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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 8 3988-3993
Copyright © 2004 by The Endocrine Society

Effects of Estrogen and Recombinant Human Insulin-Like Growth Factor-I on Ghrelin Secretion in Severe Undernutrition

Steven Grinspoon, Karen K. Miller, David B. Herzog, Kelly A. Grieco and Anne Klibanski

Neuroendocrine Unit (S.G., K.K.M., K.A.G., A.K.) and The Eating Disorders Unit (D.B.H.), Massachusetts General Hospital and the Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Steven Grinspoon, M.D., Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: sgrinspoon{at}partners.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Ghrelin is a nutritionally regulated gut peptide that increases with fasting and chronic undernutrition and decreases with food intake. Sex steroid levels change in chronic undernutrition and might signal changes in ghrelin. At the same time, chronic undernutrition is characterized by low IGF-I that might also influence ghrelin, either directly or through changes in the GH axis. Little is known regarding sex steroid regulation of ghrelin and the effects of IGF-I on ghrelin in severe undernutrition. We investigated the effects of sex steroids and IGF-I on ghrelin in 78 female subjects with anorexia nervosa simultaneously randomized to receive estrogen (Ovcon 35, 35 µg ethinyl estradiol, and 0.4 mg norethindrone) as well as recombinant human (rh)IGF-I (30 µg/kg sc twice a day) in a two-by-two factorial model, in which the individual effects of estrogen (E) and rhIGF-I on ghrelin could be determined. Subjects were 24.9 ± 0.7 (mean ± SEM) yr of age and had low weight (body mass index, 16.7 ± 0.2 kg/m2). At baseline, ghrelin was inversely correlated with body mass index (r = –0.39, P = 0.0005) and IGF-I (r = –0.30, P = 0.01). IGF-I increased significantly more in subjects receiving rhIGF-I alone ({Delta} 23.0 ± 5.8 nmol/liter) and rhIGF-I and E ({Delta} 34.9 ± 6.3 nmol/liter) compared with subjects receiving E alone ({Delta} –3.2 ± 1.9 nmol/liter) or control (C; rhIGF-I placebo and no E) ({Delta} 0.4 ± 2.0 nmol/liter) (overall P < 0.0001 by multivariate analysis of variance, P < 0.0001 for rhIGF-I vs. C, P < 0.0001 for rhIGF-I and E vs. C). Ghrelin increased significantly more over 6 months in response to E alone ({Delta} 150 ± 86 pg/ml), rhIGF-I alone ({Delta} 198 ± 116 pg/ml), and the combination (E and rhIGF-I) ({Delta} 441 ± 214 pg/ml) compared with C ({Delta} –39 ± 48 pg/ml) (overall P = 0.02 by multivariate analysis of variance, P = 0.01 for E vs. C, P = 0.04 for rhIGF-I vs. C, and P = 0.001 for rhIGF-I and E vs. C). Weight, caloric intake, and morning GH levels did not change significantly between the groups, but the change in ghrelin was inversely related to the change in GH among all subjects (r = –0.27, P = 0.03).

Our data demonstrate that, in a model of severe undernutrition, rhIGF-I and E individually increase ghrelin levels. The mechanisms of these effects are unknown and may relate to direct effects on ghrelin or changes in GH. Further studies are needed to determine the mechanisms by which rhIGF-I and E increase ghrelin in human physiology.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GHRELIN, A NUTRITIONALLY regulated gut peptide, is an important secretogogue for GH (1, 2, 3, 4, 5). The physiological regulation of ghrelin is not established. Prior studies have demonstrated increased ghrelin in patients with anorexia nervosa and severe undernutrition (2, 6, 7, 8) and suggest that increased ghrelin might drive increased GH in fasting and undernutrition (9). Severe undernutrition is characterized by decreased sex steroid levels (10), and preliminary studies suggest that sex steroids, e.g. testosterone, may increase ghrelin (11). Changes in sex steroids might contribute to changes in appetite and ghrelin in chronic undernutrition, but, to our knowledge, the effects of estrogen (E) on ghrelin have not been determined. Severe undernutrition is also characterized by increased GH and decreased IGF-I (2, 12, 13). Recent data suggest that GH might affect ghrelin, down-regulating ghrelin expression and decreasing circulating levels (14, 15, 16), but the effects of IGF-I on ghrelin are not known. Therefore, we investigated the effects of E and recombinant human (rh)IGF-I, alone and in combination, on ghrelin in a large group of women with anorexia nervosa. We hypothesized that both rhIGF-I and E might affect ghrelin, although by different mechanisms, and sought to characterize the effects of these hormones on ghrelin, caloric intake, and weight in undernutrition. Our data suggest that E and rhIGF-I independently increase ghrelin in a model of severe undernutrition. The mechanism of these changes is uncertain and may involve changes in GH or direct effects on ghrelin. Further studies are now necessary to investigate the physiologic importance and mechanisms of sex steroid and IGF-I regulation of ghrelin.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Eligible subjects (78) with Diagnostic and Statistical Manual of Mental Disorders-IV-confirmed anorexia nervosa and amenorrhea for at least 3 months were recruited into the study. No patient had received E or related hormones within 6 months of the study. Screening TSH, FSH, and prolactin levels were normal in all patients. Effects of E and rhIGF-I on clinical endpoints, IGF-I, and bone density have been previously reported in a subset of patients (17).

