in endocrine glands (2-7). Pubertal delay has been associated with primary and central gonadal failure (6-11). Growth delay has been attributed to chronic ...
00%972X/93/7602-0357$03.00/0 .Jnurnal of Clinical Endocrinology and Metabolism Copyright 0 1993 by The Endocrine Society
Multiple Hormone Hemochromatosis
Vol. 76, No. 2 Printed in U.S.A.
Deficiencies
KAREN E. OERTER, GERDINE A. KAMP*, PETER ARTHUR W. NIENHUIS, FERNANDO G. CASSORLA, PENELOPE K. MANASCO Developmental Endocrinology Clinical Hematology Branch, Bethesda, Maryland 20892
Branch, National
in Children
with
J. MUNSON, AND
National Institute of Child Health and Human Development, and Heart Lung and Blood Institute, National Institutes of Health,
ABSTRACT
bertal stage. All 14 children in puberty LH pulsatility index below the mean for pubertal stage compared to normal children. Six of the 14 had LH pulsatility index more than 2 SD below the mean for pubertal stage. This may be an indicator of abnormal pituitary function. Six
Patients with thalassemia major require multiple blood transfusions leading to hemochromatosis. These patients often have pubertal delay and growth failure, the etiology of which has not been fully elucidated. We performed an extensive endocrine evaluation which included measurements of spontaneous and stimulated levels of gonadotropins, GH, thyroid hormone, and adrenal hormones in 17 patients between the ages of 12 and 18 yr with hemochromatosis receiving desferoxamine therapy. All of the 17 patients had at least one endocrine abnormality, and 12 had more than one abnormality. Abnormalities of the hypothalamic-pituitary-gonadal axis were the most common. Six patients had clinical evidence of delayed puberty with spontaneous and stimulated gonadotropin and sex steroid levels appropriate for their delayed pu-
patients failed either the provocative GH tests (peak GH < 7 fig/L) or had a mean spontaneous GH less than 1 pg/L. The 4 patients who failed provocative tests had growth velocities more than 2 SD below the mean for bone age. Three patients had evidence of primary hypothyroidism. We conclude that all patients with hemochromatosis need periodic careful endocrine evaluations because the incidence of endocrine dysfunction is substantial and they may benefit from hormonal therapy. (J Clin Endocrinol Metab 76: 357-361, 1993)
T
HALASSEMIA major is an hereditary disorder of hemoglobin synthesis resulting in severe anemia. Treatment consists of multiple blood transfusions, a complication of which is hemochromatosis. Recently, desferoxamine has been used for treatment as a chelating agent in an attempt to prevent the complications of the iron deposition and hemochromatosis, most notably the cardiac failure which accounts for the shortened life span in these patients (1). Patients with thalassemia major receiving optimal treatment have few cardiac complications and, therefore, a greatly improved life expectancy. However, they often present with growth failure and pubertal delay. Endocrine abnormalities such as hypothyroidism and diabetes are frequently observed in these patients and have been attributed to iron deposition in endocrine glands (2-7). Pubertal delay has been associated with primary and central gonadal failure (6-11). Growth delay has been attributed to chronic disease, decreased insulin-like growth factor-l (IGF-1) activity (12), and impaired GH secretion (12-15). We studied growth rates, pubertal maturation, spontaneous and stimulated levels of GH, LH, FSH, and TSH, measurements of PRL, baseline thyroid, and adrenal function, in 17 patients with hemochromatosis between the ages
of 12 and 18 yr. We performed this evaluation in order to define the endocrine profile of these patients and thereby determine the need for endocrine testing and hormonal therapy. Subjects
and Methods
Subjects All patients between the ages of 12 and 18 yr who were participating in an ongoing NIH protocol with desferoxamine treatment were asked to participate in this study. Three patients refused to participate because they had normal height and normal pubertal development, and three patients refused to participate because they did not want to have further testing. Fifteen patients with homozygous @-thalassemia, one patient with Blackfan-Diamond anemia (patient 6), and one patient with severe sickle cell disease (patient 12) were studied. We studied nine girls and eight boys, and their average age was 14.8 f 1.3 yr (mean + SD). All patients had been transfused frequently (283 + 54 times) and had been receiving desferoxamine for 7-13 yr (9.3 + 2.0). Only one patient had started treatment before age 2 yr (patient 13). The patients’ total body iron load averaged 2832 f 1301 pg/g liver (16), and all but two of the patients (patients 3 and 11) had ferritin levels greater than 600 pg/L (600 ng/mL). Their mean growth velocity was 1.5 + 3.0 SD below the mean for bone age (range -6.0 to 5.8 SD), and their height was 1.8 f 1.3 SD below the mean (range O-3.5 SD, Table 1). Bone age was delayed an average of 2.1 + 1.6 yr. The study protocol was approved by the National Heart Lung and Blood Institutional Review Board. Informed consent was given by one parent and assent was given by each patient.
Received February 28, 1992. Address all correspondence and requests for reprints to: Dr. Karen E. Oerter, Building 10, Room lON262, National Institutes of Health, Bethesda, Maryland 20892. * Supported by a grant from the Ter Meulen-Fund, Royal Netherlands Academy of Arts and Sciences, the “Stichting de Drie Lichten”, Eli Lilly and Company, and from Genentech Inc.
Pubertal
staging
Pubertal stage was determined (K.E.O.). For purposes of analysis
in all patients by the same observer it was based on the mean pubic hair
357
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358
OERTER
TABLE
1. Clinical
Case
SSX
1 2 3 4 5 6 I 8 9 10 11 12 13 14 15 16 17
F F F F F F F F F M M M M M M M M
and laboratory
Age
(yr)
12.0 13.8 14.0 14.0 14.5 15.0 15.5 15.5 16.8 12.8 14.5 15.0 15.0 15.5 16.0 16.0 16.5
characteristics
Bone age (Yd
11.0 14.0 12.0 13.0 15.0 11.0 13.5 12.0 13.0 12.5 11.0 15.0 12.0 12.5 11.5 13.0 14.2
Pubertal stage 2.0 4.0 4.0 4.0 5.0 2.0 3.0 3.0 2.0 1.0 1.0 2.0 3.0 1.0 2.0 2.0 4.0
’ SDS, Standard deviation score; BA, bone age. * Peak GH response to arginine-insulin or L-dopa ’ P, pubertal; G, growth; T, thyroid; A, adrenal. d Greater than 2 SD below mean for this pubertal
BMI (8DS by BA)
Growth velocity (SDS by B.4)
Peak GHb h&L)
12-h GH (w/mL)
-0.9 0.0 -0.6 -1.5 -1.1 -3.0 -0.3 -2.1 -2.7 -0.3 -3.0 -0.5 -3.4 -3.5 -3.4 -3.4 -1.2
0.3 -1.3 -0.6 0.1 1.8 0.9 1.3 -0.1 -0.1 0.4 0 0.2 -0.2 -0.2 -0.5 -1 -0.1
-3.0 5.8 -2.1 -1.7 4.1 -6.0 -1.0 -3.0 -3.3 -3.1 -2.5 -0.6 -2.2 -2.3 -2.9 -4.1 2.0
8.8 17.6 9.9 27.6 9.3 5.Sd 9.0 11.9 5.3d 2.3d 7.0d 23.1 20.6 11.5 12.0 24.1 9.8
1.96 1.87 13.20 6.41 0.74d 0.71d
