Relationship between body mass index, age, and serum adrenal androgen levels in Peruvian children living at high altitude and at sea level
Gonzales, Gustavo F
Key words: body mass index, adrenal androgens, high altitude, age
Data on the age pattern of body length and thus skeletal maturation is consistent with the idea that highlanders exhibit a delayed rate of maturation (Frisancho 1976); however, the only direct evidence for delayed maturation has been provided by comparisons of median age of menarche between highland and lowland females (Greksa 1990).
Another important marker of maturation is the assessment of age at adrenarche. Adrenarche is the period during childhood characterized by a significant increase in serum adrenal androgen levels (Cutler and Loviaux 1980; Lauritzen 1979), and it provides data on a new maturational marker that can be measured in both males and females.
We have demonstrated recently that children living at high altitude have delayed onset of adrenarche compared with children living at sea level (Gonez et al. 1993). In fact, a significant increase in serum levels of adrenal androgens was observed between 6 and 8 years of age at sea level and between 7 and 9 years of age at high altitude (Gonez et al. 1993).
Nothing is known about the factors associated with the delayed rate of maturation in highlanders. Nutrition is an important factor on the effect of age at menarche (Frisch 1980), and this component may affect populations living at high altitude (Picon-Reategui 1976). Fatter children tend to mature earlier than thinner children, and several studies have shown that highlander children tend to be leaner than lowlander children (Beall et al. 1977; Frisancho and Baker 1970; Hoff 1974).
Several researchers have suggested that critical levels of body fat are necessary to trigger gonadal maturation (Frisch et al. 1973; Frisch and McArthur 1974; Frisch 1980), particularly in females, but other researchers have discarded the hypothesis of critical adiposity for gonadal maturation (Ellison 1981, 1982).
Similarly, it has been suggested that body fat may be related to the rate of adrenal androgen production (Feher and Halmy 1975a, b), which would play a role in the onset of puberty (Boyar et al. 1973; Hopper and Yen 1975; Cohen et al. 1981). Katz et al. (1985) demonstrated that in boys serum levels of dehydroepiandrosterone sulfate (DHAS) are significantly associated with fatness, as measured by body mass index (BMI), suggesting that increased fatness prepubertally could lead to increased levels of adrenal androgens and precipitate earlier sexual maturation.
Fatness, measured as BMI (Cronk et al. 1982), and serum adrenal androgens levels (Sizonenko 1987) increase with chronological age in children. Thus any correlation between BMI and serum adrenal androgen levels may be due to an age effect.
Because the primary factors that affect adrenarche at low altitude are age and BMI, it would be interesting to determine how the relationship of adrenarche to both BMI and age differs between low and high altitudes. The rationale for this study is that adolescent maturation is delayed at high altitude. We wish to determine whether or not this delay has a nutritional basis related to energy consumption assessed by the measurement of BMI. The study also aims to determine whether BMI is related to the rate of adrenal androgen production in children from low and high altitude.
MATERIALS AND METHODS
Ninety-three boys and 76 girls native to and residing in Lima, Peru (150 m above sea level), age 7-12 years, and 54 boys and 59 girls residing in Cusco, Peru (3400 m above sea level), aged 7-12 years, attending public schools were studied using a cross-sectional design. All subjects were healthy at the time of the study and were not on any special diet or medication. Both groups were from the same low socioeconomic class. The social class was determined according to the category of the school (Gonzales 1985).
This study was based on the same sample of a previous study related to adrenarche at high altitude (Gonez et al. 1993). Adrenarche is defined as the age at which mean serum adrenal androgen levels increase significantly with respect to preceding age (Gonez et al. 1993).
All children studied were mestizos, but genetically they had Quechua predominance. The subjects were classified as mestizo, predominantly Quechua, according to face appearance. According to the surnames, 36% of highlanders and 28% of lowlanders had one or two Quechua surnames, without differences between altitudes. The parents of children from Lima are predominantly migrant people from the Andean region. Therefore the ethnic origin was similar in the samples from Lima and Cusco.
At the time of examination, subjects were measured for height and weight using standard anthropometric techniques (Gonzales et al. 1982), and they had a sample of venous blood drawn for hormonal analyses. Height and weight were measured by the same observer. Intra-examiner reliability, estimated by calculating correlation coefficients between repeated measurements for the anthropometric measurements, exceeded 0.95. Body fatness was estimated indirectly (Frisancho and Flegel 1982) by calculating Quetelet’s BMI (weight/height sup 2 ). However, when the BMI was assessed by correlating with height in samples from both sea level and high altitude, we observed a significant correlation between both variables in boys from Lima (r = 0.41), in girls from Lima (r = 0.32), and in girls from Cusco (r = 0.46). Therefore we calculated another equation for the BMI that would correlate with body weight but not with height. To such purpose, we correlated the weight/height sup n index (where n = 1.1 to 3) with height and weight. The selected index was weight/height sup 2.3 . This specific index was used because the exponent of height maximizes the correlation with weight and minimizes the correlation with height.
The serum adrenal androgens dehydroepiandrosterone (DHA), dehydroepiandrosterone sulfate (DHAS), and androstenedione were measured by solid phase radioimmunoassay using commercial kits (Diagnostic Products Co., Los Angeles, California). Each hormone was labeled with sup 125 I to be used as a radioactive marker.
Assays for androstenedione and DHA required an extraction step with ethyl ether (10:1, vol:vol). For the measurement of serum DHAS, no extraction procedure was required. Each antiserum was highly specific and had low cross-reactivity with other compounds.
The sensitivities of the assays were 0.057 mu-mol/L for DHAS, 0.104 nmol/L for DHA, and 0.07 nmol/L for androstenedione.
The intra-assay coefficient of variation was 7% for DHA, 4% for DHAS, and 5% for androstenedione.
The interassay precisions were 11.7%, 7.9%, and 5.6% for DHA, 4.8%, 7%, and 4.6% for DHAS, and 8.6%, 8.6%, and 9.2% for androstenedione in the upper, middle, and lower regions of the standard curve, respectively.
Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) software. The Bartlett-Box test was used to analyze homogeneity of variances. When the data were not homogeneous, they were normalized using z scores, in which each individual value is expressed in SD units from the sex-specific mean. The data in the tables are shown as untransformed values.
BMI (weight/height sup 2.3 ) for age was compared at sea level and at high altitude using a two-way analysis of variance. Differences between pairs of means were determined by a multiple range test.
Analyses of regression were done separately for males and females and for samples at sea level and at high altitude to correlate BMI with adrenal androgen levels, adrenal androgen levels with age, and BMI with age. Mean data related to changes of serum adrenal androgen levels with age have been published previously (Gonez et al. 1993).
To determine whether age or BMI is correlated with serum levels of adrenal androgens, we used a two-way multiple analysis of covariance (MANCOVA) in which all three androgens are simultaneously compared by sex and altitude while controlling for age and BMI.
A p value was considered statistically significant when it was less than 0.05.
RESULTS
Body Mass Index and Age at Sea Level and at High Altitude. BMI values in boys from Lima and in girls from Cusco increased significantly with age (7-12 years) (p
Body Mass Index, Age, and Serum Adrenal Androgen Levels. MANCOVA shows that all three serum adrenal androgen levels correlate significantly with the variables under study. The effects of the regression and altitude were statistically significant for all three adrenal androgens. A significant interaction of sex by altitude was observed for DHA and androstenedione. A significant effect by sex was observed only for androstenedione. A significant effect of the constant was observed for DHA and DHAS (Table 2). (Table 2 omitted) The multiple coefficient of correlation was 0.42 for DHA, 0.48 for DHAS, and 0.26 for androstenedione (p
MANCOVA also shows that serum adrenal androgen levels vary with age (p
DISCUSSION
Life at high altitude, characterized by chronic hypoxia, may reflect a situation of high energy needs. Growth and development are other situations in which the requirement for energy is high. To date, the only direct evidence for delayed maturation has been provided by later median age of menarche in highland females (Greksa 1990). Measurements of serum adrenal androgen levels may give useful information about the rate of maturation between lowlanders and highlanders because the androgen levels can be measured in both males and females.