Baseline assessment

At the baseline visit, weight, height, and caloric intake were measured during a 24-h inpatient observation period during which diet was ad libitum. Serum IGF-I, ghrelin, and GH were determined at 0800 h. After the baseline assessment, subjects were simultaneously randomized to rhIGF-I [30 µg/kg sc twice a day (BID)] (Genentech, Inc., San Francisco, CA) or identical placebo and to E (Ovcon 35, 35 µg ethinyl estradiol and 0.4 mg of norethindrone) (Bristol Meyers Squibb, Inc., Princeton, NJ) or no E in a two-by-two factorial model, resulting in four study groups: 1) rhIGF-I and E, 2) rhIGF-I and no E, 3) rhIGF-I placebo and E, and 4) rhIGF-I placebo and no E [control (C)]. Placebo was prepared by the Massachusetts General Hospital pharmacy and was identical in color and consistency to active drug. The administration of rhIGF-I was blinded to the patient and the nursing staff on the General Clinic Research Center, but not to investigator or study personnel, to permit safety monitoring. E administration was not blinded to either patient or investigator. The randomization schema was prepared by the study statistician. Subjects kept an injection log and returned unused or empty vials. In addition, patients recorded menses and E pills taken in a separate log. Returned E pills were also recorded.

Subsequent study visits

Subjects were assessed for safety at 1 wk by telephone and returned for safety monitoring and assessment of IGF-I levels at 2 wk and then monthly after study initiation. Endpoints were compared after 6 months of treatment at a visit identical with the baseline visit. Weight was measured at each visit. Serum IGF-I was determined at each visit, and a dose reduction of 25% was performed for patients with an IGF-I level above the normal age-adjusted range for the assay. Dose adjustment was further made as required based on measured weight at each visit to maintain a dose of 30 µg/kg sc BID. No dose adjustment was made for placebo-treated patients. Ghrelin was assessed at 3 and 6 months. Ten subjects withdrew consent or were discontinued from the study at the initiative of the investigator. One subject in the rhIGF-I group withdrew from the study after the baseline visit for personal reasons unrelated to the study protocol. Two subjects in the E group were lost to follow-up before the 3-month visit, and one subject in the rhIGF-I and E group withdrew before the 3-month visit because of nausea. An additional subject in the rhIGF-I and E group discontinued the study medications of her own initiative and subsequently withdrew before the 3-month visit. One subject in the E group was discontinued from the study after hospitalization for myocarditis. One patient in the rhIGF-I group was discontinued for local skin irritation associated with injections. One subject in the rhIGF-I and two subjects in the C group were discontinued from the study for continued weight loss.

Data analysis

JMP Statistical Discoveries, version IV (SAS Institute, Cary, NC) was used for statistical analysis. Univariate and multivariate regression analyses were performed relating ghrelin to IGF-I, body mass index (BMI), and GH. Differences between the groups were compared at baseline by ANOVA. For all variables not normally distributed, nonparametric Wilcoxon testing was performed. Changes in ghrelin, IGF-I, and GH in the four individual treatment groups [rhIGF-I and E (n = 18), rhIGF-I and no E (n = 21), rhIGF-I placebo and E (n = 19), and rhIGF-I placebo and no E (n = 20)] were compared in a random effects model with terms for time and treatment group. Overall effect was determined by multivariate analysis of variance (MANOVA), and results of individual groups were also compared if the MANOVA was significant.

