help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Suarez, F.
Right arrow Articles by Garabédian, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Suarez, F.
Right arrow Articles by Garabédian, M.
Right arrowPubmed/NCBI databases
Medline Plus Health Information
*Child Development
*Infant and Toddler Development
The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 10 3563-3568
Copyright © 1998 by The Endocrine Society

Original Studies

Interactive Effect of Estradiol and Vitamin D Receptor Gene Polymorphisms as a Possible Determinant of Growth in Male and Female Infants

Françoise Suarez, Claude Rossignol and Michèle Garabédian

Centre National de la Recherche Scientifique, URA 583-UPR 1524, Hôpital Saint Vincent de Paul (F.S., M.G.), 75014 Paris; and Centre des Bilans de Santé de l’Enfant, CPAM de Paris (C.R.), 75011 Paris, France

Address all correspondence and requests for reprints to: Dr. M. Garabédian, CNRS URA 583, Hôpital Saint Vincent de Paul, 82 avenue Denfert Rochereau, 75014 Paris, France.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
An association between vitamin D receptor (VDR) gene polymorphism and body size has been observed in infants. We hypothesized that the estradiol receptor (ER) gene is another determinant of infant growth and that the effects of the VDR and ER genotypes may interact with each other. The ER genotype (PvuII and XbaI sites), VDR genotype (BsmI site), and body size during the first 2 yr of life were analyzed in 161 healthy Caucasian full-term babies homozygous for the BsmI polymorphism of the VDR gene (BB or bb). There was no significant association between ER polymorphism and 1) body weight in boys and girls, 2) body length in girls, or 3) body length in boys with a bb genotype. In contrast, ER polymorphism and body length were significantly associated in BB boys. Boys with the BBpp genotype were shorter at birth (P < 0.005) and at 10 months of age (P < 0.001) than boys with other genotypes. They were even shorter than girls with the same genotype. These results indicate some degree of interaction between the effects of the VDR and ER genes, leading to significant variations in body growth during infancy, especially in boys.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GROWTH is a complex process that is regulated by multiple genetic and environmental factors interacting via pathways that have not yet been fully elucidated. Infancy is a particularly important period during which to analyze this regulation, as it is the time when growth is fastest. It is also easier to study growth regulation at this age because interfering events, such as epiphyseal closure during adolescence, do not have to be taken into account. Finally, in view of a recent report showing an association between weight at 1 yr of age and the bone mineral content during the seventh decade of life (1), studies on growth in infancy may help to identify some of the regulatory pathways leading to final body size and also to bone mass in adults.

After the demonstration by Morrison et al. (2, 3) of a vitamin D receptor (VDR) gene polymorphism and its likely consequences for bone metabolism, several studies have analyzed the restriction fragment length polymorphism (RFLP) of the VDR gene. Most of them have focused on a possible association between allelic variations in the VDR locus and bone mass in adults. The results have been negative or have shown a weak association, suggesting that the VDR gene is one of the many genetic determinants of bone mass (4, 5). More recent studies suggest that the VDR gene influences bone density even before puberty (6), but this influence may be undetectable, as reported in a Norwegian study on prepubertal and pubertal girls and boys (7).

Given the possible relationship between bone mass and early body growth (1), part of the effect of the VDR gene on bone mass could be linked to its influence on prenatal and early infant growth. We (8) and others (9) have recently proposed that the VDR gene is a genetic contributor to intrauterine and early postnatal growth, at least up to the second year of life. Of interest, we showed that the association between the VDR genotype and body size differed in girls and boys (8). In other studies, this association occurred only in girls (10) or was not found when infants had not been separated according to gender (11). This suggests that the VDR genotype influences early growth via interactions with gender-related growth regulators.

Estradiol is a well known regulator of growth and skeletal maturation in girls, and clinical reports have disclosed its role in male subjects as well (12, 13, 14). The estradiol receptor (ER) gene is itself a likely determinant of growth during puberty, as suggested by the associations found between allelic variations of the ER gene and the height of adult women (15, 16, 17, 18) or the gain in weight during puberty of adolescent girls (19).

