Assessment of circulating sex steroid levels in prepubertal and pubertal boys and girls by a novel ultrasensitive gas chromatography-tandem mass spectrometry method
Abstract
CONTEXT: Estrogens and androgens play key roles for pubertal onset and sexual maturation. Most currently used immunoassays are not sensitive enough to accurately measure the low circulating levels of sex steroids in children without any signs of puberty. However, this does not exclude that sex steroids have important biological roles in prepubertal children. OBJECTIVES: To accurately determine levels of sex steroid hormones and their metabolites in serum of healthy children before any physical signs of puberty and to evaluate possible sex differences. MAIN OUTCOME MEASURES: Total (unconjugated plus conjugated) serum levels of 17beta-testosterone, 17alpha-testosterone, 5alpha-dihydrotestosterone, 5beta-dihydrotestosterone, androsterone, etiocholanolone, estradiol, and estrone measured by an ultrasensitive method based on gas chromatography-tandem mass spectrometry in samples from 81 healthy schoolchildren (42 boys) without any signs of puberty. For comparison, 48 pubertal children were studied. RESULTS: 17beta-Estradiol levels in prepubertal boys were undetectable or extremely low (median < 3.7 pmol/liter), whereas levels in prepubertal girls were significantly higher (median 9.6 pmol/liter, P < 0.001). Among the older prepubertal children (>8 yr), girls had significantly higher androsterone (4.07 vs. 1.45 nmol/liter, P < 0.05), etiocholanolone (5.45 vs. 1.95 nmol/liter, P < 0.0001), 5alpha-dihydrotestosterone (0.11 vs. <0.10 nmol/liter, P < 0.01), and 17beta-testosterone concentrations (0.69 vs. 0.47 nmol/liter, P < 0.05) compared with similarly aged prepubertal boys. CONCLUSION: Using an accurate and sensitive method, we found significantly higher levels of estrogens as well as androgen metabolites in prepubertal girls compared with age-matched boys. The higher prepubertal sex steroid levels in girls may contribute to their earlier onset of puberty including pubic hair development.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Prior to puberty, there is no sex difference in circulating testosterone concentrations between boys and girls.
“Prior to puberty, there is no sex difference in circulating testosterone concentrations or athletic performance”
From Circulating Testosterone as the Hormonal Basis of Sex Differences in Athletic Performance (2018) · cites this paper as [16]
Following puberty, testosterone production increases but remains <2 nmol/L in women, whereas in men testosterone production increases 20-fold (from 0.3 mg/d to 7 mg/d), leading to 15-fold higher circulating testosterone concentrations (15 vs 1 nmol/L).
“Following puberty, testosterone production increases (16) but remains <2 nmol/L in women, whereas in men testosterone production increases 20-fold (from 0.3 mg/d to 7 mg/d), leading to 15-fold higher circulating testosterone concentrations (15 vs 1 nmol/L).”
From Circulating Testosterone as the Hormonal Basis of Sex Differences in Athletic Performance (2018) · cites this paper as [16]
Cites
Tanner, J. M., & Whitehouse, R. H. (1976) · Archives of Disease in Childhood · doi:10.1136/adc.51.3.170 · Cited by 3,137 · see citing works
Estrogen levels in childhood determined by an ultrasensitive recombinant cell bioassay.
