Original Article
Effect of Age at the Start of Iron Chelation Therapy on Gonadal Function in β-Thalassemia Major
N Engl J Med 1990; 323:713-719September 13, 1990
- Abstract
- Abstract
Background.
Patients with transfusion-dependent thalassemia major tend to have abnormal growth and sexual maturation at puberty, presumably as a result of pituitary iron overload. This study was designed to determine whether chelation therapy with deferoxamine before the age of puberty would ameliorate this problem.
Methods.
We examined 40 patients over 14 years of age with transfusion-dependent thalassemia major. The 19 patients in group A (mean [±SD] age at study, 17.0±1.5 years) had begun nightly treatment with subcutaneous deferoxamine before the age of 10 (mean age at start of treatment, 7.5±1.8 years). The 21 patients in group B (mean age, 24.1±3.8 years) had begun treatment after the age of 10 (mean age at start of treatment, 14.4±4.7 years).
Results.
The abnormal findings were essentially confined to sexual development. The final height did not differ between groups or from the mean parental height in each group. Ninety percent of the patients in group A had normal sexual development, as compared with 38 percent of those in group B (P = 0.001). Outcomes were correlated with indexes of iron overload; the patients in group A had lower serum ferritin levels before chelation treatment (P = 0.01) and lower average serum ferritin levels during treatment (P = 0.005).
Conclusions.
Beginning chelation treatment with deferoxamine before the age of puberty can help children with transfusion-dependent thalassemia major to attain normal sexual maturation. (N Engl J Med 1990; 323: 713–9.)
Article Activity
- Article
AS the survival of patients with thalassemia major has improved, extending into the third and fourth decades of life,1 2 3 growth, sexual development, and fertility have become important issues to be addressed. With the introduction of transfusion programs in which hemoglobin levels are maintained above 6.52 mmol per liter (10.5 g per deciliter), prepubertal linear growth has approached normal rates,4 5 6 but abnormal adolescent growth is still observed in the majority of patients.6 , 7 Before the use of chelation therapy, the incidence of normal pubertal development was low,8 9 10 with the delay in development attributed to hypogonadism as a result of pituitary iron overload.10 , 11 Furthermore, a large cross-sectional survey of patients with thalassemia major treated regularly with red-cell transfusions failed to show significant improvement in growth or progression of puberty in patients who received iron chelation as well.6 , 12
This study examines the effect of long-term deferoxamine therapy and the influence of early intervention on ultimate growth and sexual maturation. Since the growth rate is generally normal in patients with transfusion-dependent thalassemia major up to the age of 10, with an irreversible delay in linear growth thereafter, we compared the growth and sexual maturation in patients who began deferoxamine therapy before the age of 10 with those in patients who began treatment at a later age.
Methods
Selection of Patients
Forty transfusion-dependent patients were studied, all of them over the age of 14 at the time of study. Thirty-eight had homozygous β-thalassemia, and two (a brother and sister) had hemoglobin Lepore β-thalassemia. The patients were followed at the Hospital for Sick Children and Toronto General Hospital.
The patients were divided into two groups: group A included 19 patients in whom nightly treatment with subcutaneous deferoxamine was begun before the age of 10 years (mean ±SD, 7.5±1.8), and group B included 21 patients who began therapy after the age of 10 years (mean, 14.4±4.7). Each group had undergone chelation therapy for approximately 9 years (mean, 9.6±1.0 and 9.3±1.9 years, respectively, for groups A and B; P>0.1), and the patients in group B were significantly older than those in group A. The clinical features of each group are presented in Table 1Table 1
Preliminary Clinical Evaluation of 40 Patients with Thalassemia Major Who Received Deferoxamine Therapy.. The patients were of Italian (15), Greek (15), Indian (4), Chinese (4), Turkish (1), and Saudi Arabian (1) origin. In 37 patients the mean hemoglobin level before transfusion had been maintained above 6.52 mmol per liter for nine years before the present analysis of growth and gonadal function. In the three remaining patients this regimen was begun seven, five, and two years before analysis. Thirty-one patients had undergone splenectomy.Eight patients in group B had evidence of symptomatic iron loading: congestive heart failure and insulin-dependent diabetes mellitus in three; congestive heart failure and hypoparathyroidism in two; congestive heart failure, hypoparathyroidism, and hypothyroidism in one; insulin-dependent diabetes mellitus, hypoparathyroidism, and hypothyroidism in one; and congestive heart failure in one. The symptoms of all patients were well controlled with appropriate medication when the study started, and the patients were ambulatory. Nine patients in group B (five male and four female patients) had received sex-hormone replacement therapy for one to two years but had discontinued it at least one year before the start of the study. No patients in group A underwent sex-hormone replacement therapy before the study.