For these reasons, we hypothesized that the ER gene is, like the VDR gene, a determinant of infant growth and that the effects of the VDR and ER genotypes may interact with each other. To test this hypothesis, we investigated possible associations among the ER genotype (PvuII and XbaI sites), the VDR genotype (BsmI site), and body growth during the first 2 yr of life, in a cohort of 161 healthy Caucasian full-term babies who were homogeneous for age, diet, and vitamin D status and who were homozygous for the BsmI polymorphism of the VDR gene.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The estradiol and VDR gene polymorphisms were analyzed in the blood samples of 161 healthy infants seen at the Centre des Bilans de Santé de l’Enfant, CPAM (Paris, France), for a systematic physical and biological examination at 10 months and 2 yr of age. These infants had been selected from a total cohort of 589 babies, previously analyzed for their VDR genotype (8). In this population, BB alleles were found in 14% of the infants, bb alleles were found in 39%, and Bb alleles were found in 47%. This distribution of the VDR genotype was similar to that reported for other Caucasian populations (4). The 161 infants had been selected from the total population on the basis of the following criteria: 1) available data on body size at birth, 2) available data on crown-heel length and weight measured in the CPAM check-up center at 10 months and/or 2 yr of age, 3) full-term birth (only babies born after 37.5 weeks of pregnancy were considered to eliminate possible interferences due to the catch-up growth of premature babies), and 4) homozygosity for the BsmI polymorphism of the VDR gene.

The selected infants included 73 girls and 88 boys. As a consequence of the selection criteria, data on body size at birth, 10 months, and 2 yr were available for 125 infants. These data were available at birth and either at 10 months or 2 yr of age for the remaining 36 infants. Almost half (42%) of the infants had all 4 grandparents originating in France. The others were of mixed European or North African origin. No information on geographical origin and past history and no blood samples others than those specifically collected for the check-up were used in this study.

Blood samples were obtained from capillary blood collected in the morning during the routine check-up. Genomic DNA was extracted from whole blood using a commercial kit and was analyzed for polymorphism of the VDR and ER genes after amplification by PCR.

Primers designed to amplify the intragenic polymorphic BsmI site of the VDR gene were the following: forward, 5'-CAACCAAGACTACAAGTACCGCGTCAGTGA-3'; and reverse, 5'-AACCAGCGGGAAGAGGTCAAGGG-3' (3). Amplification conditions, using a Perkin-Elmer (Norwalk, CT) DNA thermal cycler 480, were as follows: 94 C for 5 min followed by 35 cycles at 94 C for 60 s, 56 C for 60 s, and 72 C for 90 s and a terminal extension at 72 C for 10 min. After amplification, the PCR product (0.825 kb) was digested with restriction endonuclease BsmI and electrophoresed in a 1.2% agarose gel.

Primers designed to amplify intragenic polymorphic PvuII and XbaI sites of the ER gene were the following: forward, 5'-CTGCCACCCTATCTGTATCTTTTCCTATTCTCC-3'; and reverse, 5'-TCTTTCT-CTGCCACCCTGGCGTCGATTATCTGA-3' (20). Amplification conditions were as follows: 94 C for 5 min followed by 35 cycles at 94 C for 60 s, 61 C for 60 s, and 72 C for 90 s and a terminal extension at 72 C for 10 min. After amplification, the PCR product (1.3 kb) was digested with restriction endonucleases PvuII and XbaI and electrophoresed in a 1.2% agarose gel.