Klein, K. O., Baron, J., Colli, M. J., McDonnell, D. P., & Cutler, G. B. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117616 · Cited by 376 · see citing works
Prepubertal Gynecomastia Linked to Lavender and Tea Tree Oils
Henley, D. V., Lipson, N., Korach, K. S., & Bloch, C. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa064725 · Cited by 359 · see citing works
Nelson, R. E., Grebe, S. K. G., O’Kane, D. J., & Singh, R. J. (2004) · Clinical Chemistry · doi:10.1373/clinchem.2003.025478 · Cited by 359 · see citing works
Pubertal development in Danish children: comparison of recent European and US data
JUUL, A., TEILMANN, G., SCHEIKE, T., HERTEL, N. T., HOLM, K., LAURSEN, E. M., MAIN, K. M., & SKAKKEBÆK, N. E. (2006) · International Journal of Andrology · doi:10.1111/j.1365-2605.2005.00556.x · Cited by 300 · see citing works
Self-citationHigh-Sensitivity Tandem Mass Spectrometry Assay for Serum Estrone and Estradiol
Kushnir, M. M., Rockwood, A. L., Bergquist, J., Varshavsky, M., Roberts, W. L., Yue, B., Bunker, A. M., & Meikle, A. W. (2008) · American Journal of Clinical Pathology · doi:10.1309/lc03bhq5xjpjyekg · Cited by 209 · see citing works
Urinary markers of adrenarche: reference values in healthy subjects, aged 3–18 years
Remer, T., Boye, K. R., Hartmann, M. F., & Wudy, S. A. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1571 · Cited by 193 · see citing works
Albertsson-Wikland, K. G., Rosberg, S., Lannering, B., Dunkel, L., Selstam, G., & Norjavaara, E. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.2.3778 · Cited by 158 · see citing works
Norjavaara, E., Ankarberg‐Lindgren, C., & Albertsson-Wikland, K. G. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.11.8923866 · Cited by 125 · see citing works
Mitamura, R., Yano, K., Suzuki, N., Ito, Y., Makita, Y., & Okuno, A. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.3.6445 · Cited by 117 · see citing works
Ankarberg‐Lindgren, C., & Norjavaara, E. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.3.5524 · Cited by 114 · see citing works
Mitamura, R., Yano, K., Suzuki, N., Ito, Y., Makita, Y., & Okuno, A. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.1.5404 · Cited by 93 · see citing works
Sørensen, K., Aksglæde, L., Munch‐Andersen, T., Aachmann‐Andersen, N. J., Petersen, J. H., Hilsted, L. M., Helge, J. W., & Juul, A. (2009) · Diabetes Care · doi:10.2337/dc08-1618 · Cited by 90 · see citing works
Self-citationMitamura, R. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.85.3.1074 · Cited by 90 · see citing works
ROSS, J. L., Long, L., SKERDA, M. C., CASSORLA, F. G., Kurtz, D., Loriaux, D. L., & Cutler, G. B. (1986) · The Journal of Pediatrics · doi:10.1016/s0022-3476(86)80274-8 · Cited by 88 · see citing works
Adrenal changes associated with adrenarche
Nakamura, Y., Gang, H. X., Suzuki, T., Sasano, H., & Rainey, W. E. (2009) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-008-9092-2 · Cited by 84 · see citing works
Courant, F., Antignac, J., Laille, J., et al. (2008) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf800096f · Cited by 76 · see citing works
Self-citationDetermination of naturally occurring oestrogens and androgens in retail samples of milk and eggs
Courant, F., Antignac, J., Maume, D., et al. (2007) · Food Additives & Contaminants · doi:10.1080/02652030701329637 · Cited by 76 · see citing works
Self-citationParis, F., Servant, N., Térouanne, B., et al. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.2.8269 · Cited by 75 · see citing works
Plasma Estrogen and Androgen Concentrations in Children During Adolescence
Gupta, D., Attanasio, A. F., & RAAF, S. (1975) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-40-4-636 · Cited by 74 · see citing works
Mitamura, R. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.84.1.29 · Cited by 74 · see citing works
Estradiol levels in prepubertal boys and girls – analytical challenges
Bay, K., Andersson, A., & Skakkebæk, N. E. (2004) · International Journal of Andrology · doi:10.1111/j.1365-2605.2004.00487.x · Cited by 71 · see citing works
Self-citationPrepubertal Gynecomastia: Indirect Exposure to Estrogen Cream
Felner, E. I., & White, P. C. (2000) · PEDIATRICS · doi:10.1542/peds.105.4.e55 · Cited by 63 · see citing works
Helix pomatia induced conversion of some 3β-hydroxysteroids
Messeri, G., Cugnetto, G., Moneti, G., et al. (1984) · Journal of Steroid Biochemistry · doi:10.1016/0022-4731(84)90088-8 · Cited by 61 · see citing works
Exposure assessment of prepubertal children to steroid endocrine disrupters
Courant, F., Antignac, J., Maume, D., Monteau, F., Andersson, A., Skakkebæk, N. E., Andre, F., & Bizec, B. L. (2006) · Analytica Chimica Acta · doi:10.1016/j.aca.2006.11.002 · Cited by 59 · see citing works
Self-citationJanfaza, M., Sherman, T. I., Larmore, K. A., Brown-Dawson, J. M., & Klein, K. O. (2006) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem.2006.19.7.901 · Cited by 59 · see citing works
Ankarberg‐Lindgren, C., & Norjavaara, E. (2008) · European Journal of Endocrinology · doi:10.1530/eje-07-0403 · Cited by 57 · see citing works
Reproducibility of laboratory assays for steroid hormones and sex hormone-binding globulin.