Deferoxamine Therapy
An average dose of 30 to 70 mg of deferoxamine per kilogram of body weight was delivered by subcutaneous infusion over a 12-hour period each night with standard ambulatory pumps. At the initiation of deferoxamine therapy, each patient was hospitalized and given the lowest dose that produced maximal urinary iron excretion, up to a dose limit of 2 g per day. After 1984, the dose of deferoxamine was adjusted to 50 mg per kilogram per day. The mean daily dose of deferoxamine prescribed for the duration of treatment was 53.0±9.0 (range, 39 to 70) mg per kilogram per day in group A and 48.9±7.3 (range, 31 to 61) mg per kilogram per day in group B.
Drug Compliance
Compliance with deferoxamine therapy was originally assessed by questioning the patients and examining infusion sites. In 1989, however, we carried out a retrospective reanalysis of compliance, using the results of interviews between the patients and a single physician; a retrospective chart review of each patient visit since 1982, in which records of the number of days missed per month were available for half the visits; and a telephone interview by one physician unacquainted with the patients, who obtained independent estimates by each patient and one parent of the number of days missed per month over the past 10 years. The actual amount of deferoxamine administered was estimated by multiplying the prescribed dose by the number of days of use per year and dividing by the body weight in kilograms (Table 1).
Estimated Iron Load
The estimated iron load received in transfusion by each patient since the first transfusion was calculated from the total number of transfusions, with the assumption that 250 ml of packed cells contains 200 mg of iron. This weight was expressed as grams per kilogram of body weight (Table 1).
Protocol
This study was approved by the Human Subjects Review Committee of the Hospital for Sick Children. Written informed consent was obtained from each patient or from a parent if the patient was under 16 years of age.
The patients were interviewed, examined, weighed, and measured throughout the study by a single observer. Bone age was determined by a single observer. Mean ferritin and aspartate aminotransferase levels in individual patients were calculated from measurements taken two to four times per year. Base-line laboratory tests measured serum concentrations of calcium, phosphate, alkaline phosphatase, aspartate aminotransferase, total protein, albumin, fasting glucose, thyroxine, dihydroepiandrosterone sulfate, testosterone or estradiol, insulin-like growth factor I (IGF-I), luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone, cortisol, thyrotropin, and prolactin; triiodothyronine (T3) resin uptake (T3RU); and prothrombin time.
After an overnight fast, the response of the LH, FSH, thyrotropin, prolactin, growth hormone, and cortisol levels to the simultaneous intravenous administration of gonadotropin-releasing hormone (GnRH) (100 μg), thyroid-releasing hormone (TRH) (200 μg), and insulin (0.05 U per kilogram) was assessed after 30, 60, and 90 minutes. The TRH test was performed in 34 patients, the GnRH test in 37, and the insulin-tolerance test in 13. Difficulty in providing supervisory medical personnel limited the administration of the insulin-tolerance test to patients at the Hospital for Sick Children.
All male patients in group A and three male patients with hypogonadism in group B were given a single intramuscular injection of human chorionic gonadotropin (1500 U per square meter of body-surface area). The serum testosterone level was measured before and 72 hours after the injection.13
Clinical Methods and Laboratory Tests
Height was assessed with a wall-mounted stadiometer and expressed as standard deviations from the normal height for the patient's chronologic age.14 Pubertal staging,15 , 16 bone age,17 predicted final height,18 and serum ferritin measurements19 were determined by standard methods. Serum levels of gonadotropins, growth hormone, testosterone, estradiol-17β, and dihydroepiandrosterone sulfate were measured with radioimmunoassay kits as described elsewhere.20 , 21 Levels of thyrotropin, total thyroxine, cortisol, and prolactin were assayed with commercial radioimmunoassay kits whose use is well established in our laboratory. IGF-I levels were measured with a radioimmunoassay kit (Nichols Institute Diagnostics, San Juan Capistrano, Calif).