The RFLPs were coded as Bb (BsmI), Pp (PvuII), and Xx (XbaI), where the uppercase letter signifies the absence of the site, and the lowercase letter signifies its presence.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The selected infants were homozygous for the VDR genotype; 124 had a bb genotype (BsmI site present), and 37 had a BB genotype (BsmI site absent). Two areas of the ER gene were analyzed, the PvuII and XbaI sites. The allele frequencies at the PvuII and XbaI polymorphism sites were similar to those reported for other Caucasian populations (20, 21) in both the bb and BB subpopulations (Table 1Go). PvuII and XbaI alleles were closely linked (81%), and there were 6 RFLP genotypes with a frequency greater than 1%: PpXx (42%), ppxx (29%), Ppxx (10%), PPXX (9%), PPXx (7%), and PPxx (3%).


View this table:
[in this window]
[in a new window]
  		Table 1. ER genotype in 161 infants: PvuII and XbaI allele frequencies (percentages)

 
Interactions between the effects of ER and VDR polymorphisms on body size were analyzed using the PvuII RFLP to allow comparison with the published studies on ER in older subjects (15, 16, 17, 18, 19). Six subgroups were identified. Homozygous groups were mainly bbpp (22% of the total cohort), bbPP (15%), and BBpp (7%). Only five girls and one boy had a BBPP genotype (4% of the total cohort).

Associations between anthropometric data and genotypes were analyzed at birth, 10.1 ± 0.6 months of age, and/or 22.9 ± 1.0 months of age (mean ± 1 SD). As reported previously (8), BB boys were significantly smaller (P = 0.03) and lighter (P = 0.03) than bb boys at 10 months of age (Tables 2Go and 3Go).


View this table:
[in this window]
[in a new window]
  		Table 2. Sex differences in body length according to VDR and ER genotype (mean ± 1 SD)

 

View this table:
[in this window]
[in a new window]
  		Table 3. Sex differences in body weight according to VDR and ER genotype (mean ± 1 SD)

 
There was no association between ER polymorphism and weight in any of the male groups at any age tested (Table 3Go) or between ER polymorphism and length in the bb group of boys (Fig. 1Go). In contrast, there was a significant association between ER polymorphism and body length in the BB boys (Fig. 1Go). Boys with the BBpp genotype were shorter at birth (P < 0.005) and at 10 months of age (P < 0.001) than boys with other genotypes (BBPp or any of the bb genotypes). The mean crown to heel length of these BBpp boys was 1 SD less the mean length of French reference male populations at birth (50 ± 1.5 cm) (22) and at 10 months of age (72 ± 2 cm) (22, 23). The mean lengths of the BBpp boys was also below the 25th percentile value at birth (49 cm) and was close to the 10th percentile value at 10 months of age (70.6 cm) with respect to the reference curves for Caucasian children living in the United States (24). The mean body lengths of the other genotypic groups were slightly above the French reference values and were between the 50th and 75th percentile values of the American reference curves. The smaller size of the BBpp boys was not related to a slower growth rate between birth and 10 months of age (Table 4Go) and was no longer observed at 2 yr of age (Fig. 1Go).



View larger version (48K):
[in this window]
[in a new window]
  		Figure 1. Crown to heel length in relation to VDR and ER genotypes. Length was measured at birth, 10 months of age, and/or 2 yr of age in 87 male (upper part) and 73 female (lower part) full-term babies homozygous for the VDR genotype at the BsmI site (BB and bb). Values are the mean ± 1 SE of body length in the five subgroups of infants identified on the basis of their VDR (BsmI site) and ER (PvuII site) genotypes. The number of infants in each subgroup is shown in the bars. *, P = 0.0049 (by Mann-Whitney U test); P = 0.031 (by Kruskal-Wallis test) compared with the other subgroups of infants of the same age and sex. **, P = 0.0006 (by Mann-Whitney U test); P = 0.025 (by Kruskal-Wallis test) compared with the other subgroups of infants of the same age and sex.

