bone marrow transplantation. Journal of Pediatrics, 130, 785–792. , , , , , , & (
- 1989) Growth in children following irradiation for bone marrow transplantation. American Journal of Pediatric Hematology/Oncology, 11, 134–140. , , , & (
- 1994a) Prospective study of pituitary-gonadal function to evaluate short-term effects of ablative chemotherapy or total body irradiation with autologous or allogenic marrow transplantation in post-menarchial female patients. Bone Marrow Transplantation, 13, 511–517. , , , & (
- 1994b) Germ cell failure and Leydig cell insufficiency in post-pubertal males after autologous bone marrow transplantation with BEAM for lymphoma. Bone Marrow Transplantation, 13, 519–522. , , , & (
- 2000) Cavernosal arterial insufficiency and erectile dysfunction in recipients of high dose chemotherapy and total body irradiation for multiple myeloma. Lancet, 356, 169. , , , & (
- 1996) Final height and hormonal function after bone marrow transplantation in children. Journal of Pediatrics, 129, 544–550. , , , , & (
- 1996) Final height of patients who underwent bone marrow transplantation during childhood. Archives of Diseases of the Child, 74, 437–440. , , , , , , , & (
- 1999) 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, 93, 4109–4115. , , , , , , , , , , , , & (
- 2000) Changes in height, weight and plasma leptin after bone marrow transplantation. Bone Marrow Transplantation, 26, 1205–1210. , , , , & (
- 1992) Abdominal irradiation in childhood: the potential for pregnancy. British Journal of Obstetrics and Gynaecology, 99, 392–394. , , , , & (
- 1993) Adrenocorticotrophin and cortisol secretionin children after low dose cranial irradiation. Clinical Endocrinology, 39, 297–305. , , , , & (
- 1989) Consequences and treatment of ovarian failure after total body irradiation for leukaemia. British Medical Journal, 299, 1494–1497. , , , & (
- 1997) Growth after recombinant human growth hormone (rhGH) treatment in transplanted thalassemic patients. Bone Marrow Transplantation, 20, 567–573. , , , , , , , , & (
- 2001) Human oocyte cryopreservation: new perspectives regarding oocyte survival. Human Reproduction, 16, 411–416. , , , , & (
- 1995) Role of busulfanand total body irradiation on growth of prepubertal childrenreceiving bone marrow transplantation and results of treatment with recombinant human growth hormone. Blood, 86, 825–831. , , , , , , , , , , & & (
- 1994) Restoration of fertility to oophorectomized sheep by ovarian autografts stored at −196°C. Human Reproduction, 9, 597–603. , , & (
- 2000) Reproductive status in long-term bone marrow transplant survivors receiving busulfan-cyclophosphamide (120 mg/kg). Bone Marrow Transplantation, 26, 1089–1095. , , & (
- 1998) Late onset unilateral renal dysfunction combined with non-insulin dependent diabetes mellitus and bronchial asthma following allogeneic bone marrow transplantation for acute lymphoblastic leukaemia in a child. Bone Marrow Transplantation, 22, 923–926. , , , , , , , , , & (
- 1995) Pubertal maturation of the internal genitalia: an ultrasound evaluation of 166 healthy girls. Ultrasound Obstetrics and Gynecology, 6, 175–181. , , & (
- 1996) Growth, growth hormone and final height after BMT. Possible recovery of irradiation-induced growth hormone insufficiency. Bone Marrow Transplantation, 18, 163–170. , , , , , , & (
- 1999) Ultrasound B-mode changes in the uterus and ovaries and Doppler changes in the uterus after total body irradiation and allogeneic bone marrow transplantation in childhood. Bone Marrow Transplantation, 23, 259–263. , , , , & (
- 1998) Uses and growth of hematopoietic cell transplantation. In: Hematopoietic Cell Transplantation, 2nd edn. (ed. by E.D.Thomas, K.G.Blume & S.J. Forman), pp. 12–18. Blackwell, Oxford. (
- 1990) Growth failure and growth hormone deficiency in children after bone marrow transplantation for leukaemia. Bone Marrow Transplantation, 5, 183–186. , , , , & (
- 1995) Growth in children after bone marrow transplantation for acute leukaemia. Blood, 86, 819–824. , , , & (
- 1997) Early high dose chemotherapy intensification with autologous bone marrow transplantation in lymphoma associated with retention of fertility and normal pregnancies in females. Scotland and Newcastle Lymphoma Group, U.K. Leukemia and Lymphoma, 28, 127–132. , , , , , , , & (
- 1995) Fertility after bonemarrow transplantation following conditioning with cyclophosphamide and total body irradiation. Bone Marrow Transplantation, 15, 483–484. , & (
- 2000) Effects of allogeneic bone marrow transplantation on recipient bone mineral density: a prospective study. Biology of Blood and Marrow Transplantation, 6, 344–351. , , , , , , , , , , , , , , , , & (
