0021-972x/92/7503-0%2$03.00/0 dournal of Clinical Endocrinology and Metabolism Copyright I% 1992 by The Endocrine Society
Vol. 75, No. 3 Printed in (IS A
The Effect of Anorexia Nervosa and Refeeding on Growth Hormone-Binding Protein, the Insulin-Like Growth Factors (IGFs), and the IGF-Binding Proteins DEBRA R. COUNTS, MICHAEL LESEM,
HARRY GWIRTSMAN, LENA GORDON B. CUTLER, JR.
M. S. CARLSSON,
AND
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, and the Clinical Neuroendocrinology Branch, National Institute of Mental Health (H.G., M.L.), National Institutes of Health, Bethesda, Maryland 20892; and the Endocrine Research Department, Genentech, Inc. (L.M.S.C.), South San Francisco, California 94080 ABSTRACT We studied the relationship of serum insulin-like growth factor-I (IGF-I), IGF-II, the IGF-binding proteins IGFBP-1, IGFBP-2, and IGFBP-3, and GH-binding protein (GHBP; which is postulated to be derived from the extracellular portion of the GH receptor) in normal volunteers and patients with anorexia nervosa before and after a refeeding program. Serum GHBP, IGF-I, and IGFBP-3 were all significantly decreased in low weight patients with anorexia nervosa and returned to nearly normal levels with refeeding. Fasting serum GH and serum IGFBP-1 and IGFBP-2 were significantly increased in low
weight patients with anorexia nervoaa and also returned to nearly normal levels with refeeding. Serum IGF-II was 27% lower in the low weight group than in normal subjects, but this difference was not statistically significant. Both serum IGF-I and IGF-II were positively correlated with serum IGFBP-3 and negatively correlated with serum IGFBP-1 and IGFBP-2. These data are consistent with the hypothesis that nutritional deprivation alters the GH-IGF axis by down-regulation of the GH receptor or its postreceptor mechanisms, and that this effect is reversible with refeeding. (J Clin Endocrinol Metub 75: 762-767, 1992)
P
IGFs and their binding proteins (IGFBPs) in patients with anorexia nervosa before and after a refeeding program.
ATIENTS with anorexia nervosa may have multiple endocrine abnormalities, including hypothyroidism, amenorrhea, hypercortisolism, and elevated GH, with suppressed insulin-like growth factor-I (IGF-I). These derangements resolve with nutritional therapy (1). Hypersomatotropism with low IGF-I is seenin other diseasesassociatedwith malnutrition and points to the importance of nutritional regulation of IGF-I secretion and growth. The effect of short term fasting to decrease IGF-I, IGFbinding protein-3 (IGFBP-3), and GH-binding protein (GHBP) has been documented in humans (Z-4). However, to our knowledge, the binding proteins for the IGFs and GH have not been examined in patients with anorexia nervosa under conditions when nutrition-induced alterations in IGFs and GH-related proteins presumably have reached a steady state. Since caloric deprivation in anorexia nervosa leads to increased GH and decreased IGF-I, we hypothesized that prolonged nutritional deprivation in anorexia nervosa induces a state of down-regulation of the GH receptor or its postreceptor mechanisms. This would explain the fall in the levels of GH-dependent serum proteins IGF-I and IGFBP-3 and a rise in GH, presumably by decreased feedback inhibition by IGF-I. Since the circulating GHBP is structurally identical to the extracellular domain of the GH receptor and is thought to be derived from it by enzymatic cleavage (5, 6), we measured GHBP and examined its relationship to the Received September 3, 1991. Address all correspondence and requests for reprints to: Debra R. Counts, M.D., National Institutes of Health, Building 10, Room lON262, 9000 Rockville Pike, Bethesda, Maryland 20892.