 

View this table:
[in this window]
[in a new window]
  		Table 4. Sex differences in body length gain according to VDR and ER genotype (mean ± 1 SD)

 
Body size parameters were not significantly associated with genotype in girls, but, unlike boys, girls with the BBpp genotype tended to be longer and heavier than girls with the other genotypes at birth and 10 months of age, rather than shorter and lighter (Tables 2Go and 3Go and Fig. 1Go). Because of the different associations between body size and genotype in boys and girls, gender-related differences in length and weight were observed in only some of the genotypic subgroups. As expected, boys at birth, 10 months, and 2 yr were significantly taller (Table 2Go) and heavier (Table 3Go) than girls in the three groups with a bb genotype, but the boys and girls in the overall BB group had similar body lengths and weights at all ages tested, whereas the boys in the BBpp group were even shorter than the girls at birth (P = 0.007) and 10 months of age (P = 0.04).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
A number of clinical and experimental studies have pointed out the crucial influence of estradiol on skeletal growth and maturation in both women and men. The present finding of a relationship between body size in infancy and polymorphism of both the ER (PvuII) and VDR (BsmI) genes suggests that these genes interact to influence the regulation of prenatal and infantile growth, especially in boys.

This study first confirms the previously reported association between the BsmI polymorphism of the VDR gene and body size during infancy (8, 9). A cluster of linked polymorphisms has been reported in the 3'-end of the VDR gene, including the BsmI polymorphism in the intron separating exons VIII and IX (3). This latter polymorphism does not influence the amino acid sequence of the VDR protein, but it may be linked to other genetic variations affecting crucial steps of the synthesis or regulation of this protein. For example, BsmI has been linked in some populations to poly(A) microsatellite repeats in the 3'-untranslated region, a genetic variation that may influence trans-activation activity and messenger ribonucleic acid stability (25).

The results of this study also provides support for the hypothesis that ER genotype is another determinant of intrauterine and early postnatal growth, as suggested by the association between the PvuII polymorphism of the ER gene and the crown to heel length of BB boys at birth and 10 months of age. The size of the variations linked to ER/VDR polymorphism was about 1 SD on the reference growth curve for French children (22). Two ER types have been reported, ER-{alpha} and ER-ß. The analyzed PvuII polymorphism appears to be specific for ER-{alpha}, as at least one of the primer sequences chosen for PCR amplification is not present in the ER-ß gene. Similar to those of the VDR gene polymorphism, the functional consequences of the studied ER gene polymorphism are not clear. Although this PvuII RFLP has been associated with breast cancer (21) and variations in the final body size of healthy individuals (15, 16, 17, 18, 19), it reflects a T/C point variation in the intron I of the ER gene and therefore has no influence on the amino acid sequence of the ER protein (26).

Estrogens appear to influence not only pubertal but also prepubertal growth, even when circulating levels of estrogen are low (27, 28). Low doses of ethinyl estradiol increase growth velocity in prepubertal girls (29) as well as boys (30), and there appears to be a significant positive association between the neonatal serum concentration of estradiol and the height of boys and girls aged approximately 4 yr (31). In view of the present results, estradiol may also influence statural growth during prenatal and early postnatal life, when growth is fastest. An association between the ER/VDR polymorphism and the crown to heel length was found in boys at birth and at 10 months of age, but it was no longer found at 2 yr and did not result from variations in growth velocity during the first year of life. The hypothesis of an early effect of estradiol on statural growth fits well with the very high blood levels of estradiol found at birth, because of placental production throughout pregnancy (32), and with the postnatal estradiol levels that remain slightly above prepubertal levels during the first 2 months of life in both girls and boys (33). There is also a marked surge in testosterone production in boys between birth and the first 2–3 months of life (33). This testosterone may be a local source of estradiol due to aromatization in its target tissues. Also consistent with estradiol being an early regulator of skeletal growth, estradiol receptors have been found in both female and male human fetal cartilage (34). However, it is not yet possible to say whether the association between the ER gene polymorphism and body size in male infants results from an action of estrogen on growth plate cartilage and/or on the pituitary or even hypothalamic cells, as endogenous estrogen appears to facilitate the neuroendocrine control of the somatotropic axis in adolescent males (35).

