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Age-Related Changes in Serum 17-Hydroxypregnenolone and 17-Hydroxypregnenolone Sulfate Concentrations in Human Infancy and Childhood

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Age-Related Changes in Serum 17-Hydroxypregnenolone and 17-Hydroxypregnenolone Sulfate Concentrations in Human Infancy and Childhood Endocrinol. Japon. 1988, 35 (2), 189-195 Age-Related Changes in Serum 17-Hydroxypregnenolone and 17-Hydroxypregnenolone Sulfate Concentrations in Human Infancy and Childhood KAZUHIKO SHIMOZAWA, SUMITAKA SAISHO, JUN-ICHI YATA AND AKIRA KAMBEGAWA* Department of Pediatrics, Faculty of Medicne, Tokyo Medical and Dental University, Tokyo 113, Japan Department of Obstetrics and Gynecology*, School of Medicine, Teikyo University, Tokyo 173, Japan Abstract In order to clarify some of the developmental processes of the human adrenal cortex or steroidogenesis in infancy and childhood, serum concentrations of 17-hydroxypregnenolone, 17-hydroxypregnenolone sulfate and 17-hydroxy- progesterone were measured by means of a combined radioimmunoassay method, and the age-related changes in these steroids were also examined. The actual ranges of serum concentrations of 17-hydroxypregnenolone, 17- hydroxypregnenolone sulfate and 17-hydroxyprogesterone in umbilical cord blood were 27.1-80.5, 1,560-5,030 and 53.3-304nmol/l, respectively. These values subsequently decreased to nadirs of 0.95-2.09nmol/l of 17-hydroxy- pregnenolone in subjects 1 to 2years old, 0.93-7.03nmool/l of 17-hydroxy- pregnenolone sulfate in subjects 3 to 6years old and 0.18-0.78nmol/l of 17- hydroxyprogesterone in subjects 1 to 2years old, respectively, and they were followed by gradual increases to the adult levels. This study thus revealed the age-related changes in 17-hydroxypregnenolone and its sulfate concentrations in infancy and childhood and indicated that, in the process in which the adrenal cortex was differentiated to the definitive form, the decrease in the activity of steroid sulfotransferase in infancy and childhood occurred more slowly than the increase in that of 3ƒÀ-hydroxy- steroid dehydrogenase. It is widely recognized that the activity Vihko, 1970; Laatikainen et al., 1973), while of 3 ƒÀ-hydroxysteroid dehydrogenase is lower that of steroid sulfotransferase is higher in (Bermudez et al., 1972; Huhtaniemi and the fetal adrenal cortex and peripheral tissues than in those of adults (Korte et al., Received April 15, 1987 1982; Seron-Ferre et al., 1978). Address reprint requests to Dr. KAZUHIKO To better understand the developmental SHIMOZAWA at the Department of Pediatrics, Faculty of Medicine, Tokyo Medical and Dental process of the adrenal cortex and steroid- University. 1-5-45 Yushima, Bunkyo-ku, Tokyo ogenesis in human infancy and childhood, 113, Japan. it would help to study the age-related Endocrinol. Japon. 190 SHIMOZAWA et al. April 1988 changes in serum concentrations of adrenal one were measured by a combined RIA method unconjugated ƒ¢5-steroids and their 3-sulfates. previously reported (Shimozawa et al., 1985). The method consisted of the following pro- Although there have been many reports on cedures: (1) diethyl ether extraction and chro- the serum pregnenolone, dehydroepiandro- matographic separation of unconjugated steroids sterone (DHA) and their 3-sulfate con- (17-OH-pregnenolone and 17-OH-progesterone), centrations and their age-related changes (2) enzymatic hydrolysis of 17-OH-pregnenolone (Mathur et al., 1980; Peretti et al., 1976; sulfate using the residue of diethyl ether extrac- Reiter et al., 1977), little is known about 17- tion for a material, (3) diethyl ether extraction hydroxypregn enolone (17-OH-pregnenolone) and chromatographic purification of hydrolyzed 17-OH-pregnenolone sufate and (4) RIAs for 17- and its 3-sulfate (17-OH-pregnenolone OH-pregnenolone to estimate 17-OH-pregneno- sulfate), which are known as the inter- lone and its sulfate hydrolyzed, and for 17- mediate steroids in adrenal and gonadal OH-progesterone. steroid production. Extracted 17-OH-pregnenolone was well sepa- In this paper, we examined the age- rated from 17-OH-progesterone by Sephadex related changes in serum concentrations of LH-20 microcolumn chromatography, using a 17-OH-pregnenolone and its sulfate as well benzene/methanol=95/5 (v/v) solvent as a mobile as 17-hydroxyprogesterone (17-OH-progester- phase. The most suitable method for hydrolysis one), by means of a combined radio- of 17-OH-pregnenolone sulfate was an enzymatic hydrolysis with arylsulfatase from Helix immunoassay (RIA) method for a simul- Pomatia (obtained from Boehringer-Mannheim taneous determination of these steroids which BmbH, West Germany) in an appropriate we devised (Shimozawa et al., 1985). condition in which the percent hydrolysis was 92.9±2.7(mean±SD)%.Final recovery values Materials and Methods were 90.7±3.1% for 17-OH-pregnenolone,78.1 ±4.7% for 17-OH-pregnenolone sulfate and 88.7 Subjects ±2.7% for 17-OH-progesterone,respectively. We examined 11 umbilical cord blood 0.25ml of 1:12,000 diluted anti-17-OH-preg- specimens