Statistical Analysis
Simple and multiple regression methods were used to assess the correlation between hormonal levels, age at the start of therapy, and indexes of iron overload. The frequencies of conditions were compared by two-tailed Fisher's exact test. Data for groups are presented as means ±SD. Mean values were compared by Student's t-test, paired or unpaired as appropriate. These methods were also applied to logarithmically transformed data.
Results
Clinical Observations
Compliance with Therapy
There was a steady and significant decline in compliance noted in patients between 10 to 20 years of age (P<0.05). The total dose of deferoxamine administered over the period of therapy was significantly higher in the patients in group A than in those in group B (Table 1).
Pubertal Status
In group A, 10 of 11 female patients 14 to 19 years of age had Tanner stage 5 breast development and were menstruating. All had a normal LH response to GnRH (more than a threefold increase from base line).22 The mean age at menarche was 13.8±1.3 years (mean age at menarche for North American girls, 12.65±1.17).23
Seven of eight male patients 14 to 17 years of age were considered normal, with testicular volumes of ≥12 ml, appropriate levels of testosterone (>10 nmol per liter),24 and pubertal increases in serum levels of LH after exogenous GnRH stimulation (more than a fourfold increase from base line).25
In group B, only one of eight women 19 to 30 years of age was menstruating. Six had primary amenorrhea, and one had three years of secondary amenorrhea after five years of regular menstruation. In all seven women with amenorrhea, the estradiol levels were in the prepubertal range, and there were hypogonadal responses (less than double the basal levels) to GnRH testing (Fig. 1Figure 1
Mean (±SD) Serum LH Levels at Base Line and after Stimulation with Intravenous GnRH.).Six of 13 men 20 to 32 years of age had testicular volumes below 12 ml, serum testosterone levels ranging from 0.8 to 3.3 nmol per liter, and inadequate LH responses to intravenous GnRH. Although the LH response to GnRH was normal for the group as a whole (Fig. 1), the peak LH response in these six men was 2.1±1.8 U per liter.
Thus, only 2 of 19 patients in group A (10.5 percent) had abnormal puberty, whereas in group B 13 of 21 patients (62 percent) had abnormal puberty (P = 0.001, by two-tailed Fisher's exact test).
Height
Twelve of the 19 patients in group A (group age, 17.0±1.5 years) had reached their final adult stature, whereas 19 of the 21 patients in group B (group age, 24.1±3.8 years) had completed their growth (bone age in male patients ≥17 years; in female patients ≥15 years) (Table 2Table 2
Clinical Characteristics of the Patients at the Most Recent Assessment.). Three patients in group A had bone-age retardation of ≥2 SD below the mean for their chronologic age. In group B, two patients had such retardation. However, one or more years before the study, nine patients in group B (five male and four female patients) had received sex-hormone replacement therapy for periods ranging from six months to two years. Although such treatment can clearly influence the development of secondary characteristics, its effect on final height is negligible.26 The final height (or standard deviation score) of the patients in group A was not significantly different from that of the patients in group B. There was a significant correlation between the midparental height27 and the actual and predicted final heights of the patients in both groups (P = 0.001 for group A, and P = 0.003 for group B). The parental heights were less than the mean for the normal population,16 with no significant difference between the midparental heights of the patients in the two groups.
Hormonal Studies
Abnormalities in hypothalamic-pituitary function were essentially confined to gonadotropin secretion, with evidence of mild thyroid dysfunction only in four patients from group B (Table 3Table 3
Results of a Hormone Evaluation in the Patients Who Received Deferoxamine Therapy.*).In all the patients tested, basal levels of serum cortisol, thyroxine, and prolactin were normal, but basal and TRH-stimulated thyrotropin concentrations were significantly higher in the patients in group B. Serum cortisol and growth hormone responses to insulin-induced hypoglycemia were normal in the 13 patients from group A who were tested.
There was no significant difference in plasma levels of IGF-I between the groups, or between the ratios of measured IGF-I levels and levels expected for bone age (Nichols Institute Diagnostic).
Figure 1 shows the basal and GnRH-stimulated LH levels for male and female patients in each group. Sex-steroid concentrations are shown in Table 3. Seven female patients in group B had subnormal responses to GnRH, whereas all 11 in group A had normal, mature responses. Seven of eight male patients in group A had appropriate responses to GnRH testing, adult serum levels of testosterone, and 2-to-10-fold increases in the testosterone level after stimulation with human chorionic gonadotropin. In contrast, only 7 of 13 male patients in group B had normal testosterone concentrations. The mean response to GnRH was significantly reduced in the male patients with hypogonadism (2.1±1.8 U per liter vs. 12.1±5.4 U per liter in the seven patients with normal levels of serum testosterone). The normal increases in the testosterone level in response to human chorionic gonadotropin (from 2.9±1.0 to 11.3±4.3 nmol per liter) in three male patients with hypogonadism indicated normal Leydig-cell function, confirming that a central mechanism was the basis of their condition.