Potischman, N. A., Falk, R. T., Laiming, V. A., et al. (1994) · PubMed · Cited by 48 · see citing works
Ikegami, S., Moriwake, T., Tanaka, H., Inoue, M., Kubo, T., Suzuki, S., Kanzaki, S., & Seino, Y. (2001) · Clinical Endocrinology · doi:10.1046/j.1365-2265.2001.01416.x · Cited by 47 · see citing works
Conversion of free 3β-hydroxy-5-ene-steroids by incubation with Helix pomatia
Vanluchene, E., Eechaute, W., & Vandekerckhove, D. (1982) · Journal of Steroid Biochemistry · doi:10.1016/0022-4731(82)90107-8 · Cited by 44 · see citing works
Pediatric reference values of estradiol, testosterone, lutropin, follitropin and prolactin.
Gässler, N., Peuschel, T., & Pankau, R. (2000) · PubMed · Cited by 41 · see citing works
Hormone-Containing Cosmetics May Cause Signs of Early Sexual Development
Zimmerman, P. A., Francis, G. L., & Poth, M. (1995) · Military Medicine · doi:10.1093/milmed/160.12.628 · Cited by 38 · see citing works
Ankarberg‐Lindgren, C., & Norjavaara, E. (2008) · BMC Endocrine Disorders · doi:10.1186/1472-6823-8-10 · Cited by 38 · see citing works
Juul, A., Sørensen, K., Aksglæde, L., Garn, I. D., Meyts, E. R., Hullstein, I. R., Hemmersbach, P., & Ottesen, A. M. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-1984 · Cited by 33 · see citing works
Self-citationEvaluation of androgenic bioactivity in human serum by recombinant cell line: preliminary results
Paris, F., Servant, N., Térouanne, B., & Sultan, C. (2002) · Molecular and Cellular Endocrinology · doi:10.1016/s0303-7207(02)00375-1 · Cited by 33 · see citing works
Local biosynthesis and metabolism of oestrogens in the human breast
Thijssen, J. H. H. (2004) · Maturitas · doi:10.1016/j.maturitas.2004.06.004 · Cited by 27 · see citing works
Low endogenous estrogen levels--analytical problems and tissue sensitivity.