Of interest, unlike in boys, associations between body size and ER/VDR polymorphism were not significant in girls. This sex difference may be artifactual and related to the small size of the studied populations, but it could also reflect the marked differences in the circulating levels of sex steroids, especially of testosterone, at this age (33); gender-related differences in the sensitivity of cartilage cells to estradiol despite similar receptor levels in males and females (34, 36); or gender-related differences in other regulatory or structural genes that influence growth (37).

Finally, the effect of ER gene polymorphism was seen in the infants with a BB genotype at the VDR gene locus, but not in those with a bb genotype. Thus, there appears to be a gene-gene interaction on infant growth for polymorphism of both the ER and VDR genes. Similarly, other interactions between the VDR and ER genes have been reported to influence bone mineral density in pre- and postmenopausal women (38, 39) and weight gain in adolescent girls (19). The mechanism and site(s) of these interactions remain unknown, but different hypotheses can be proposed. In the numerous cell types that express both ER and VDR, these receptors may interact on gene transcription via a heterodimerization similar to that described between VDR and other receptors of the same family, mainly retinoid X receptor (40). VDR and ER may also interact via effects of each on the expression of the other. Estrogens modulate the expression of the VDR gene, as reported in bone cells (41) and breast cancer cells (42). Inversely, 1,25-dihydroxyvitamin D3 modulates ER expression, as reported in bone marrow-derived cells (43). Thus, VDR and ER polymorphisms may interact to modulate the activities of osteoblasts, chondrocytes, and possibly other cells producing hormones and factors involved in the regulation of statural growth. Another and potentially crucial possibility of interaction between estrogens and vitamin D during growth derives from the direct effect of the vitamin D-VDR complex on messenger ARN expression and enzymatic activity of the aromatase cyctochrome P450 in bone cells (44). As this enzyme converts androgens to estrogens in placenta, gonads, brain, adipose tissue, and bone cells, VDR polymorphism may influence the effect of ER polymorphism on growth via direct modulation of the cell responses to estrogens and by stimulating the local production of estrogens during fetal and early postnatal life.

Our results, therefore, indicate some degree of interaction between the effects of the vitamin D and estradiol receptor genes leading to significant variations in body growth during infancy, especially in boys. Most association studies to date on the genetic effects of the ER and VDR genes have focused on the body size and bone mineral content of women. Further studies will show whether the early genetic effect found in boys influences final body size and/or bone mineral content.


   Acknowledgments
 
The authors thank all of the biologists at the Centre des Bilans de Santé de l’Enfant for their help and friendly interest, and Dr. Owen Parkes for his help with the English text edition.

Received March 9, 1998.

Revised July 2, 1998.

