Sexual dimorphism in cortisol secretion starts after age 10 in healthy children: urinary cortisol metabolite excretion rates during growth
Abstract
Detailed data on the physiological pattern of adrenocortical activity during normal growth are lacking. An established method to determine adrenocortical glucocorticoid secretion is the measurement of 24-h excretion rates of major urinary cortisol metabolites (C21). To test the hypothesis that the frequently reported higher cortisol secretion in men than in women develops during puberty, we examined C21 together with excretions of combined urinary free and conjugated cortisol (F(comb)) in 400 healthy boys and girls aged 3-18 yr using GC-MS. Daily excretion rates of C21, F(comb), and body surface area (BSA)-corrected F(comb) significantly increased with age in both sexes. In contrast, C21/BSA (microgxm(-2).day(-1)) declined from the age of 3-4 yr to 7-8 yr in boys and girls (P < 0.01; e.g., in boys: from 3,991 +/- 1,167 to 3,193 +/- 804), then increased in both sexes, and finally became discordant after the age of 11-12 yr with a further rise in males only (17- to 18-yr-olds: boys, 5,275 +/- 1,414; girls 3,939 +/- 1,586, P < 0.01). This pattern was associated with the occurrence of a lower index for 5alpha-reductase activity (allotetrahydrocortisol/tetrahydrocortisol) in females compared with males. Our results demonstrate dynamic changes in adrenocortical activity in healthy children resulting in an emerging sexual dimorphism in cortisol secretion after age 11. The latter can be explained, at least partly, by diverging 5alpha-reductase activities in boys and girls. F(comb), a frequently analyzed GC-MS parameter, proved not to reflect dynamic changes in cortisol secretion. In conclusion, the varying metabolic need for cortisol during normal growth may have implications for future improvements in glucocorticoid replacement therapy.
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Usually, a spot urine sample is sufficient for diagnosing an adrenal enzyme defect.
“Usually, a spot urine sample is sufficient for diagnosing an adrenal enzyme defect (268,294,295).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [294]
The ontogeny functions focused on the maturation of 5α-reductase, 11-β hydroxysteroid dehydrogenase 2, and cortisol binding globulin, which are known to be influential on hydrocortisone pharmacokinetics.
“These ontogeny functions focused on the maturation of 5α-reductase, 11-β hydroxysteroid dehydrogenase 2 (11-βHSD2), and cortisol binding globulin (CBG), known to be influential on hydrocortisone PK ( Hadjian et al., 1975 ; Walker and Seckl, 2003 ; Wudy et al., 2007 ).”
From Insights in the maturational processes influencing hydrocortisone pharmacokinetics in congenital adrenal hyperplasia patients using a middle-out approach (2023) · cites this paper as Wudy et al., 2007
Cites
Endocrinology of the stress response
Charmandari, E., Tsigos, C., & Chrousos, G. (2005) · Annual Review of Physiology · doi:10.1146/annurev.physiol.67.040403.120816 · Cited by 1,799 · see citing works
11β-Hydroxysteroid Dehydrogenase
Stewart, P. M., & Krozowski, Z. S. (1997) · Vitamins and hormones · doi:10.1016/s0083-6729(08)60646-9 · Cited by 716 · see citing works
Orth, D. N. (1995) · New England Journal of Medicine · doi:10.1056/nejm199503233321207 · Cited by 562 · see citing works
Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry
ESTEBAN, N. V., LOUGHLIN, T., YERGEY, A. L., ZAWADZKI, J. K., BOOTH, J. D., WINTERER, J. C., & LORIAUX, D. L. (1991) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-72-1-39 · Cited by 481 · see citing works
Remer, T., Neubert, A., & Maser‐Gluth, C. (2002) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/75.3.561 · Cited by 395 · see citing works
Self-citationObesity and Gender Influence Cortisol Secretion and Metabolism in Man
Andrew, R., Phillips, D. I. W., & Walker, B. R. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.5.4951 · Cited by 351 · see citing works
Hypertension and the cortisol-cortisone shuttle
Quinkler, M., & Stewart, P. M. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030138 · Cited by 286 · see citing works
Matos, V., van Melle, G., Boulat, O., et al. (1997) · The Journal of Pediatrics · doi:10.1016/s0022-3476(97)70162-8 · Cited by 269 · see citing works
Mass spectrometry in the diagnosis of steroid-related disorders and in hypertension research
Shackleton, C. H. L. (1993) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/0960-0760(93)90132-g · Cited by 247 · see citing works
Cortisol production rate in childhood and adolescence
Linder, B. L., Esteban, N. V., Yergey, A. L., Winterer, J. C., Loriaux, D. L., & Cassorla, F. (1990) · The Journal of Pediatrics · doi:10.1016/s0022-3476(05)80128-3 · Cited by 202 · 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
Self-citationWesterbacka, J., Yki‐Järvinen, H., Vehkavaara, S., Häkkinen, A., Andrew, R., Wake, D. J., Seckl, J. R., & Walker, B. R. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030596 · Cited by 176 · see citing works
Cortisol production rate. II. Normal infants, children, and adults.
Kenny, F. M., PREEYASOMBAT, C., & Migeon, C. J. (1966) · PubMed · Cited by 159 · see citing works
Tsilchorozidou, T., Honour, J. W., & Conway, G. S. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-030240 · Cited by 155 · see citing works
Kenny, F. M., PREEYASOMBAT, C., Spaulding, J. S., & Migeon, C. J. (1966) · PEDIATRICS · doi:10.1542/peds.37.6.960 · Cited by 127 · see citing works
Kraan, G. P. B., Dullaart, R. P. F., Pratt, J. J., Wolthers, B. G., Drayer, N. M., & de Bruin, R. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.4.4694 · Cited by 120 · see citing works
Diagnostics of Endocrine Function in Children and Adolescents
(2003) · KARGER eBooks · doi:10.1159/isbn.978-3-318-00913-2 · Cited by 110 · see citing works
Remer, T., Fonteyn, N., Alexy, U., & Berkemeyer, S. (2006) · American Journal of Clinical Nutrition · doi:10.1093/ajcn.83.3.639 · Cited by 101 · see citing works
Self-citationTomlinson, J., Sherlock, M., Hughes, B., Hughes, S. V., Kilvington, F., Bartlett, W. A., Courtney, R., Rejto, P. A., Carley, W. W., & Stewart, P. M. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-2325 · Cited by 98 · see citing works
Finken, M. J. J., Andrews, R. C., Andrew, R., & Walker, B. R. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.9.6009 · Cited by 88 · see citing works
Migeon, C. J., Kenney, F. M., Richards, C., & Lawrence, B. (1966) · The Journal of Pediatrics · doi:10.1016/s0022-3476(66)80124-5 · Cited by 80 · see citing works
Classic congenital adrenal hyperplasia and puberty
Charmandari, E., Brook, C. G. D., & Hindmarsh, P. C. (2004) · European Journal of Endocrinology · doi:10.1530/eje.0.151u077 · Cited by 74 · see citing works
Intercomparison of Four Methods for Measuring Cortisol Production
Zumoff, B., Fukushima, D. K., & HELLMAN, L. (1974) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-38-2-169 · Cited by 69 · see citing works
Gas Chromatography-Mass Spectrometry Profiling of Steroids in Times of Molecular Biology
Wudy, S. A., & Hartmann, M. F. (2004) · Hormone and Metabolic Research · doi:10.1055/s-2004-814565 · Cited by 68 · see citing works
Self-citationUrinary free cortisol values in normal children and adolescents
Gomez, M. T., Malozowski, S., Winterer, J. C., Vamvakopoulos, N. C., & Chrousos, G. P. (1991) · The Journal of Pediatrics · doi:10.1016/s0022-3476(05)80496-2 · Cited by 68 · see citing works
Boye, K. R., Dimitriou, T., Manz, F., Schöenau, E., Neu, C. M., Wudy, S. A., & Remer, T. (2002) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/76.3.628 · Cited by 67 · see citing works
Self-citationWeaver, J. U., Taylor, N., Monson, J. P., Wood, P. J., & Kelly, W. F. (1998) · Clinical Endocrinology · doi:10.1046/j.1365-2265.1998.00494.x · Cited by 66 · see citing works
Sex differences in the human metabolism of cortisol
Raven, P. W., & Taylor, N. F. (1996) · Endocrine Research · doi:10.1080/07435809609043772 · Cited by 64 · see citing works
Remer, T., Boye, K. R., Hartmann, M. F., Neu, C. M., Schöenau, E., Manz, F., & Wudy, S. A. (2003) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2003.18.8.1539 · Cited by 62 · see citing works
Self-citationGender differences in the urinary excretion rates of cortisol and androgen metabolites
Shamim, W., Yousufuddin, M., Bakhai, A., Coats, A. J. S., & Honour, J. W. (2000) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1258/0004563001900084 · Cited by 54 · see citing works
Quinkler, M. O., Zehnder, D., Lepenies, J., Petrelli, M., Moore, J. S., Hughes, S. V., Cockwell, P., Hewison, M., & Stewart, P. M. (2005) · European Journal of Endocrinology · doi:10.1530/eje.1.01954 · Cited by 51 · see citing works
Brandon, D. D., Isabelle, L. M., Samuels, M. H., Kendall, J. W., & Loriaux, D. L. (1999) · Steroids · doi:10.1016/s0039-128x(98)00112-3 · Cited by 50 · see citing works
Sex-specific differences in cortisol production rates in humans
Vierhapper, H., Nowotny, P., & Waldhäusl, W. K. (1998) · Metabolism · doi:10.1016/s0026-0495(98)90353-5 · Cited by 47 · see citing works
Rubín, R. T., & Phillips, J. J. (1991) · Investigative Radiology · doi:10.1097/00004424-199105000-00015 · Cited by 47 · see citing works
Chin, D., Shackleton, C. H. L., Prasad, V., Kohn, B., David, R., Imperato‐McGinley, J., Cohen, H., McMahon, D. J., & Oberfield, S. E. (2000) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem.2000.13.3.253 · Cited by 46 · see citing works
MAUVAIS-JARVIS, P., Floch, H. H., & Bercovici, J. P. (1968) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-28-4-460 · Cited by 44 · see citing works
Comprehensive study of urinary cortisol metabolites in hyperthyroid and hypothyroid patients
Hoshiro, M., Ohno, Y., Masaki, H., et al. (2005) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2005.02412.x · Cited by 44 · see citing works
Toogood, Taylor, Shalet, S. M., & Monson (2000) · Clinical Endocrinology · doi:10.1046/j.1365-2265.2000.00874.x · Cited by 42 · see citing works
7 11β-hydroxysteroid dehydrogenase
Stewart, P. M. (1994) · Baillière s Clinical Endocrinology and Metabolism · doi:10.1016/s0950-351x(05)80257-5 · Cited by 40 · see citing works
Assessing Cortisol Production in Preterm Infants: Do Not Dispose of the Nappies
Heckmann, M., Hartmann, M. F., Kampschulte, B., Gack, H., Bödeker, R., Gortner, L., & Wudy, S. A. (2005) · Pediatric Research · doi:10.1203/01.pdr.0000153947.51642.c1 · Cited by 39 · see citing works
Self-citationFree cortisol and creatinine in urine of healthy children.
Bertrand, P. V., Rudd, B. T., Weller, P., & Day, A. J. (1987) · Clinical Chemistry · doi:10.1093/clinchem/33.11.2047 · Cited by 33 · see citing works
Kurina, L. M., Weiss, L. A., Graves, S. W., Parry, R. R., Williams, G. H., Abney, M., & Ober, C. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0384 · Cited by 31 · see citing works
Charmandari, E. (2002) · Archives of Disease in Childhood · doi:10.1136/adc.86.4.266 · Cited by 30 · see citing works
Production Rates of Cortisol in Obesity
Vierhapper, H., Nowotny, P., & Waldhäusl, W. K. (2004) · Obesity Research · doi:10.1038/oby.2004.178 · Cited by 24 · see citing works
Urine steroid excretion rates in childhood reflect growth and activity of the adrenal cortex
Honour, J. W., Kelnar, C. J. H., & Brook, C. G. D. (1991) · European Journal of Endocrinology · doi:10.1530/acta.0.1240219 · Cited by 23 · see citing works
A genetic study of cortisol measured before and after endurance training: The HERITAGE Family Study
Feitosa, M. F., Rice, T., Rosmond, R., Borecki, I. B., An, P., Gagnon, J., Leon, A. S., Skinner, J. S., Wilmore, J. H., Bouchard, C., et al. (2002) · Metabolism · doi:10.1053/meta.2002.30519 · Cited by 19 · see citing works
Samuels, M. H., Brandon, D. D., Isabelle, L. M., Cook, D. M., Graham, K. E. R., Purnell, J. Q., & Loriaux, D. L. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.1.6259 · Cited by 15 · see citing works
Aranoff, G. S., & Rosier, A. (1980) · European Journal of Endocrinology · doi:10.1530/acta.0.0940371 · Cited by 15 · see citing works
Kraan, G. P. B., & Drayer, N. M. (1990) · Steroids · doi:10.1016/0039-128x(90)90104-j · Cited by 14 · see citing works
Adrenal Gland Volume After Spinal Cord Injury
Lee, W., Wang, Y., Su, C., et al. (2002) · American Journal of Physical Medicine & Rehabilitation · doi:10.1097/00002060-200207000-00003 · Cited by 12 · see citing works
Mai, K., Kullmann, V., Bobbert, T., Maser‐Gluth, C., Möhlig, M., Bähr, V., Pfeiffer, A. F. H., Spranger, J., & Diederich, S. (2005) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2005.02362.x · Cited by 12 · see citing works
Profiling Steroids by Gas Chromatography-Mass Spectrometry: Clinical Applications
Wudy, S., & Homoki, J. (2003) · KARGER eBooks · doi:10.1159/000073561 · Cited by 10 · see citing works
Self-citationActivity of 11beta-hydroxysteroid dehydrogenase type 2 in normotensive blacks and whites.
Shankar, K., Ferrari, P., Dick, B., et al. (2005) · PubMed · Cited by 4 · see citing works
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- Authors
- Wudy, S. A., Hartmann, M. F., & Remer, T.
- Affiliations
- Justus-Liebig-Universität Gießen (DE)
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2007-10
- Volume
- 293
- Issue
- 4
- Pages
- E970-E976
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2112366597
- Cited by
- 101
- References
- 53
- Citations by year
- 2026: 6 · 2025: 1 · 2024: 5 · 2023: 7 · 2022: 7 · 2021: 8 · 2020: 7 · 2019: 7 · 2018: 2 · 2017: 6 · 2016: 4 · 2015: 1 · 2014: 9 · 2013: 6 · 2012: 3
- FWCI
- 4.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Keywords
- sexual dimorphism, cortisol secretion, adrenocortical function, children, puberty, urinary cortisol metabolites, 24-hour urinary excretion, 5alpha-reductase activity, tetrahydrocortisol, growth, glucocorticoid replacement therapy
- MeSH terms
- Adolescent, Aging, Child, Child Development, Child, Preschool, Female, Growth, Humans, Hydrocortisone, Male, Models, Biological, Sex Characteristics
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