Safety monitoring

An independent Data Safety Monitoring Board met every 3 months to review all adverse events associated with the study, as well as safety data related to glucose, weight, and IGF-I levels. The protocol was approved by the Subcommittee on Human Studies of the Massachusetts General Hospital (Boston, MA). Informed consent was obtained from all patients, in accordance with the Helsinki II guidelines on the conduct of human research.

Methods

Height was determined by stadiometer. Weight was determined on a calibrated scale to the nearest 0.1 kg. Caloric intake was determined by calorie count during a 24-h inpatient observation period and by 4-d food record collected before admission. Prolactin, FSH, and TSH were determined at screening by previously reported methods (18). Serum IGF-I was assessed by RIA after alcohol extraction with an intraassay coefficient of variation (CV) of 2.4–3.0% (Nichols Institute, San Juan Capistrano, CA). Serum total ghrelin was assessed by RIA (Phoenix Pharmaceuticals, Belmont, CA) with an intraassay CV of 8.7% and interassay CV of less than 10%. Serum GH was determined by RIA (Nichols Institute), with an intraassay CV of 4.4% and interassay CV of 6.6%.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline clinical characteristics are shown in Table 1Go. Ninety-eight percent of subjects were Caucasian, 1% were Asian, and 1% were Hispanic. BMI was slightly greater at baseline in the rhIGF-I-treated groups compared with C. All other variables were similar at baseline, including ghrelin, IGF-I, and GH. Ghrelin was inversely correlated with BMI (r = –0.39, P = 0.0005) (Fig. 1Go) and IGF-I (r = –0.30, P = 0.01) at baseline. In multivariate regression analysis controlling for BMI and IGF-I simultaneously, BMI (estimate = –58.84, P = 0.03) but not IGF-I (estimate = –4.3, P = 0.29) remained a significant predictor of baseline ghrelin.


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  		TABLE 1. Clinical characteristics of study subjects

 


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  		FIG. 1. Correlation between baseline BMI and serum ghrelin levels in women with anorexia nervosa (n = 78, r = –0.39, P = 0.0005).

 
IGF-I increased significantly more in subjects receiving rhIGF-I alone ({Delta} 23.0 ± 5.8 nmol/liter) and rhIGF-I and E ({Delta} 34.9 ± 6.3 nmol/liter) compared with subjects receiving E alone ({Delta} –3.2 ± 1.9 nmol/liter) or C ({Delta} 0.4 ± 2.0 nmol/liter) (overall P < 0.0001 by MANOVA, P < 0.0001 for rhIGF-I vs. C, and P < 0.0001 for rhIGF-I and E vs. C).

Ghrelin increased significantly more over 6 months in response to E alone ({Delta} 150 ± 86 pg/ml), rhIGF-I alone ({Delta} 198 ± 116 pg/ml), and the combination (E and rhIGF-I) ({Delta} 441 ± 214 pg/ml) compared with C ({Delta} –39 ± 48 pg/ml) (overall P = 0.02 by MANOVA, P = 0.01 for E vs. C, P = 0.04 for rhIGF-I vs. C, and P = 0.001 for rhIGF-I and E vs. C) (Fig. 2Go). Weight and morning GH levels did not change significantly between the groups (Table 2Go), but the change in GH was inversely related to the change in ghrelin among all subjects (r = –0.27, P = 0.03). Neither caloric intake by calorie count (Table 2Go) nor by food record (data not shown) changed significantly between the groups.



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  		FIG. 2. Change in serum ghrelin levels in women with anorexia nervosa by randomization group. *, P = 0.02 by MANOVA over 6 months in four-group analysis: P = 0.001 for rhIGF-I and E vs. C, P = 0.09 for rhIGF-I and E vs. E alone, P = 0.42 for rhIGF-I and E vs. rhIGF-I alone, P = 0.04 for rhIGF-I alone vs. C, and P = 0.01 for E alone vs. C.

 

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  		TABLE 2. Baseline and change over time by randomization group

 
Mean IGF-I levels were maintained within the normal range during the 6 months of observation. In seven of the subjects randomized to rhIGF-I and E combined and four of the subjects randomized to rhIGF-I alone, IGI-I levels increased to above the age-adjusted normative ranges on one or more visits in the study. Furthermore, IGF-I levels were within the normal range in all but 6% of the 403 individual monthly assessments performed on the rhIGF-I- or rhIGF-I- and E-treated patients. Because few dose reductions were required, the average daily dose for the rhIGF-I-treated subjects remained 30 µg/kg sc BID for the duration of the study. The rhIGF-I was well tolerated. Significant erythema was noted at the injection site in one patient in the rhIGF-I-alone group, resulting in discontinuation from the study. Nadir blood glucose remained above 50 mg/dl after rhIGF-I injection in all patients, and hypoglycemic symptoms were not reported acutely after rhIGF-I injection or at any time throughout the study.