When the percent change in the LH response to GnRH was correlated with the age at which chelation therapy was started (Fig. 2Figure 2
Correlations between Measures of Iron Loading, Start of Chelation Therapy, and Hormonal Response.), a significant negative correlation was found for both male (P = 0.014) and female (P = 0.008) patients. The correlation between mean ferritin levels and age at the start of chelation therapy was significant for both male (P = 0.036) and female (P = 0.001) patients. The correlation between the percent increase in LH in response to GnRH and the mean serum aspartate aminotransferase level was not significant for either sex.These statistical analyses were repeated with use of logarithmically transformed data, which yielded similar conclusions.
Normal and Abnormal Puberty
The patients with abnormal puberty (Table 4Table 4
Relation of Treatment Variables to Pubertal Outcome in Patients Who Received Deferoxamine.*) not only were significantly older at the start of deferoxamine therapy but also had higher serum ferritin levels before chelation and longer exposure to suboptimal chelation therapy (serum ferritin levels, >2000 μg per liter). In addition, these patients had relatively more anemia for longer periods, because the hyper-transfusion program became standardized only in 1979. Differences in the duration and dose of deferoxamine therapy, the cumulative iron load, and the mean serum ferritin level were not statistically significant.Of the 25 patients who had normal puberty, 10 (40 percent) had mean serum ferritin concentrations above 2000 μg per liter, whereas the concentrations reached this level in 11 of the 15 patients who did not have normal puberty (73 percent). Nevertheless, the difference in mean serum ferritin level between those with normal and abnormal puberty was not statistically significant.
With respect to the measures listed in Table 4, there were no significant differences between the female patients in group B who did not reach normal puberty and the patients in group B, both male and female, who did, except for a significant difference in the mean aspartate aminotransferase level.
Discussion
The poor pubertal growth and impairment or absence of sexual function in 60 to 80 percent of patients with thalassemia major receiving chelation therapy have been attributed to selective central hypogonadism6 , 9 , 10 , 28 a deficiency of IGF-I,29 30 31 or both. This is supported by histologic findings of selective iron deposition in pituitary gonadotropes32 and by the reversibility of the hypogonadal state in primary hemochromatosis with intensive phlebotomy.33 , 34 Similarly, the low serum levels of IGF-I have been attributed to the interference of extensive iron overload with the production of this hormone.29 Ninety percent of our patients who began regular therapy with deferoxamine at a mean age of 7.5 years had reached normal pubertal status 9 years later. After receiving chelation therapy for a period of the same length, only 38 percent of the patients who began taking deferoxamine at a mean age of 14.4 years had reached normal puberty. The mean heights at the end of the study did not differ between groups and were in keeping with the midparental heights in each group. This difference in the age at which patients began deferoxamine therapy may be important if transfusional iron deposition or damage cannot be reversed. Preventing high concentrations of serum iron and the consequent deposition of iron in tissue therefore becomes critical if normal growth and pubertal development are to be attained.
