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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-2631
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 2 629-635
Copyright © 2007 by The Endocrine Society

The Insulin-Like Growth Factor-I Response to Growth Hormone Is Increased in Prepubertal Children with Obesity and Tall Stature

Natacha Bouhours-Nouet, Frédérique Gatelais, Florence Boux de Casson, Stéphanie Rouleau and Régis Coutant

Departments of Pediatrics (N.B.-N., F.G., S.R., R.C.) and Nuclear Medicine (F.B.d.C.), University Hospital, 49033 Angers Cedex 01, France

Address all correspondence and requests for reprints to: Régis Coutant, Department of Pediatrics, University Hospital, 4 rue Larrey, 49033 Angers Cedex 01, France. E-mail: recoutant{at}chu-angers.fr.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Children with obesity [body mass index (BMI) > +2 SD score (SDS)] and children with constitutional tall stature [CTS; height > +2 SDS)] have normal-high serum IGF-I levels, associated with a low and broad range of GH secretion, respectively. This suggests increased sensitivity to GH, whereas children with idiopathic short stature (ISS; height < –2 SDS) are believed to have decreased GH sensitivity.

Objective, Design, and Main Outcome Measure: To compare the responsiveness to GH in 62 prepubertal children (43 females, 19 males) with obesity, CTS, or ISS and 26 controls (15 females, 11 males; height and BMI –2 to +2 SDS), we used an IGF-I generation test and studied the IGF-I concentration 24 h after a single injection of GH (2 mg/m2).

Patients: Twenty patients with obesity, 20 with CTS, 22 with ISS, and 26 controls were studied. The mean age was 8.3 ± 2.9 yr, with no difference in age or gender between groups.

Results: Compared with controls, the mean IGF-I increment was 80% higher in obese children and 36% higher in tall children (P < 0.05 obese or tall vs. control children; P = 0.05 obese vs. tall children). Conversely, the IGF-I increment was similar in short compared with control children, despite a mean baseline IGF-I 62% lower in short children (P < 0.05 vs. controls). In all groups, the IGF-I increment was correlated with the BMI SDS or the fat mass percentage (r = 0.51–0.58, P < 0.05).

Conclusion: Obese children tend to have greater GH responsiveness than tall children, and both have greater GH responsiveness than controls. GH responsiveness was similar in controls and short children, despite a lower baseline IGF-I in short children. Whether the differences in the IGF-I response to GH between these children reflect differences in the respective anabolic (growth promotion) and metabolic (i.e. insulin action modulation) roles of circulating IGF-I is unknown.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CONSTITUTIONAL TALL STATURE is defined as a height 2 SD score (SDS) above the mean height for a given age and sex (1, 2). Studies of the 24-h GH secretion in tall children have shown heterogeneity, with some children having high GH secretion rates and others showing low GH secretion (3, 4). Overall, there is no evidence for a physiological increase in GH secretion as a universal cause of tall stature. Normal to high levels of IGF-I and IGF binding protein (IGFBP)-3 have been consistently measured in such children (4, 5, 6), however, which may be suggestive of an increased responsiveness to GH in some cases. This situation could inversely mirror that in children with idiopathic short stature (ISS), who often have normal GH secretion contrasting with relatively low levels of IGF-I, thus suggesting partial insensitivity to GH action (2, 7, 8).

Obese children often display increased linear growth and modestly accelerated bone age (2). Obesity is characterized by decreased spontaneous GH secretion and a blunted response of GH to stimulation tests, contrasting with high serum GH-binding protein (GHBP) and normal to high IGF-I levels (9, 10, 11, 12). This situation, as in tall stature, may suggest an increase in responsiveness to GH.

GH sensitivity can be assessed by the IGF-I generation tests, which were originally used to evaluate children with short stature (13, 14). However, the interpretation of the results has been hampered by the lack of normative data in most studies. Recently the IGF-I generation data from 38 normal children, whose mean height was –1.1 SDS, were published (13). In this work, the study of 16 children with ISS revealed that they had low-normal baseline and GH-stimulated IGF-I concentrations in comparison with controls (13), whereas some patients with GH deficiency (GHD) had both baseline and stimulated IGF-I levels that overlapped the levels in patients with verified GH insensitivity. In addition to evaluating children with short stature, the IGF-I generation tests have been increasingly used to assess GH responsiveness in subjects with other conditions, such as obese adults (9, 15), menopausal women with various estrogen substitutions (16, 17), aging subjects (16, 18), and adolescents during pubertal development or upon sex steroid administration (19, 20). These tests have proved to be valuable tools in determining the factors that influence GH sensitivity.