- 1990) Thyroid dysfunction following bone marrow transplantation: Long-term follow-up of 80 pediatric patients. Bone Marrow Transplantation, 5, 335–340. , , , , , & (
- 1998) Long-term effects of allogeneic bone marrow transplantation (BMT) on pituitary, gonad, thyroid and adrenal function in adults. Bone Marrow Transplantation, 22, 331–337. , , , & (
- 1999) Bone mineral density after allogeneic bone marrow transplantation. Bone Marrow Transplantation, 24, 885–889. , , , , , & (
- 1987) The effect of total body irradiation and bone marrow transplantation during childhood and adolescence on growth and endocrine function. British Journal of Haematology, 67, 419–426. , , , , , & (
- 1987) Outcome of pregnancy in survivors of Wilms' Tumour. Journal of American Medical Association, 257, 216–219. , , , , , , & (
- 1994) Late effects of intensive treatment for acute myeloid leukaemia and myelodysplasia in childhood. Journal of Clinical Oncology, 12, 916–924. , , & (
- 1991) Endocrine and reproductive dysfunction following fractionated total body irradiation in adults. Quarterly Journal of Medicine, 287, 265–274. , , & (
- 1995) Hyperinsulinemia in children and adolescents after bone marrow transplantation. Bone Marrow Transplantation, 15, 873–877. , , , , & (
- 1989) Growth and endocrine function after bone marrow transplantation for thalassaemia. In: Advances and Controversies in Thalassaemia Therapy: Bone Marrow Transplantation and Other Approaches, (ed.by C.D.Buckner, R.P.Gale & G. Lucarelli), pp. 273–280. Liss, New York. , & (
- 1995) Successful pregnancy after allogeneic bone marrow transplantation following conditioning with total body irradiation. Bone Marrow Transplantation, 15, 637–638. , , , , , , , , , & (
- 1999) Ovarian function after bone marrow transplantation performed before menarche. Archives of Diseases of the Child, 80, 452–454. , , , , , , , , & (
- 1998) Patterns of gonadal dysfunction following bone marrow transplantation. Bone Marrow Transplantation, 22, 345–350. , , & (
- 1997) Late effects of allogeneic bone marrow transplantation for children with acute myeloblastic leukaemia in first complete remission. The impact of conditioning regimen without total-body irradiation – A report from the Societe Francaise de Greffe de Moelle. Journal of Clinical Oncology, 15, 2238–2246. , , , , , , , , , , , , , , , , & (
- 1996) Cytokine mobilized blood CD34-expressing cells are not cycling. Bone Marrow Transplantation, 17, 467. , , , , & (
- 1995) Gonadal function and psychosexual adjustment in male long-term survivors of bone marrow transplantation. Bone Marrow Transplantation, 16, 253–259. , , & (
- 2000) Bone mass after allogeneic BMT for childhood leukaemia or lymphoma. Bone Marrow Transplantation, 25, 191–196. , , , , , & (
- 1992) Endocrine deficit after fractionated total body irradiation. Archives of Diseases of the Child, 67, 10. , , , , , & (
- 1993) Growth hormone function and treatment following bone marrow transplant for neuroblastoma. Bone Marrow Transplantation, 12, 381–385. , , & (
- 1991) Growth hormone treatment of growth failure secondary to total body irradiation and bone marrow transplantation. Archives of Diseases of the Child, 66, 689–692. , , , & (
- 1960) The fertility of mice and orthotopic ovarian grafts derived from frozen tissue. Journal of Reproduction Fertility, 1, 230–241. (
- 2001) Orthotopic reimplantation of cryopreserved ovarian cortical strips after high-dose chemotherapy for Hodgkin's lymphoma. Lancet, 357, 1172–1175. , , , , , , , , , & (
- 1997) Follicular cell carcinoma of the thyroid in a child after bone marrow transplantation for acute lymphoblastic leukaemia. Acta Haematologica, 97, 225–227. , , , , , & (
- 2001) Pregnancy outcomes after peripheral blood or bone marrow transplantation: a retrospective survey. Lancet, 358, 271–276. , , , , , , , , , , & (
- 1994) Growth and development after bone marrowtransplantation. In: Bone Marrow Transplantation (ed. by S.J.Forman, K.G.Blume & E.D. Thomas), pp. 527–537. Blackwell Scientific Publications, Boston. (
- 1999) Growth and Development After Hematopoietic Cell Transplantation; Hematopoietic Cell Transplantation, 2nd edn. (ed. by E.D.Thomas, K.G.Blume & S.J. Forman), pp.764–775. Blackwell Science, Boston. (
- The Seattle Bone Marrow Transplant Team (1991) The impact of marrow transplant preparative regimens on subsequent growth and development. Seminars in Hematology, 28, 244–249. &