Differences apparently due to age could reflect other variables, including the level of serum ferritin before chelation, the effectiveness of chelation therapy, and differences in compliance or the degree of early anemia. Our two groups were significantly different with respect to all these variables. The 25 patients who entered normal puberty had elevated concentrations of serum ferritin for significantly fewer years, and lower serum ferritin levels before chelation, than the patients who did not have normal puberty but had the same number of years of chelation. Furthermore, the only two patients in group A who did not have normal puberty either had high serum ferritin levels before chelation or extended periods during which these levels were high. One female patient had the highest serum ferritin level before chelation of all the group A patients, and one male patient had a serum ferritin level that remained above 2000 μg per liter for the longest time observed in any group A patient. In patients with severe iron overload, a fraction of free, non-transferrin-bound iron appears in serum and may result in greater tissue uptake than does protein-bound iron,35 as in vitro studies of hepatic and cardiac cells have demonstrated.36 Patients with high levels of iron before chelation or persistent tissue uptake may be at highest risk, but differences in individual susceptibility may account for the observed variation in morbidity. The observation that patients with thalassemia major occasionally have normal growth and sexual maturation despite sustained hyperferritinemia is unexplained. Magnetic resonance imaging may permit quantitation of tissue iron deposition (or removal), as has been suggested in hemochromatosis.37
Our findings on pubertal status differ from those of previous reports. Borgna-Pignatti et al.12 reviewed the growth and sexual development of 250 adolescents with thalassemia major to whom deferoxamine was administered for 7 to 10 years, but only for 3 years by the subcutaneous route. There was no indication that patients receiving more intensive chelation therapy fared better with regard to sexual maturation. The median age of these patients was 13.8 years, with a median duration of subcutaneous deferoxamine therapy of 40 months. Therefore, although some patients may have begun taking deferoxamine before the age of expected puberty, many were evaluated after only four years of deferoxamine therapy. Sklar et al.38 studied eight patients with thalassemia major who had received deferoxamine therapy for 4 to 8 years, beginning at a mean age of 5.5 years. Only one of six patients who were more than 13 years old at the time of the study had evidence of pubertal development, and in six of the eight patients, bone age was delayed and height was more than 2 SD below the mean. Maurer et al.6 evaluated the effect of deferoxamine therapy on growth and pubertal maturation in 16 patients receiving subcutaneous deferoxamine for periods ranging from one to six years. Linear growth in these patients was normal until the age of 10, when it declined into the lower percentile ranges. Tanner stages were below normal, and only two patients had normal rates of pubertal maturation. Only three patients were evaluated four or more years after the start of deferoxamine therapy, however.
In contrast to these three reports, our study noted a positive effect of deferoxamine therapy on sexual maturation, perhaps related to the effectiveness of chelation therapy. In the study of Borgna-Pignatti et al., the median serum ferritin level over 40 months of deferoxamine therapy was 3500 μg per liter, and in the eight patients of Sklar et al. the mean serum ferritin level was 6206 μg per liter — comparable to the mean level in our patients who did not have normal puberty. Similarly, in half the 16 patients studied by Maurer et al., the serum ferritin values were above 2000 μg per liter at the time of evaluation.
The benefits of early, intensive therapy with deferoxamine on later growth and sexual maturation must be weighed against the reports of deferoxamine-induced growth failure in patients treated in the first 14 months of life.39 None of our patients began taking deferoxamine before the age of five. However, we have observed previously described deferoxamine-induced bony changes and a decline in growth percentile in one young patient who began treatment at the age of five. Preventing the accumulation of iron with intensive chelation may be the key to normal growth and sexual development. It is not known whether this therapy can reverse iron-induced damage to the pituitary. Diabetes mellitus and hypoparathyroidism may not improve even after reduction of the iron load.40 Our study demonstrates that with effective chelation using deferoxamine, normal growth and sexual maturation can be expected in patients with thalassemia major. The best prognosis for gonadal function can be predicted for those in whom chelation therapy is begun before there are profound elevations in the serum ferritin level and for those who have relatively low serum ferritin levels because of dedicated compliance with deferoxamine treatment.
Supported by Eli Lilly, Canada. Dr. Bronspiegel-Weintrob is a research fellow in endocrinology, supported in part by Eli Lilly, Canada, and by the American Physicians Fellowship. Dr. Olivieri is a Career Scientist of the Ontario Ministry of Health.
We are indebted to Dr. W.H. Francombe of Toronto General Hospital; to Holly Carley, R.N., and Debbie Filek, M.D.; to Nila Soriano, B.S., and Dr. Graham Ellis, Department of Biochemistry, Hospital for Sick Children, for laboratory assistance; to Marion Calderbank for providing computerized growth data; and to Esther Naraine for her invaluable assistance in the preparation of the manuscript.
Source Information
From the Division of Endocrinology and the Research Institute (N.B.-W., F.J.H.)and the Division of Hematology (N.F.O., M.H.F.), the Hospital for Sick Children; the Department of Hematology, Toronto General Hospital (N.F.O., B.T.); and the Department of Preventive Medicine and Biostatistics, University of Toronto (D.F.A.); all in Toronto. Address reprint requests to Dr. Holland at the Division of Endocrinology, Hospital for Sick Children, Rm. 5114, 555 University Ave., Toronto, ON M5G 1X8, Canada.
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