In this work, we used an acute generation test, in which the IGF-I concentration 24 h after a single injection of GH (2 mg/m2) was measured (9, 17, 18, 19, 20), to compare GH responsiveness in 62 prepubertal children with constitutional tall stature (n = 20; height > +2 SDS), obesity [n = 20; body mass index (BMI) > +2 SDS], or ISS (n = 22; height < – 2 SDS) and controls matched for age and sex (n = 26, height between –2 and +2 SDS and BMI between –2 and +2 SDS).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

We studied 88 prepubertal children aged 4–12 yr (mean 8.3 ± 2.8 yr): 58 girls and 30 boys. No children in puberty were included (21, 22).

Twenty children (16 girls, 4 boys) had constitutional tall stature, defined as a height greater than +2 SDS for age and sex (23). Excess GH was ruled out by demonstration of suppressed serum GH concentrations after oral glucose loading. None of the tall children was obese (BMI < +2 SDS for age and sex) (24), and none had any metabolic, endocrine, or genetic disease. Twenty children (14 girls, 6 boys) were obese, defined as a BMI greater than +2 SDS for age and sex (24). None of the obese children had any metabolic, endocrine, or genetic disease other than obesity, and none had short stature [height > – 2 SDS for age and sex, (23)]. Twenty-two children (13 girls, 9 boys) had ISS, defined as a height below –2 SDS for age and sex (2, 23). GHD was ruled out [GH peak to the insulin tolerance test or the arginine-insulin test > 10 µg/liter]. The children were all in good health, with none presenting with obesity, chromosomal abnormalities, dysmorphic syndromes, skeletal dysplasia, chronic illness, or any endocrine or metabolic disease. Twenty-six children (15 girls, 11 boys) were included in the control group. They had a height greater than –2 SDS for age and sex (23). These children had primarily been referred to our clinic either because their height was 1 SDS or more below the midparental height or it had not maintained on a stable growth channel or because they had complained about their height, perceiving it as too short (even though it was over –2 SDS): the range of control heights was –1.9 to +1.5 SDS. GHD was ruled out (GH peak to the insulin tolerance test or the arginine-insulin test > 10 µg/liter). The children were all in good health, with none presenting with obesity, chromosomal abnormalities, dysmorphic syndromes, skeletal dysplasia, chronic illness, or any endocrine or metabolic disease. All had a predicted adult height calculated from their bone age greater than –2 SDS (25, 26). None of the studied children was taking medication.

The protocol was approved by our institutional review board. All subjects and families gave their informed consent.

Study design

The children received recombinant human GH (Maxomat; Sanofi-Aventis, Paris, France) at a dose of 2 mg/m2 at 0800 h after a physiological overnight fast (9, 17, 18, 19, 20). Treatment was administered by sc abdominal injection by a registered nurse. Blood was sampled 0 and 24 h after injection for measurement of IGF-I and IGFBP-3. The subjects were permitted a normal oral diet: they had three major meals and one snack.

Body composition

Body composition was investigated in the children with ISS and obesity by dual-energy x-ray absorptiometry using a Hologic QDR 4500A densitometer (Hologic Inc., Waltham, MA). Whole-body scans were performed, and body compartments were analyzed using Hologic software (version V8.24a:3). Total and regional body composition was assessed. Fat mass was expressed as fat percentage.

Hormone assays

Serum total IGF-I measurements were performed by immunoradiometric assay (IRMA) after acid-ethanol extraction; serum IGFBP-3 was also measured by IRMA (Immunotech; Beckman Coulter, Villepinte, France). The intra- and interassay coefficients of variation were 5.7 and 8.6% for IGF-I and 4.8 and 6.4% for IGFBP-3, respectively. Serum GH was measured by IRMA (Immunotech; Beckman Coulter). The sensitivity was 0.05 µg/liter, and the intra- and interassay coefficients of variation were 1.5 and 14.03%, respectively.