Accepted July 13, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Cooper C, Fall C, Egger P, Hobbs R, Eastell R, Barker D. 1997 Growth in infancy and bone mass in later life. Ann Rheum Dis. 56:17–21.[Abstract/Free Full Text]
  2. Morrison NA, Yeoman R, Kelly PJ, Eisman JA. 1992 Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphisms and circulating osteocalcin. Proc Natl Acad Sci USA. 89:6665–6669.[Abstract/Free Full Text]
  3. Morrison NA, Qi JC, Tokita A, et al. 1994 Prediction of bone density from vitamin D receptor alleles. Nature. 367:284–287.[CrossRef][Medline]
  4. Cooper GS, Umbach DM. 1996 Are vitamin D receptor polymorphisms associated with bone mineral density? A meta-analysis. J Bone Miner Res. 11:1841–1849.[Medline]
  5. Riggs BL. 1997 Vitamin D-receptor genotypes and bone density. N Engl J Med. 337:125–126.[Free Full Text]
  6. Sainz J, Tornout JV, Loro L, Sayre J, Roe TF, Gilsanz V. 1997 Vitamin D-receptor gene polymorphisms and bone density in prepubertal American girls of Mexican descent. N Engl J Med. 337:77–82.[Abstract/Free Full Text]
  7. Gunnes M, Berg JP, Halse J, Lehmann EG. 1997 Lack of relationship between vitamin D receptor genotype and forearm bone gain in healthy children, adolescents, and young adults. J Clin Endocrinol Metab. 82:851–855.[Abstract/Free Full Text]
  8. Suarez F, Zeghoud F, Rossignol C, Walrant O, Garabédian M. 1997 Association between vitamin D receptor gene polymorphism and sex-dependent growth during the first two years of life. J Clin Endocrinol Metab. 82:2966–2970.[Abstract/Free Full Text]
  9. Keen RW, Egger P, Fall C, et al. 1997 Polymorphisms of the vitamin D receptor, infant growth, and adult bone mass. Calcif Tissue Int. 60:233–235.[CrossRef][Medline]
  10. Keen RW, Egger P, Major PJ, Spector TD, Cooper C. 1995 Polymorphisms of the vitamin D receptor, infant growth and adult bone mass [Abstract P241]. J Bone Miner Res. 11(Suppl 1):S189.
  11. Specker BL, Williams LA, Kalkwarf H, et al. 1995 Vitamin D receptor genotype and its relation to bone growth and bone mineralization in infants 3 to 12 months of age [Abstract P238]. J Bone Miner Res. 11(Suppl 1):S188.
  12. Smith EP, Boyd J, Frank GR, et al. 1994 Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med. 331:1056–1061.[Abstract/Free Full Text]
  13. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K. 1995 Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab. 80:3689–3698.[Abstract]
  14. Carani C, Qin K, Simoni M, et al. 1997 Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med. 337:91–95.[Free Full Text]
  15. Lehrer S, Rabin J, Stone J, Berkowitz GS. 1994 Association of an estrogen receptor variant with increased height in women. Horm Metab Res. 26:486–488.[Medline]
  16. Keen RW, Woodford-Richens KL, Lanchbury JS, Spector TD. 1996 Polymorphism at the oestrogen receptor gene and its association with menopausal bone loss and skeletal size [Abstract T530]. J Bone Miner Res. 11(Suppl 1):S432.
  17. Tokita A, Miura Y, Tawa T, et al. 1996 Estrogen receptor gene RFLP and peak bone density in Japanese [Abstract T534]. J Bone Miner Res. 11(Suppl 1):S433.
  18. Tawa T, Tokita A, Unno A, et al. 1996 Estrogen receptor genotype and body constitution and bone density in sport students [Abstract T535]. J Bone Miner Res. 11(Suppl 1):S433.
  19. Klisovic D, Ilich JZ, Skugor M, Young AP, Matkovic V. 1996 Different distribution of growth related gain in weight, lean body mass, and bone area according to vitamin D-receptor gene (VDR) polymorphism within distinct estrogen receptor (ER) genotype [Abstract S487]. J Bone Miner Res. 11(Suppl 1):S211.
  20. Kobayashi S, Inoue S, Hosoi T, Ouchi Y, Shiraki M, Orimo H. 1996 Association of bone mineral density with polymorphism of the estradiol receptor gene. J Bone Miner Res. 11:306–311.[Medline]
  21. Hill SM, Fuqua SAW, Chamness GC, Greene GL, McGuire WL. 1989 Estrogen receptor expression in human breast cancer associated with an estrogen receptor gene restriction fragment length polymorphism. Cancer Res. 49:145–148.[Abstract/Free Full Text]
  22. Sempé M, Pedron G, Roy-Pernot MP. 1979 Auxologie, méthodes et séquences. Paris: Théraplix.
  23. Deheeger M, Rolland-Cachera MF, Pequignot F, Labadie MD, Rossignol C. 1990 Etude longitudinale de l’alimentation des enfants âgés de 10 mois, 2 ans et 4 ans. Longitudinal study of the feeding of 10 months:2 and 4 years old children. Arch Fr Pediatr. 47:531–537.[Medline]
  24. Hamil PVV. National Center for Health Statistics. NCHS growth charts 1976. Monthly Vital Stat Rep. 25:3.