- 1986) Growth and development following marrow transplantation for leukemia. Blood, 68, 1129–1135. , , , , , , , , , , & (
- 1988a) Growth and development in children after bone marrow transplantation. Hormone Research, 30, 92–97. , , , , , , & (
- 1988b) Ovarian function following marrow transplantation for aplastic anaemia or leukaemia. Journal of Clinical Oncology, 6, 813–818. , , , , , , , , & (
- 1996) Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood, 87, 3045–3052. , , , , , , , , , & (
- 1997) Gonadal function after bone marrow transplantation for acute leukemia during childhood. Journal of Pediatrics, 130, 210–216. , , & (
- 1994) Cancer therapy and gonadal dysfunction. In: Clinical Endocrine Oncology (ed. by R.Sheaves, P.Jenkins & J.A.H. Wass), pp. 510–513. Blackwell Science Ltd, Oxford, UK. (
- 1998) The diagnosis of growth hormone deficiency in children and adults. Endocrine Reviews, 19, 203–223. , , & (
- 1996) Melphalan alone prior to allogeneic bone marrow transplantation from HLA-identical sibling donors for hematologic malignancies: alloengraftment with potential preservation of fertility in women. Bone Marrow Transplantation, 18, 1049–1055. , , , , & (
- 1984) Testicular function following bone marrow transplantation performed during or after puberty. Cancer, 53, 1498–1501. , & (
- 2000) Abnormalities of the thyroid in survivors of Hodgkin's Disease; data from the Childhood Cancer Survivor Study. Journal of Clinical Endocrinological Metabolism, 85, 3227–3232. , , , , , , , & (
- 1990) Impaired glucose tolerance after autologous bone marrow transplantation. Bone Marrow Transplantation, 6, 89–92. , , & (
- 2000) New malignant diseases after allogeneic marrow transplantation for childhood acute leukaemia. Journal of Clinical Oncology, 18, 348–357. , , , , , , , , , , , , , & (
- 2001) Bone density loss after allogeneic hematopoietic stem cell transplantation; a prospective study. Bone Marrow Transplantation, 7, 257–264. , , , , , & (
- 1984) Late complications after marrow transplantation. Seminars in Hematology, 21, 53–63. , , , , , , , , & (
- 1994) Cumulative conception and live-birth rates after in vitro fertilisation with and without the long, short, and ultrashort regimens of the gonadotrophin-releasing hormone agonist buserelin. American Journal of Obstetrics and Gynecology, 171, 513–520. , , , , , , , & (
- 1998) Increase in height during the first year after bone marrow transplantation reflecting nutritional status of children. Bone Marrow Transplantation, 22, 689–692. & (
- 2000) Impaired glucose tolerance and dyslipidaemia as late effects after bone-marrow transplantation in childhood. Lancet, 356, 993–997. , , & (
- 1998) Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure. Bone Marrow Transplantation, 22, 989–994. , , , & (
- 1972) Evidence for a specific seminiferous tubular factor affecting follicle-stimulating hormone in man. Journal of Clinical Investigations, 51, 1009–1019. , , & (
- 1993a) Growth following single fraction and fractionated total body irradiation for bone marrow transplantation. European Journal of Pediatrics, 152, 888–892. , , & (
- 1993b) Endocrine function following single fraction and fractionated total body irradiation for bone marrow transplantation in childhood. Acta Endocrinologica, 128, 508–512. , , & (
- 1994) Papillary thyroid carcinoma after total body irradiation. Archives of Diseases of the Child, 71, 256–258. , , , , , , & (
- 1999) A prospective study of bone loss and turnover after allogeneic bone marrow transplantation: effect of calcium supplementation with or without calcitonin. Bone Marrow Transplantation, 23, 355–361. , , , , , , , & (
- 2000) Erectile dysfunction with chemotherapy. Lancet, 356, 169. , , & (
- 1989a) Ovarian failure following total abdominal irradiation in childhood: the radiosensitivity of the human oocyte. British Journal of Radiology, 62, 995–998. , , , & (
- 1989b) Ovarian failure following abdominal irradiation in childhood: natural history and prognosis. Clinical Oncology, 1, 75–79. , , , & (
- 1998) Successful pregnancy following very high dose total body irradiation (1575 cGy) and bone marrow transplantation in a woman with acute myeloid leukaemia. Bone Marrow Transplantation, 21, 415–417. , , , , , & (
- 1992) Growth in children after bone marrow transplantation for advanced neuroblastoma compared with growth after transplantation for leukaemia or aplastic anaemia. Journal of Pediatrics, 120, 726–732. , , , , & (
- 1992) Growth in children after bone marrow transplantation: busulfan plus cyclophosphamide versus cyclophosphamide plus total body irradiation. Blood, 79, 1068–1073. , , , , , , , & (