Statistical methods

Quantitative variables that were normally distributed, as assessed by the Komolgorov-Smirnov test, were expressed as means ± SD. Analyses of variance were used to compare quantitative variables among the four groups of children (obesity, tall stature, ISS, and controls). If a statistically significant difference was found, the post hoc Fisher least significant differences test was used. Qualitative variables were compared using the {chi}2 test. To compare the responsiveness to GH among groups independently of other factors, ANOVAs followed by the post hoc Fisher least significant differences test were performed, with age, gender, and baseline IGF-I as adjusting variables. The IGF-I increment in response to GH (change in IGF-I from baseline = difference between stimulated and baseline IGF-I) was used as the dependent variable. IGF-I was expressed as micrograms per liter. Normal age-related IGF-I values in our laboratory are 40–300 µg/liter (4–8 yr) and 75–350 µg/liter (8–12 yr, prepuberty) in boys, and 50–350 µg/liter (4–8 yr) and 100–400 µg/liter (8–11 yr, prepuberty) in girls (for IGF-I: to convert values to nanomoles per liter, divide by 7.65. Midparental height was calculated as previously described (27). Significance was defined as P < 0.05. All analyses were two tailed and performed with the SPSS 11.5 statistical package (SPSS Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Characteristics of the children (Table 1Go)

The mean age was 8.3 ± 2.9 yr, with no difference among groups. There was no gender difference among groups. Birth length and midparental height were significantly greater in children with tall stature, compared with the other groups (P < 0.05), and significantly lower in the children with short stature, compared with the other groups (P < 0.05), thus indicating the early onset of the specific growth pattern in the tall and short children and the genetic participation in the stature of these children (Table 1Go).


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  		TABLE 1. Clinical characteristics of the subjects

 
IGF-I responsiveness to GH (Table 2Go and Fig. 1Go)

Baseline IGF-I was significantly different among the groups of children (P < 0.0001 by ANOVA): it was 34% higher in obese (318 ± 93 µg/liter) and tall children (314 ± 142 µg/liter), compared with controls (237 ± 98 µg/liter; P < 0.05 for both comparisons) and 62% lower in short children (148 ± 81 µg/liter), compared with controls (P < 0.05). The same differences were observed when baseline IGF-I was expressed as SDS. GH concentrations were comparable among groups 4 and 24 h after recombinant human GH administration (Table 2Go).


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  		TABLE 2. Biological characteristics of the subjects

 

Figure 1
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  		FIG. 1. Baseline (H0) and stimulated (H24) serum IGF-I in children with obesity, constitutional tall stature, ISS, and controls. Black bars disclose the means for baseline and stimulated IGF-I. The mean IGF-I increment in response to GH (defined as the difference between stimulated and baseline IGF-I) is figured as a dashed line between mean baseline and mean stimulated IGF-I. Significant comparisons between groups for the IGF-I increment in response to GH are indicated as P values. To convert IGF-I values to nanomoles per liter, divide by 7.65.

 
Whereas stimulated IGF-I was similar in obese (505 ± 158 µg/liter) and tall (453 ± 180 µg/liter) children (P > 0.05), it was significantly higher in these two groups, compared with controls (341 ± 156 µg/liter; P < 0.05 for both comparisons) and short children (233 ± 128 µg/liter; P < 0.05 for both comparisons). The stimulated IGF-I values were also higher in controls, compared with short children (P < 0.05). Notably, stimulated IGF-I in the short children attained values that were comparable with those of the baseline IGF-I in the controls, thus indicating a clear difference in the regulation of the circulating IGF-I levels between these two groups (Fig. 1Go and Table 2Go). Stimulated IGF-I was correlated with baseline IGF-I (r = 0.92, P < 0.0001 for the whole cohort).