Carlström, K. (1996) · PubMed · Cited by 24 · see citing works
Turan, S., Bereket, A., Güran, T., Akçay, T., Papari-Zareei, M., & Auchus, R. J. (2008) · European Journal of Endocrinology · doi:10.1530/eje-08-0632 · Cited by 21 · see citing works
Biancotto, G., Angeletti, R., Traldi, P., et al. (2002) · Journal of Mass Spectrometry · doi:10.1002/jms.397 · Cited by 16 · see citing works
Testosterone concentration within the tunica vaginalis of boys and adult men
Karpe, B., Fredricsson, B., Svensson, J., & Ritzén, E. M. (1982) · International Journal of Andrology · doi:10.1111/j.1365-2605.1982.tb00288.x · Cited by 16 · see citing works
Effects of scientific advances on the decision-making process: Analytical chemistry
Horwitz, W. (1984) · Fundamental and Applied Toxicology · doi:10.1016/0272-0590(84)90257-4 · Cited by 7 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Circulating Testosterone as the Hormonal Basis of Sex Differences in Athletic Performance
Handelsman, D. J., Hirschberg, A. L., & Bermon, S. (2018) · Endocrine Reviews · doi:10.1210/er.2018-00020 · Cited by 594 · see citing works
Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty
Kuiri-Hänninen, T., Sankilampi, U., & Dunkel, L. (2014) · Hormone Research in Paediatrics · doi:10.1159/000362414 · Cited by 470 · see citing works
Growth hormone plus childhood low-dose estrogen in Turner's syndrome
Ross, J. L., Quigley, C. A., Cao, D., Feuillan, P., Kowal, K., Chipman, J. J., & Cutler, G. B. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1005669 · Cited by 212 · see citing works
Frederiksen, H., Johannsen, T. H., Andersen, S. E., Albrethsen, J., Landersoe, S. K., Petersen, J. H., Andersen, A. N., Vestergaard, E. T., Schorring, M. E., Linneberg, A., et al. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgz196 · Cited by 211 · see citing works
Self-citationAlternative (backdoor) androgen production and masculinization in the human fetus
O’Shaughnessy, P. J., Antignac, J. P., Le Bizec, B., Morvan, M.-L., Svechnikov, K., Söder, O., Savchuk, I., Monteiro, A., Soffientini, U., Johnston, Z. C., et al. (2019) · PLOS Biology · doi:10.1371/journal.pbio.3000002 · Cited by 177 · see citing works
Self-citationQuigley, C. A., Wan, X., Garg, S., Kowal, K., Cutler, G. B., & Ross, J. L. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-4518 · Cited by 56 · see citing works
Role of senescence in the chronic health consequences of COVID-19
Wissler Gerdes, E. O., Vanichkachorn, G., Verdoorn, B. P., Hanson, G. J., Joshi, A. Y., Murad, M. H., Rizza, S. A., Hurt, R. T., Tchkonia, T., & Kirkland, J. L. (2022) · Translational Research · doi:10.1016/j.trsl.2021.10.003 · Cited by 38 · see citing works
Androgenic potential of human fetal adrenals at the end of the first trimester
Savchuk, I., Morvan, M. L., Antignac, J. P., Gemzell-Danielsson, K., Le Bizec, B., Söder, O., & Svechnikov, K. (2017) · Endocrine Connections · doi:10.1530/ec-17-0085 · Cited by 20 · see citing works
Ruszala, A., Wojcik, M., Zygmunt-Gorska, A., Janus, D., Wojtys, J., & Starzyk, J. B. (2017) · Journal of Endocrinological Investigation · doi:10.1007/s40618-017-0665-3 · Cited by 10 · see citing works
- Authors
- Courant, F., Aksglaede, L., Antignac, J.-P., Monteau, F., Sorensen, K., Andersson, A.-M., Skakkebaek, N. E., Juul, A., & Bizec, B. L.
- Affiliations
- Laboratoire d’Etude des Résidus et Contaminants dans les Aliments (LABERCA) (F.C., J.-P.A., F.M., B.L.B.), Unité Sous Contrat 2013 Institut National de la Recherche Agronomique, Ecole Nationale Vétérinaire de Nantes, F-44307 Nantes, France
- Department of Growth and Reproduction (L.A., K.S., A.-M.A., N.E.S., A.J.), Copenhagen University Hospital, DK-2100 Copenhagen, Denmark
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Copenhagen University Hospital (DK)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2010-01-01
- Volume
- 95
- Issue
- 1
- Pages
- 82-92
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2160720198
- Cited by
- 172
- References
- 41
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 4 · 2023: 11 · 2022: 13 · 2021: 11 · 2020: 9 · 2019: 13 · 2018: 12 · 2017: 8 · 2016: 8 · 2015: 15 · 2014: 19 · 2013: 8 · 2012: 10
- FWCI
- 11.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Keywords
- sex steroids, prepubertal children, puberty onset, sex differences, estradiol, androgens, androsterone, etiocholanolone, dihydrotestosterone, pubic hair development, pubertal timing
- MeSH terms
- Adolescent, Age Factors, Blood Chemical Analysis, Calibration, Child, Chromatography, Gas, Female, Humans, Male, Puberty, Sex Factors, Gonadal Steroid Hormones, Reproducibility of Results, Tandem Mass Spectrometry
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review