Materials and Methods Patients Control patients were 11 women of normal weight [body mass index (BMI), 18.3-26.71 with normal menstruation. The patients with anorexia nervosa all met DSM III criteria (7), including weight less than 85% of expected, intense fear of being fat, disturbed body image, and amenorrhea for three or more consecutive menstrual cycles (Table 1). Twelve patients were evaluated in the low weight state after rehydration and correction of electrolyte abnormalities, and 10 were reexamined in the short term weight-recovered state. The time for weight recovery was, on the average, 2 months, and short term weight recovery was weight stabilization for 2-3 weeks. Only the 10 patients for whom there were weight-recovered data were included in the paired analyses. Control patients and patients with anorexia nervosa were admitted to the Eating Disorders Unit at the NIH Clinical Center. All blood samples were fasting morning samples.
Serum
measurements
Serum IGF-I, by RIA (Endocrine ethanol extraction assay coefficients 11% for IGF-II, GH determinations IGFBP-1 and David Clemmons of variation were IGFBP-2. Serum GHBP
IGF-II, and IGFBP-3 determinations were performed Sciences, Calabasas Hills, CA) of IGFs after acidand of IGFBP-3 directly on serum. Intra- and interof variation were 6.4% and 10% for IGF-I, 1.3% and and 1.7% and 11% for IGFBP-3, respectively. Serum were made at Hazelton Laboratories (Vienna, VA). IGFBP-2 were measured by RIA in the laboratory of (Chapel Hill, NC). Intra- and interassay coefficients 7% and 18% (8) for IGFBP-1 and 4% and 14% (9) for was measured
in duplicate
by ligand-mediated
762
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 25 October 2015. at 15:44 For personal use only. No other uses without permission. . All rights reserved.
immu-
GH-IGF TABLE
1. Clinical
and the normal
control
features of the patients subjects
with
AXIS
anorexia
IN ANOREXIA
NERVOSA
763
nervosa
Diagnosis Clinical
Anorexia
characteristics
Normal (n = 11)
Age
W
Ht (cm)
nervosa
Low wt
Recovered
(n = 12)
(n = 10)
24.6 (21-35) 164 (158-172)
24.7 (18-31) 161 (155-173)
(5?73, 22.4 (18.3-26.7)
(237240, 12.2 (10.5-14.3) 5.9 (2-13)
$35, Same
Wt (kg) BMI
(kg/m’)
Duration Fasting
of anorexia GH
(pg/L)”
(yrs) 0.48 (
Vol. 75, No. 3 Printed in (IS A
The Effect of Anorexia Nervosa and Refeeding on Growth Hormone-Binding Protein, the Insulin-Like Growth Factors (IGFs), and the IGF-Binding Proteins DEBRA R. COUNTS, MICHAEL LESEM,
HARRY GWIRTSMAN, LENA GORDON B. CUTLER, JR.
M. S. CARLSSON,
AND
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, and the Clinical Neuroendocrinology Branch, National Institute of Mental Health (H.G., M.L.), National Institutes of Health, Bethesda, Maryland 20892; and the Endocrine Research Department, Genentech, Inc. (L.M.S.C.), South San Francisco, California 94080 ABSTRACT We studied the relationship of serum insulin-like growth factor-I (IGF-I), IGF-II, the IGF-binding proteins IGFBP-1, IGFBP-2, and IGFBP-3, and GH-binding protein (GHBP; which is postulated to be derived from the extracellular portion of the GH receptor) in normal volunteers and patients with anorexia nervosa before and after a refeeding program. Serum GHBP, IGF-I, and IGFBP-3 were all significantly decreased in low weight patients with anorexia nervosa and returned to nearly normal levels with refeeding. Fasting serum GH and serum IGFBP-1 and IGFBP-2 were significantly increased in low
weight patients with anorexia nervoaa and also returned to nearly normal levels with refeeding. Serum IGF-II was 27% lower in the low weight group than in normal subjects, but this difference was not statistically significant. Both serum IGF-I and IGF-II were positively correlated with serum IGFBP-3 and negatively correlated with serum IGFBP-1 and IGFBP-2. These data are consistent with the hypothesis that nutritional deprivation alters the GH-IGF axis by down-regulation of the GH receptor or its postreceptor mechanisms, and that this effect is reversible with refeeding. (J Clin Endocrinol Metub 75: 762-767, 1992)
P
IGFs and their binding proteins (IGFBPs) in patients with anorexia nervosa before and after a refeeding program.