The IGF-I increment (stimulated minus baseline IGF-I) was significantly different between groups (P < 0.0001 by ANOVA) and was correlated with baseline IGF-I (r = 0.55, P < 0.0001). Adjustment for baseline IGF-I, age, and gender did not change the significance of the comparisons among groups: the IGF-I increment was 80% greater in obese children (187 ± 108 µg/liter) and 35% greater in tall children (140 ± 70 µg/liter), compared with controls (104 ± 64 µg/liter) (P < 0.05 for both comparisons) and tended to be greater in obese compared with tall children (P = 0.05). Conversely, there was no significant difference in the IGF-I increment between controls and short children (85 ± 63 µg/liter) (P = 0.73) (Fig. 1Go): despite a clear difference in baseline IGF-I (see above), responsiveness to GH was similar in the short and control children. Stimulated IGF-I showed the same significant differences among groups as the IGF-I increment after adjustment on baseline IGF-I, age, and gender.

When IGF-I data were expressed as SDSs, the significance of the between-group comparisons of baseline and stimulated IGF-I and the IGF-I increment remained the same (Table 2Go).

The IGF-I increment expressed as a percentage of baseline showed a 54 ± 37% increase over the baseline value, higher in obese than in control children (P < 0.05), whereas other comparisons were nonsignificant (Table 2Go).

IGFBP-3 and IGF-I to IGFBP-3 responsiveness to GH (Table 2Go)

The mean IGFBP-3 increment was 130 ± 436 µg/liter with no difference among groups, corresponding to a 5 ± 15% increase over the baseline value. The baseline and stimulated IGF-I to IGFBP-3 molar ratios showed the same differences among groups as the baseline and stimulated IGF-I.

Influence of body composition on the responsiveness to GH

To study the potential determinants of the responsiveness to GH, simple correlation analyses between the IGF-I increment and other variables were calculated. Given the heterogeneity of the groups of children, the correlation analyses were performed separately in each group (Table 3Go). Three variables were consistently associated with the responsiveness to GH in all groups: age (r = 0.57–0.72, P < 0.05), bone age (r = 0.51–0.72, P < 0.05), and the fat mass percentage (r = 0.51–0.58, P < 0.05), as measured by dual-energy x-ray absorptiometry in the obese and short children and estimated by the BMI SDS in the tall and control children, were positive statistical determinants of the responsiveness to GH.


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  		TABLE 3. Significant simple correlation analyses between the IGF-I increment in response to GH and the clinical parameters in each group of children

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study in prepubertal children demonstrated that the responsiveness to GH, as estimated by the IGF-I increment in response to GH, was increased in obese compared with tall children and in these children, compared with short children and controls, whereas it was similar in short children and controls. In addition, the fat mass percentage, either measured by DEXA or estimated by the BMI SDS, was a positive statistical determinant of the IGF-I increment in response to GH, showing that body composition was a significant predictor of the responsiveness to GH.

The pathophysiology of constitutional tall stature has always been controversial. Besides the putative genetic factors, relatively high levels of IGF-I and IGFBP-3 have been measured in such children, compared with normal children (4, 5, 6). Theoretically, these high levels could result from an increase in GH production, an increase in responsiveness to GH, and/or an increased production of IGF-I independent of GH. Physiological hypersecretion of GH has been shown in several cases of tall stature (28). However, Tauber et al. (4) demonstrated a clear heterogeneity of GH secretion in a large cohort of tall children, with some of them having high GH secretion rates and others having even low GH secretion. In agreement with these studies, we observed that baseline IGF-I level was significantly higher in tall children, compared with short and control children. Furthermore, we showed that the IGF-I increment in response to GH was significantly greater in tall compared with short and control children, which was suggestive of an increased responsiveness to GH. Lastly, based on the assumption that circulating IGF-I adequately reflects tissue IGF-I, this indicates that an increased GH sensitivity may partly contribute to the tall stature in these children.

Obesity is associated with a decreased spontaneous GH secretion and a blunted response of GH to stimulation tests (10, 11). Despite hyposecretion of GH, IGF-I levels, which somewhat reflect GH bioactivity, were reported as normal or high in obese children (11). In addition, increased GHBP levels were found in both obese adults and obese children (9, 12). Insofar as GHBP levels mirror cell surface GH receptor density, increased GHBP levels could reflect an increase in GH responsiveness in obese patients (9, 12). Using an IGF-I generation test, Gleeson et al. (9) indeed observed a larger increment of IGF-I in obese adults, compared with healthy normal or overweight controls. In agreement with these findings, we showed that the IGF-I response to GH was the highest in obese prepubertal children, in comparison with tall, short, and normal prepubertal children. We also consistently found that fat mass percentage and/or BMI SDS were positively related to the IGF-I increment in response to GH in tall, control, and short children separately. Similarly, positive correlations were described between serum IGF-I and BMI in treated GHD children (29). Overall, these results provide evidence that fat mass is associated with GH sensitivity, i.e. the ability to produce IGF-I in response to GH, and suggest a link between the energy stores and the anabolic action of GH. The increased linear growth in obese children could therefore be partly explained by this increase in GH sensitivity.

Whether circulating IGF-I plays an important role in growth is discussed. Animal studies have shown that it mostly arises from the liver (30) and is involved in the control of insulin sensitivity (31). Deletion of the liver IGF-I gene in mice did not alter growth, which could be mainly dependent on tissue IGF-I (30, 31). Alternatively, the normal free IGF-I levels in the circulation in these mice could have maintained somatic growth (30). In humans, IGF-I administration stimulates growth of subjects with GH insensitivity syndrome. Conversely, reports have shown marginal growth failure in cases of low circulating IGF-I associated with an acid-labile subunit gene mutation (32, 33). Circulating IGF-I could be at least a marker if not an actor of growth if it reflects tissue IGF-I: positive correlations between circulating IGF-I and growth velocity have been found in several studies (19, 20, 34, 35). Alternatively, the increase in circulating IGF-I after GH administration could have a prevailing metabolic rather than anabolic role (modulating insulin sensitivity rather than promoting growth), and this role might be especially important with regard to obese subjects.

ISS describes short children in whom the etiology of the short stature is undefined (14). Although the majority of patients with ISS do not have clear abnormality of the GH-IGF-I axis, they have usually been thought to have partial insensitivity to GH action insofar as they often have normal GH secretion contrasting with relatively low levels of IGF-I (2, 8, 13, 14, 36). Buckway et al. (13) reported that children with ISS had low-normal baseline IGF-I concentrations and GH-stimulated IGF-I concentrations in the lower range of the control baseline values. In agreement with these findings, we found that the mean baseline and stimulated IGF-I values were, respectively, 62 and 68% lower in short children, compared with controls, the stimulated IGF-I values in short children being comparable with the baseline IGF-I values in the controls. This indicates a clear difference in the regulation of the circulating IGF-I levels between these two groups. Despite this divergence, the mean IGF-I increment was only 18% lower in short children, compared with controls, which was not significantly different. Because none of these children had a GHD, the striking difference in circulating baseline IGF-I between short children and controls may arise from differences in GH-independent IGF-I production rather than from differences in GH sensitivity. Further studies will be needed to fully understand this point.

Age was positively related to the IGF-I increment in all groups of children, suggesting that GH responsiveness does increase with age. The hypothesis of a progressive increase in GH responsiveness with age in prepubertal children has been suggested from the observation of a decrease in GH and an increase in IGF-I from birth to prepuberty in normally growing children (37). A lower responsiveness to GH has also been shown in very young children with GHD, compared with older children (38), although the reason for this change in GH responsiveness is unknown.

The acute IGF-I generation test has previously been used to assess responsiveness to GH in short children during puberty, obese adults, menopausal women, and aging subjects (9, 17, 18, 19, 20): the potentially confounding influence of changes in endogenous GH secretion was eliminated by examining the IGF-I response to a supraphysiological dose of GH (17). In pharmacodynamic studies, serum GH concentrations in response to a parenteral dose have been found to peak 2–4 h after treatment and to rapidly disappear after 6 h (39). The median time to peak IGF-I has consistently been found to be 18–24 h in adults with GHD, obese adults, and postmenopausal women (9, 17, 39). We did not perform additional pharmacokinetic studies in our 88 prepubertal children and therefore could not rule out the possibility that some of the difference in GH responsiveness among groups was due to pharmacokinetic differences; however, we verified that the GH concentrations were comparable among groups 4 and 24 h after GH administration. The GH dose used in our study led to a mean 54% increase in serum IGF-I over the baseline value, which was clearly more than the intraassay variation. Conversely, the mean IGFBP-3 increase was 5 ± 15% over the baseline value, which was similar to the intraassay coefficient of variation (4.8%), thus showing that the IGFBP-3 response to a single administration of GH does not allow the estimation of GH responsiveness. The IGF-I to IGFBP-3 molar ratio has been suggested as a potential indicator of the amount of unbound and biologically active IGF-I (40). In this study, between-group comparisons of the baseline IGF-I to IGFBP-3 ratios, stimulated ratios and the ratio increments showed the same differences as the comparisons of baseline IGF-I, stimulated IGF-I, and the IGF-I increments. This suggests that the changes in total and free IGF-I after GH administration were similar.

We determined in a previous study of children with ISS that the reliability of this acute IGF-I generation test, as measured by the intraclass correlation coefficient, was 0.72, indicating fair reliability (20). This finding was similar to the test reliability determined in adults in similar conditions (41), thus indicating that the acute generation test as performed in this work provided an acceptable estimation of GH sensitivity.

Alternatively, we could have chosen stimulated IGF-I or the percent IGF-I increase over the baseline value instead of the absolute increment (expressed as micrograms per liter or SDS) to estimate GH responsiveness. However, only the absolute increment indicates the increase in the molecular amount of circulating IGF-I that may act on its receptor. Stimulated IGF-I was highly dependent on baseline IGF-I in this study: because baseline IGF-I differed between groups, the comparison of stimulated IGF-I between the children did not allow us to distinguish differences in GH responsiveness from differences in baseline IGF-I levels. Notably, after adjustment for baseline IGF-I, the significance of the differences among groups was the same for the IGF-I increment as for the stimulated IGF-I, indicating that they were equivalent markers of GH responsiveness. Similarly, the meaning of the percent IGF-I increase can be misinterpreted if it is presented independently of the denominator values (here baseline IGF-I) (42).

A limitation of our study could be the height of the children in our control group: although all the controls had a height over –2 SDS, the mean height was –1.2 SDS. This might indicate that they should not be considered as normally growing children. Nevertheless, their birth weight, birth length, height, and baseline and stimulated IGF-I levels were significantly higher than those of the short children, thus indicating a completely different growth pattern and IGF-I regulation. Mean baseline IGF-I was +0.0 ± 1.0 SDS in the controls, as expected from a control group, whereas it was –0.7 ± 1.1 SDS in the short children. The only other work that provides normative IGF-I generation data studied 38 normal children (including 12 subjects less than 10 yr), whose mean height was –1.1 SDS, a mean value very close to ours (13). As in the present study, the stimulated IGF-I levels of the short children in this work were in the range of the baseline values of the controls, suggesting that the IGF-I regulation of the control children in both studies was comparable. However, normative IGF-I generation data from children whose mean height is close to the mean for age and sex are still needed.

In conclusion, we showed that GH responsiveness in prepubertal children, as measured by the IGF-I increment in response to a single dose of GH, is increased in obese children, compared with tall children, and in these children, compared with short children and controls, whereas it is similar in short children and controls. GH responsiveness is dependent on the fat mass percentage, which suggests a link between the energy stores and the anabolic action of GH. Because circulating IGF-I may not be important to growth and does not necessarily reflect tissue IGF-I production, the circulating IGF-I response after GH administration could alternatively serve a prevailing metabolic rather than anabolic role. Further work will be needed to clarify this point.


   Footnotes
 
This work was supported by the Programe Hospitalier de Recherche Clinique 1998 (PHRC 1998, Ministère de la Santé).

Author Disclosure Summary: N.B.-N., F.G., F.B.d.C., S.R., and R.C. have nothing to declare.

First Published Online November 7, 2006

Abbreviations: BMI, Body mass index; GHBP, GH-binding protein; GHD, GH deficiency; IGFBP, IGF binding protein; IRMA, immunoradiometric assay; ISS, idiopathic short stature; SDS, SD score.

Received December 7, 2005.

Accepted October 30, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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E. S Schernhammer, S. S Tworoger, A H. Eliassen, S. A Missmer, J. M Holly, M. N Pollak, and S. E Hankinson
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