Compliance was equivalent among the study groups in terms of rhIGF-I and E administration. Subjects returned an average of 9.8 ± 0.8 (rhIGF-I and E), 8.6 ± 1.0 (rhIGF-I), 9.9 ± 0.9 (E), and 8.3 ± 1.0 (C) vials of study medication (P = 0.53). Subjects randomized to rhIGF-I or rhIGF-I and E therapy missed a mean of 1.9 ± 0.4 d of rhIGF-I treatment, whereas subjects randomized to E or rhIGF-I and E missed an average of 9.5 ± 2.1 d of E treatment over the study, according to returned medication diaries.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study, we demonstrate that E, in the form of an oral contraceptive, increases ghrelin over 6 months in chronic undernutrition. Simultaneously, we demonstrate that rhIGF-I, administered at a physiological dose, increases ghrelin and that this effect may be additive, although not synergistic, with that of E in severe undernutrition. GH levels did not change significantly between groups, but the changes in GH were inversely correlated with the changes in ghrelin among all patients. These data suggest a potential effect of sex steroids as well as IGF-I to increase ghrelin in severe undernutrition. rhIGF-I may increase ghrelin through direct mechanisms or through inhibitory effects on GH in this model.

A novel finding in this study is the positive effect of E on ghrelin. This effect was seen among patients receiving E, without rhIGF-I, and was significant in comparison with the C group. The change in ghrelin in this group occurred in the context of stable weight and caloric intake, thus ruling out an indirect effect of changes in nutritional status. To our knowledge, prior studies have not assessed the effects of E on ghrelin, but one prior study demonstrated that testosterone administration to hypogonadal men increases ghrelin (11). Women with anorexia nervosa are severely E deficient with low estradiol levels and amenorrhea. In addition, it is notable that the change in ghrelin in response to E took place among a population with already high ghrelin levels. The response to high-dose E in an oral contraceptive may be supraphysiological, and further studies of the effects of lower-dose E on ghrelin in normally nourished and undernourished women are necessary.

In other populations of normally nourished women, oral E decreases IGF-I and increases GH and responsiveness of GH to GHRH (19, 20, 21). In contrast, the effects of higher-dose oral E on GH and the IGF-I axis in anorexia nervosa, characterized by very high GH and already low IGF-I, are unknown. In this study, IGF-I decreased in the E-alone-treated group by approximately 10%, but the decrease in IGF-I in the E-alone group did not reach significance. Furthermore, GH tended to decrease in the E-alone group by approximately 20%, but this change was also not significant, perhaps related to the variability associated with a single GH sample. Thus, the effects of E on ghrelin may be direct or occur via changes in the GH axis that we could not appreciate in our model, and further studies will be needed in this regard. Because we administered E in the form of an oral contraceptive, we cannot rule out an effect of the progesterone, norethindrone, on ghrelin.

The clinical implications of increased ghrelin in response to E are not known. Further studies are needed in patients without anorexia nervosa to determine whether E increases ghrelin and whether this accounts in part for weight gain or increased appetite associated with E. Subjects in the current study did not gain weight in response to E in the setting of increased ghrelin, but significant behavioral abnormalities may have prevented such an effect. An effect of endogenous sex steroids to increase ghrelin and thus appetite might help ensure adequate fertility, nutrient intake, and growth during pregnancy. In this regard, it would be interesting to see whether ghrelin increases with the periovulatory surge in estradiol in healthy women and/or during pregnancy.

Ghrelin increased significantly, by approximately 200 pg/ml or 25%, in response to rhIGF-I, in the setting of stable weight and caloric intake over 6 months. IGF-I levels were reduced at baseline and increased significantly, but generally within the normal range, in response to rhIGF-I, suggesting that IGF-I dosing was physiological. To our knowledge, prior studies have not investigated the effects of rhIGF-I on ghrelin. GH resistance is seen in undernutrition (22, 23, 24, 25, 26, 27), with increased GH due in part to decreased IGF-I feedback. It is known that rhIGF-I decreases GH in response to overnight fasting (28, 29). Therefore, one possible explanation of our data is that rhIGF-I decreased GH, leading to increases in ghrelin by a feedback mechanism. In contrast, BMI but not IGF correlated significantly with ghrelin in multivariate regression analysis at baseline, suggesting the importance of nutritional factors in addition to the potential effects of IGF-I on ghrelin regulation.