ATIENTS with anorexia nervosa may have multiple endocrine abnormalities, including hypothyroidism, amenorrhea, hypercortisolism, and elevated GH, with suppressed insulin-like growth factor-I (IGF-I). These derangements resolve with nutritional therapy (1). Hypersomatotropism with low IGF-I is seenin other diseasesassociatedwith malnutrition and points to the importance of nutritional regulation of IGF-I secretion and growth. The effect of short term fasting to decrease IGF-I, IGFbinding protein-3 (IGFBP-3), and GH-binding protein (GHBP) has been documented in humans (Z-4). However, to our knowledge, the binding proteins for the IGFs and GH have not been examined in patients with anorexia nervosa under conditions when nutrition-induced alterations in IGFs and GH-related proteins presumably have reached a steady state. Since caloric deprivation in anorexia nervosa leads to increased GH and decreased IGF-I, we hypothesized that prolonged nutritional deprivation in anorexia nervosa induces a state of down-regulation of the GH receptor or its postreceptor mechanisms. This would explain the fall in the levels of GH-dependent serum proteins IGF-I and IGFBP-3 and a rise in GH, presumably by decreased feedback inhibition by IGF-I. Since the circulating GHBP is structurally identical to the extracellular domain of the GH receptor and is thought to be derived from it by enzymatic cleavage (5, 6), we measured GHBP and examined its relationship to the Received September 3, 1991. Address all correspondence and requests for reprints to: Debra R. Counts, M.D., National Institutes of Health, Building 10, Room lON262, 9000 Rockville Pike, Bethesda, Maryland 20892.
Materials and Methods Patients Control patients were 11 women of normal weight [body mass index (BMI), 18.3-26.71 with normal menstruation. The patients with anorexia nervosa all met DSM III criteria (7), including weight less than 85% of expected, intense fear of being fat, disturbed body image, and amenorrhea for three or more consecutive menstrual cycles (Table 1). Twelve patients were evaluated in the low weight state after rehydration and correction of electrolyte abnormalities, and 10 were reexamined in the short term weight-recovered state. The time for weight recovery was, on the average, 2 months, and short term weight recovery was weight stabilization for 2-3 weeks. Only the 10 patients for whom there were weight-recovered data were included in the paired analyses. Control patients and patients with anorexia nervosa were admitted to the Eating Disorders Unit at the NIH Clinical Center. All blood samples were fasting morning samples.
Serum
measurements
Serum IGF-I, by RIA (Endocrine ethanol extraction assay coefficients 11% for IGF-II, GH determinations IGFBP-1 and David Clemmons of variation were IGFBP-2. Serum GHBP
IGF-II, and IGFBP-3 determinations were performed Sciences, Calabasas Hills, CA) of IGFs after acidand of IGFBP-3 directly on serum. Intra- and interof variation were 6.4% and 10% for IGF-I, 1.3% and and 1.7% and 11% for IGFBP-3, respectively. Serum were made at Hazelton Laboratories (Vienna, VA). IGFBP-2 were measured by RIA in the laboratory of (Chapel Hill, NC). Intra- and interassay coefficients 7% and 18% (8) for IGFBP-1 and 4% and 14% (9) for was measured
in duplicate
by ligand-mediated
762
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 25 October 2015. at 15:44 For personal use only. No other uses without permission. . All rights reserved.
immu-
GH-IGF TABLE
1. Clinical
and the normal
control
features of the patients subjects
with
AXIS
anorexia
IN ANOREXIA
NERVOSA
763
nervosa
Diagnosis Clinical
Anorexia
characteristics
Normal (n = 11)
Age
W
Ht (cm)
nervosa
Low wt
Recovered
(n = 12)
(n = 10)
24.6 (21-35) 164 (158-172)
24.7 (18-31) 161 (155-173)
(5?73, 22.4 (18.3-26.7)
(237240, 12.2 (10.5-14.3) 5.9 (2-13)
$35, Same
Wt (kg) BMI
(kg/m’)
Duration Fasting
of anorexia GH
(pg/L)”
(yrs) 0.48 (