  25. Ingles SA, Haile RW, Henderson BE, et al. 1997 Strength of linkage disequilibrium between two vitamin D receptor markers in five ethnic groups: implications for association studies. Cancer Epidemiol Biomarkers Prev. 6:93–98.[Abstract]
  26. Yaich L, Dupont WD, Cavener DR, Parl FF. 1992 Analysis of the PvuII restriction fragment-length polymorphism and exon structure of the estrogen receptor gene in breast cancer and peripheral blood. Cancer Res. 52:77–83.[Abstract/Free Full Text]
  27. Klein KO, Baron J, Colli MJ, McDonnell DP, Cutler Jr GB. 1994 Estrogen levels in childhood determined by an ultrasensitive recombinant cell bioassay. J Clin Invest. 94:2475–2480.
  28. Klein KO, Martha Jr PM, Blizzard RM, Herbst T, Rogol AD. 1996 A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. II. Estrogen levels as determined by an ultrasensitive bioassay. J Clin Endocrinol Metab. 81:3203–3207.[Abstract]
  29. Martinez A, Heinrich JJ, Domene H, et al. 1987 Growth in Turner’s syndrome: long term treatment with low dose ethinyl estradiol. J Clin Endocrinol Metab. 65:253–257.[Abstract/Free Full Text]
  30. Caruso-Nicoletti M, Cassorla F, Skerda M, et al. 1985 Short-term, low-dose estradiol accelerates ulnar growth in boys. J Clin Endocrinol Metab. 61:896–898.[Abstract/Free Full Text]
  31. Jacklin CN, McBride C, McCrory P, Gallahan L. 1994 Neonatal sex-steroid hormones and physical size at four years. J Pediatr Endocrinol. 7:253–259.[Medline]
  32. Shutt DA, Smith ID, Shearman RP. 1974 Oestrone, oestradiol-17ß and oestriol levels in human foetal plasma during gestation and at term. J Endocrinol. 60:333–341.[Abstract/Free Full Text]
  33. Forest MG, Ducharme JR. 1993 Gonadotropic and gonadal hormones. In: Bertrand J, Rappaport R, Sizonenko PC. eds. Pediatric endocrinology. Physiology, pathophysiology, and clinical aspects. Baltimore: Williams and Wilkins; 100–120.
  34. Ben-Hur H, Thole HH, Mashiah A, et al. 1997 Estrogen, progesterone and testosterone receptors in human fetal cartilaginous tissue: immunohistochemical studies. Calcif Tissue Int. 60:520–526.[CrossRef][Medline]
  35. Metzger DL, Kerrigan JR. 1994 Estrogen receptor blockade with tamoxifen diminishes growth hormone secretion in boys: evidence for a stimulatory role of endogenous estrogens during male adolescence. J Clin Endocrinol Metab. 79:513–518.[Abstract]
  36. Nasatzky E, Schwartz Z, Boyan BD, Soskolne WA, Ornoy A. 1993 Sex-dependent effects of 17-beta estradiol on chondrocyte differentiation in culture. J Cell Physiol. 154:359–367.[CrossRef][Medline]
  37. Loesch DZ, Hopper JL, Rogucka E, Huggins RM. 1995 Timing and genetic rapport between growth in skeletal maturity and height around puberty: similarities and differences between girls and boys. Am J Hum Genet. 56:753–759.[Medline]
  38. Sowers MF, Aron D, Burns T, Clark K, Willing M. 1997 Bone mineral density and its change in white women: estrogen and vitamin D receptor genotypes and their interaction [Abstract P295]. J Bone Miner Res. 12(Suppl 1):S175.
  39. Gennari L, Beccherini L, Masi L, et al. 1997 Vitamin D and estrogen receptor allelic variants in postmenopausal women: evidence of an additive effect on bone mineral density [Abstract F581]. J Bone Miner Res. 12(Suppl 1):S371.
  40. Haussler MR, Whitfield GK, Haussler CA, et al. 1998 The nuclear vitamin D receptor: biological and molecular regulatory properties revealed. J Bone Miner Res. 13:325–349.[CrossRef][Medline]
  41. Liel Y, Kraus S, Levy J, Shany S. 1992 Evidence that estrogens modulate activity and increase the number of 1,25-dihydroxyvitamin D receptors in osteoblast-like cells (ROS17/2.8). Endocricnology. 130:2597–2601.
  42. Escaleira MTF, Sonohara S, Brentani MM. 1993 Sex steroids induced up-regulation of 1,25-(OH)2 vitamin D3 receptors in T47 breast cancer cells. J Steroid Biochem Mol Biol. 45:257–263.[CrossRef][Medline]
  43. Bellido T, Girasole G, Passeri G, et al. 1993 Demonstration of estrogen and vitamin D receptors in bone marrow-derived stromal cells: up-regulation of the estrogen receptor by 1,25-dihydroxyvitamin D3. Endocrinology. 133:553–562.[Abstract/Free Full Text]
  44. Tanaka S, Haji M, Takayanagi R, Tanaka S, Sugioka Y, Nawata H. 1996 1,25-Dihydroxyvitamin D3 enhances the enzymatic activity and expression of the messenger ribonucleic acid for aromatase cytochrome P450 synergistically with dexamethasone depending on the vitamin D receptor level in cultured human osteoblasts. Endocrinology. 137:1860–1869.[Abstract]