Although we were unable to assess GH levels more comprehensively, e.g. through overnight sampling, due to sample volume constraints, we did assess morning GH levels. Relatively modest effects of rhIGF-I to decrease but not normalize GH were obtained in a prior study investigating GH response over 5 h to a single dose of rhIGF-I in women with anorexia nervosa (30). In the current study, GH tended to decrease more in the IGF-I group more than in the C group, although this was not significant; therefore, the changes in the two groups might be similar. However, the change in ghrelin was inversely associated with the change in GH, e.g. the lower the GH, the more the ghrelin increased. Alternatively, given the relatively similar changes in GH between the groups, it is possible that rhIGF-I increases ghrelin through other as yet unknown mechanisms. Further studies investigating the mechanism of rhIGF-I effect on ghrelin with more detailed measures of GH are needed.

In prior studies, GH administration was shown to lower ghrelin concentrations in patients with GH deficiency (16). In animal studies, GH administration was shown to decrease stomach ghrelin mRNA secretion (15). In acromegaly, cure of GH excess resulted in increased ghrelin (14). Thus, preliminary human and animal studies, taken together, suggest that GH may negatively regulate ghrelin, and our studies suggest that an effect of rhIGF-I on GH may be one mechanism by which rhIGF-I administration increases ghrelin in severe undernutrition. Alternatively, there may be direct effects of rhIGF-I on ghrelin, and further studies will be necessary to determine the mechanism of rhIGF-I effects on ghrelin. Ghrelin increased in the rhIGF-I-alone and E-alone groups, and a relatively greater increase was seen in the combined groups. However, a clear additive or synergistic effect of rhIGF-I and E could not be determined from the study because the ghrelin response in the combined rhIGF-I and E group was not significantly greater than the ghrelin response in the rhIGF-I-alone group or in comparison with the ghrelin response in the E-alone group.

This study has a number of advantages and some limitations. The study was randomized and placebo controlled, enrolling a large number of women with anorexia with follow-up over a number of months. Consistent with the underlying diagnosis, the great majority of subjects were Caucasian. The IGF-I dose was physiological, and four groups were recruited such that the independent effects of E and rhIGF-I as well as the combined effects could be compared with the C group. Previous studies have not, to our knowledge, examined the effects of either E or rhIGF on ghrelin. Because we investigated a model of extreme undernutrition, it is not clear that these results would apply to normal physiology in well-nourished patients with greater racial diversity, and further studies will be needed in this regard. Furthermore, we were unable to comprehensively assess the GH, either by frequent sampling or pulse dynamics, and further information on GH would be important.

In summary, our data demonstrate increased ghrelin in response to E and rhIGF-I in women with severe undernutrition. Our study suggests the potential for sex steroid regulation of ghrelin in women, although further studies are necessary at more physiological E levels in models of varying nutritional status. The effects of rhIGF-I on ghrelin seen in this study may be due to direct effects of rhIGF-I on ghrelin or due to decreases in GH, which may further derepress and stimulate ghrelin in undernutrition. Further studies are necessary to study the effects of E and IGF-I on ghrelin in human physiology.


   Acknowledgments
 
The authors thank the nursing and bionutrition staffs of the General Clinical Research Center for their dedicated patient care and Jeff Breu of the Massachusetts Institute of Technology General Clinical Research Center (Cambridge, MA) for his help with the RIAs.


   Footnotes
 
This work was supported in part by National Institutes of Health Grants DK 52625 (to A.K.) and M01-RR-01066 and by The Harvard Eating Disorders Center. rhIGF-I was supplied by Genentech, Inc. under Food and Drug Administration Investigational New Drug 38,809. None of the authors received grant support or financial assistance from Genentech, Inc.

Abbreviations: BID, Twice a day; BMI, body mass index; C, control; CV, coefficient(s) of variation; E, estrogen; MANOVA, multivariate analysis of variance; rh, recombinant human.

Received February 13, 2004.

Accepted April 12, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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