We had previously demonstrated that age at adrenarche is delayed in boys and girls living at high altitude (Gonez et al. 1993). Other researchers have suggested that differences in levels of serum adrenal androgens may be due to differences in BMI (Katz et al. 1985). Here, we have studied how the relationship between serum adrenal androgen levels and BMI and age differs between low and high altitudes and whether delayed age of adrenarche may have a nutritional basis, as assessed by BMI.
The data for the present study do not support the hypothesis that delayed adrenarche at high altitude is due to low BMI. Our results do not demonstrate differences in BMI between children living at sea level and at high altitude, except at 12 years of age in boys and at 10 years of age in girls. In fact, BMI did not change between 7 and 9 years of age, the period of time at which adrenarche is occurring (Cutler and Loviaux 1980; Gonez et al. 1993), suggesting that differences in onset of adrenarche at high altitude may be due to factors other than nutritional status.
Our data also do not demonstrate an association between changes in serum adrenal androgen levels and BMI in children, age 7-12 years, as suggested by Katz et al. (1985). After controlling for age, the BMI of 10-21 kg/cm sup 2.3 did not correlate positively with any of the adrenal androgen levels studied. However, age correlated positively with serum adrenal androgen levels in all groups, suggesting that the effect of aging is a more important factor than BMI in determining actual values of serum adrenal androgen levels.
Our results are in disagreement with Katz et al.’s (1985) study, which emphasized the role of BMI on serum adrenal androgen levels in boys before the onset of puberty. In Katz’s study variable age was not considered in the analysis; thus Katz could not analyze the independent effect of each variable (age and BMI). In addition, Katz used the ratio weight/height sup 2 as the BMI, but in the present study we found that this value correlated with height, meaning that a BMI calculated as weight/height sup 2 is not a good marker of body fatness. A BMI calculated as weight/height sup 2.3 correlates with weight but not with height, and we used this ratio as a marker of BMI. Other studies have also demonstrated that weight/height sup 2 significantly correlates with height in children and is thus not valued as a marker of fatness in children (Abdel-Malek et al. 1985; Benn 1971).
The absence of a correlation between BMI and serum adrenal androgen levels has also been demonstrated in other studies under different conditions. For instance, in adults or adolescents with eumenorrheic obesity, plasma concentrations of androgens do not appear to be increased and may actually be decreased with respect to normal weight controls (Azziz 1989). Similarly, adrenal androgen production clearly decreases with age, beginning at about 20 years, despite the fact that obesity may increase, indicating that other factors may regulate the actual levels of serum adrenal androgens.
In summary, our study does not show a relationship between BMI and serum adrenal androgen levels in children at sea level and at high altitude when age is controlled for. Further studies are required to demonstrate the mechanisms controlling the association between adrenal androgen levels and onset of puberty.
GUSTAVO F. GONZALES,(1,2) ARTURO VILLENA,(1) CARMEN GONEZ,(1) AND MAURICIO ZEVALLOS(1)
(1) Instituto de Investigaciones de la Altura, PO Box 1843, Universidad Peruana Cayetano Heredia, Lima, Peru.
(2) Department of Physiological Sciences, Faculty of Sciences, Universidad Peruana Cayetano Heredia, Lima, Peru.
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Acknowledgments This study was supported in part by a Long Institutional Developmental Grant from the World Health Organization, Special Programme of Research, Development and Research Training in Human Reproduction, and by Consejo Nacional de Ciencias y Tecnologia (CONCYTEC), Lima, Peru.
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