This article has been cited by other articles:


Home page
 Hum Mol GenetHome page
A. Dempfle, S. A. Wudy, K. Saar, S. Hagemann, S. Friedel, A. Scherag, L. D. Berthold, G. Alzen, L. Gortner, W. F. Blum, et al.
Evidence for involvement of the vitamin D receptor gene in idiopathic short stature via a genome-wide linkage study and subsequent association studies
Hum. Mol. Genet., September 15, 2006; 15(18): 2772 - 2783.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
D-H Xiong, F-H Xu, P-Y Liu, H Shen, J-R Long, L Elze, R R Recker, and H-W Deng
Vitamin D receptor gene polymorphisms are linked to and associated with adult height
J. Med. Genet., March 1, 2005; 42(3): 228 - 234.
[Abstract] [Full Text] [PDF]

Home page
 Am J EpidemiolHome page
L. Gennari, D. Merlotti, V. De Paola, A. Calabro, L. Becherini, G. Martini, and R. Nuti
Estrogen Receptor Gene Polymorphisms and the Genetics of Osteoporosis: A HuGE Review
Am. J. Epidemiol., February 15, 2005; 161(4): 307 - 320.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
E. M. Colin, A. G. Uitterlinden, J. B. J. Meurs, A. P. Bergink, M. Van De Klift, Y. Fang, P. P. Arp, A. Hofman, J. P. T. M. van Leeuwen, and H. A. P. Pols
Interaction between Vitamin D Receptor Genotype and Estrogen Receptor {alpha} Genotype Influences Vertebral Fracture Risk
J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3777 - 3784.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
H. Lilienthal, A. Fastabend, J. Hany, H. Kaya, A. Roth-Harer, L. Dunemann, and G. Winneke
Reduced Levels of 1,25-Dihydroxyvitamin D3 in Rat Dams and Offspring after Exposure to a Reconstituted PCB Mixture
Toxicol. Sci., October 1, 2000; 57(2): 292 - 301.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Suarez, F.
Right arrow Articles by Garabédian, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Suarez, F.
Right arrow Articles by Garabédian, M.
Right arrowPubmed/NCBI databases
Medline Plus Health Information
*Child Development
*Infant and Toddler Development

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals