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      A Normative Model of Serum Inhibin B in Young Males

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          Abstract

          Inhibin B has been identified as a potential marker of Sertoli cell function in males. The aim of this study is to produce a normative model of serum inhibin B in males from birth to seventeen years. We used a well-defined search strategy to identify studies containing data that can contribute to a larger approximation of the healthy population. We combined data from four published studies (n = 709) and derived an internally validated model with high goodness-of-fit and normally distributed residuals. Our results show that inhibin B increases following birth to a post-natal peak of 270 pg/mL (IQR 210–335 pg/mL) and then decreases during childhood followed by a rise at around 8 years, peaking at a mean 305 pg/mL (IQR 240–445 pg/mL) at around age 17. Following this peak there is a slow decline to the standard mature adult normal range of 170 pg/mL (IQR 125–215 pg/mL). This normative model suggests that 35% of the variation in Inhibin B levels in young males is due to age alone, provides an age-specific reference range for inhibin B in the young healthy male population, and will be a powerful tool in evaluating the potential of inhibin B as a marker of Sertoli cell function in pre-pubertal boys.

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          The central role of Sertoli cells in spermatogenesis.

          Sertoli cells are the somatic cells of the testis that are essential for testis formation and spermatogenesis. Sertoli cells facilitate the progression of germ cells to spermatozoa via direct contact and by controlling the environment milieu within the seminiferous tubules. The regulation of spermatogenesis by FSH and testosterone occurs by the action of these hormones on the Sertoli cells. While the action of testosterone is necessary for spermatogenesis, the action of FSH minimally serves to promote spermatogenic output by increasing the number of Sertoli cells. Copyright 1998 Academic Press.
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            A Validated Model of Serum Anti-Müllerian Hormone from Conception to Menopause

            Background Anti-Müllerian hormone (AMH) is a product of growing ovarian follicles. The concentration of AMH in blood may also reflect the non-growing follicle (NGF) population, i.e. the ovarian reserve, and be of value in predicting reproductive lifespan. A full description of AMH production up to the menopause has not been previously reported. Methodology/Principal Findings By searching the published literature for AMH concentrations in healthy pre-menopausal females, and using our own data (combined ) we have generated and robustly validated the first model of AMH concentration from conception to menopause. This model shows that 34% of the variation in AMH is due to age alone. We have shown that AMH peaks at age 24.5 years, followed by a decline to the menopause. We have also shown that there is a neonatal peak and a potential pre-pubertal peak. Our model allows us to generate normative data at all ages. Conclusions/Significance These data highlight key inflection points in ovarian follicle dynamics. This first validated model of circulating AMH in healthy females describes a transition period in early adulthood, after which AMH reflects the progressive loss of the NGF pool. The existence of a neonatal increase in gonadal activity is confirmed for females. An improved understanding of the relationship between circulating AMH and age will lead to more accurate assessment of ovarian reserve for the individual woman.
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              Time course of the serum gonadotropin surge, inhibins, and anti-Müllerian hormone in normal newborn males during the first month of life.

              Newborns with ambiguous genitalia or males with nonpalpable gonads usually require an early assessment of the presence and functional state of testicular tissue. Our objective was to characterize the precise ontogeny of the serum patterns of gonadotropins, testosterone, anti-Müllerian hormone (AMH), and inhibins in normal newborn boys. We conducted a cross-sectional and longitudinal study. Serum samples were obtained in 57 boys and 13 girls on d 2 of life. A second sample was obtained on d 7, 10, 15, 20, and 30 (boys) and on d 30 (girls). Serum levels of gonadotropins, testosterone, AMH, and inhibins were measured. In males, LH and FSH were undetectable or very low on d 2. By d 7, LH increased to 3.94 +/- 3.19 IU/liter (mean +/- sd) and FSH to 2.04 +/- 1.67 IU/liter. LH/FSH ratios were 0.40 +/- 0.11 (d 2) and 2.02 +/- 0.20 (d 30). AMH rose from 371 +/- 168 pmol/liter (d 2) to 699 +/- 245 pmol/liter (d 30), and inhibin B rose from 214 +/- 86 ng/liter (d 2) to 361 +/- 93 ng/liter (d 30). The inhibin alpha-subunit precursor (pro-alphaC) remained stable during the first month of life. Testosterone levels were 66 +/- 42 ng/dl (d 2), 82 +/- 24 ng/dl (d 20), and 210 +/- 130 ng/dl (d 30). A sexual dimorphism was observed in AMH and inhibin B (lower in girls on d 2 and 30), in LH/FSH ratio (lower in girls on d 30) and in testosterone (lower in girls on d 30). Sertoli cell markers AMH and inhibin B are the earliest useful markers indicating the existence of normal testicular tissue.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                14 April 2016
                2016
                : 11
                : 4
                : e0153843
                Affiliations
                [1 ]School of Computer Science, University of St Andrews, St Andrews KY16 9SX, United Kingdom
                [2 ]School of Medicine, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom
                [3 ]MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom
                [4 ]Department of Haematology/Oncology, Royal Hospital for Sick Children, Edinburgh EH9 1LF, United Kingdom
                University of Sydney, AUSTRALIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: TWK AEM RAA RTM WHBW. Performed the experiments: TWK AEM. Analyzed the data: TWK AEM RAA RTM WHBW. Wrote the paper: TWK AEM RAA RTM WHBW.

                Author information
                http://orcid.org/0000-0002-8091-1458
                Article
                PONE-D-15-56272
                10.1371/journal.pone.0153843
                4831823
                27077369
                6d01bf63-6e62-4f33-a906-cf0dca55887b
                © 2016 Kelsey et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 31 December 2015
                : 5 April 2016
                Page count
                Figures: 3, Tables: 4, Pages: 10
                Funding
                RTM is supported by a Wellcome Trust Intermediate Clinical Fellowship (Grant No: 098522), http://www.wellcome.ac.uk/Funding/Biomedical-science/Funding-schemes/Fellowships/Clinical-fellowships/wtd004402.htm. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Epithelial Cells
                Sertoli Cells
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Epithelium
                Epithelial Cells
                Sertoli Cells
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Epithelium
                Epithelial Cells
                Sertoli Cells
                Medicine and Health Sciences
                Endocrinology
                Endocrine Physiology
                Puberty
                Biology and Life Sciences
                Physiology
                Endocrine Physiology
                Puberty
                Medicine and Health Sciences
                Physiology
                Endocrine Physiology
                Puberty
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Cycle and Cell Division
                Meiosis
                Spermatogenesis
                Biology and Life Sciences
                Cell Biology
                Chromosome Biology
                Meiosis
                Spermatogenesis
                Biology and Life Sciences
                Physiology
                Reproductive Physiology
                Spermatogenesis
                Medicine and Health Sciences
                Physiology
                Reproductive Physiology
                Spermatogenesis
                Research and Analysis Methods
                Database and Informatics Methods
                Database Searching
                Physical Sciences
                Mathematics
                Statistics (Mathematics)
                Confidence Intervals
                Medicine and Health Sciences
                Health Care
                Health Services Research
                Biology and Life Sciences
                Biochemistry
                Hormones
                Androgens
                Testosterone
                Biology and Life Sciences
                Biochemistry
                Hormones
                Lipid Hormones
                Testosterone
                Research and Analysis Methods
                Research Design
                Longitudinal Studies
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                All relevant data are within the paper and its Supporting Information file.

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