and sera from 82 children of various nenolone-3-succinate-BSA serum (obtained from ages and 20 adults with no endocrinological Teikoku Hormone Mfg, Kawasaki, Japan) was abnormalities. The 82 children were divided optimal for the reaction and 5,000 dpm of into the following groups: (1) 44 neonates and [7-3H(N)] 17-OH-pregnenolone (obtained from infants aged from 23days to 2months (23 boys Amersham International plc., Buckinghamshire, and 21 girls), (2) three infants aged from 3 to 4 England) was most suitable as a tracer for RIA months (two boys and one girl), (3) three in- of both 17-OH-pregnenolone and its sulfate fants aged from 5 to 11 months (one boy and hydrolyzed also. For RIA of 17-OH-progester- two girls), (4) three children aged from 1 to 2 one, 0.25ml of 1:32,000 diluted anti-17-OH- years (two boys and one girl), (5) seven progesterone-3-carboxymethyloxime-BSA serum children aged from 3 to 6years (three boys and (obtained from Teikoku Hormone Mfg.) and four girls), (6) eight school children aged from 10,000 dpm of [1, 2-3H(N)] 17-OH-progesterone 7 to 9years (four boys and four girls), (7) seven (obtained from New England Nuclear, Boston, preadolescents aged from 10 to 12years (five USA) were used. The specificities of both boys and two girls) and (8) seven adolescents antisera were discussed in previous papers (Saito, aged from 13 to 15years (two boys and five 1980; Shimozawa et al., 1985). In both RIAs, girls). The adults ranged from 21 to 32years we used a saturated ammonium sulfate solution old and included ten men and ten women, and for separation the bound from free steroid. The of the latter seven were in the follicular and intra- and interassay coefficients of variation three were in the luteal phase. for this method were 17.3•}2.1 (mean•}SD) % and 17.5•}2.5% for 17-OH-pregnenolone, 13.3•} Measurements 2.9% and 18.7±4.7% for its sulfate,and 12.2± Serum concentrations of 17-OH-pregnenolone, 2.1% and 15.0±2.4% for 17-OH-progesterone, 17-OH-pregnenolone sulfate and 17-OH-progester- respectively. Vol.35, No.2 SERUM 17-OH-PREGNENOLONE AND ITS SULFATE 191 Since the distribution of the data was and 17-OH-progesterone in the subjects of markedly skewed and their common logarithmic different ages are shown in Tables 1 and 2, values showed normal distribution, data are and the 95% toleran ce limits of 17-OH- expressed and statistically analyzed after common pregnenolone and its sulfate are shown in logarithmic transformation. Data are expressed Fig. 1. as the mean•}SD, and the median values, the actual ranges and their 95% tolerance limits are In umbilical cord blood, the serum con- also described. Statistical analysis was carried centrations of 17-OH-pregnenolone, 17-OH- out with Student's unpaired t-test. pregnenolone sulfate and 17-OH-progesterone were all significantly higher (P<0.001) than those in infancy, childhood and adulthood. Results These values all subsequently decreased to nadirs of 17-OH-pregnenolone in children 1 The serum concentrations of 17-OH- to 2years old, 17-OH-pregnenolone sulfate pregnenolone, 17-OH-pregnenolone sulfate in children 3 to 6yeras old and 17-OH- Table 1. Serum concentrations of 17-OH-pregnenolone, 17-OH-pregnenolone sulfate and 17-OH-progesterone in normal human umbilical cords, infants and children The median value, actual range and the 95% tolerance limit: nmol/l Endocrinol. Japon. 192 SHIMOZAWA et al. April 1988 Table 2. Serum concentrations of 17-OH-pregnenolone, 17-OH-pregnenolone sulfate and 17-OH-progesterone in normal adults The median value, actual range and the 95% tolerance limit: nmol/1 LP: luteal phase, FP: follicular phase 17-OH-pregnenolone 17-OH-pregnenolone sulphate Fig. 1. The 95% tolerance limits of serum concentra- tions of 17-OH- pregnenolone and 17-OH-pregneno- lone sulfate in nor- mal control sub- jects. UB: umbili- cal cord blood, A: adult, M: male, F: female. progesterone in children 1 to 2years old, including pregnenolone, 17-OH-pregnenolone and they were followed by gradual increases and DHA, which are mainly secreted as up to the adult levels. their sulfate conjugates. Although the role of the high activity of sulfotransferase in the fetal adrenal cortex has not been Discussion revealed, a possible explanation is that the fetal adrenal cells are protected by this In fetal adrenal steroidogenesis, the phenomenon from the accumulation of free major products are 3ƒÀ-ƒ¢5-hydroxysteroids, or unconjugated steroids which are much Vol.35, No.2 SERUM 17-OH-PREGNENOLONE AND ITS SULFATE 193 more potent inhibitors of 3ƒÀ-hydroxysteroid maternal plasma. However, there have been dehydrogenase than their sulfate conjugates no reports on the age-related changes in (Winter 1985). Besides this, to account for serum 17-OH-pregnenolone sulfate concen- the increased adrenal androgen secretion in tration in man. In this study, therefore, adrenarche, various changes in adrenal in order to obtain more detailed information enzyme activity from childhood to adult- on the maturation of the adrenal cortex, hood have been demonstrated.
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