|
1
|
Hornig N, Batista RL. Androgen insensitivity and the evolving genetic heterogeneity. Best Pract Res Clin Endocrinol Metab 2025:102000. [PMID: 40335402 DOI: 10.1016/j.beem.2025.102000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/09/2025]
Abstract
Androgen Insensitivity Syndrome (AIS) is a 46,XY difference of sex development (DSD) classically caused by mutations in the androgen receptor (AR) gene, leading to variable androgen resistance and a broad phenotypic spectrum traditionally classified as complete, partial, or mild. Phenotypic variability can occur even with identical AR mutations, particularly those within the ligand-binding domain of the AR. Emerging evidence implicates non-coding regulatory variants, deep intronic mutations, AR co-regulator dysfunction, and oligogenic inheritance in the aetiology of AIS. The molecular diagnostic workflow should incorporate either targeted AR sequencing or whole-exome sequencing, depending on the clinical context. Biochemical and functional assays remain clinically useful, especially when AR variants are not detected or when variants of unknown significance (VUS) are identified. Advances in patient-derived hiPSC models and testicular organoids provide new insights into AR function and therapeutic strategies. Expanding genomic and epigenetic research will refine diagnostic accuracy, and personalized care, ultimately optimizing patient outcomes in AIS.
Collapse
Affiliation(s)
- Nadine Hornig
- Institute of Human Genetics, Christian Albrechts University of Kiel (CAU) and University Hospital Schleswig-Holstein, Kiel, Germany.
| | - Rafael Loch Batista
- Developmental Endocrinology Unit and Laboratório de Investigações Médicas (LIM/42), Endocrinology Division, Internal Medicine Department, Medical School, University of São Paulo (USP), São Paulo, SP, Brazil.
| |
Collapse
|
|
2
|
Blanchett R, Chen H, Vlasova RM, Cornea E, Maza M, Davenport M, Reinhartsen D, DeRamus M, Edmondson Pretzel R, Gilmore JH, Hooper SR, Styner MA, Gao W, Knickmeyer RC. White matter microstructure and functional connectivity in the brains of infants with Turner syndrome. Cereb Cortex 2024; 34:bhae351. [PMID: 39256896 PMCID: PMC11387115 DOI: 10.1093/cercor/bhae351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 08/01/2024] [Accepted: 08/13/2024] [Indexed: 09/12/2024] Open
Abstract
Turner syndrome, caused by complete or partial loss of an X-chromosome, is often accompanied by specific cognitive challenges. Magnetic resonance imaging studies of adults and children with Turner syndrome suggest these deficits reflect differences in anatomical and functional connectivity. However, no imaging studies have explored connectivity in infants with Turner syndrome. Consequently, it is unclear when in development connectivity differences emerge. To address this gap, we compared functional connectivity and white matter microstructure of 1-year-old infants with Turner syndrome to typically developing 1-year-old boys and girls. We examined functional connectivity between the right precentral gyrus and five regions that show reduced volume in 1-year old infants with Turner syndrome compared to controls and found no differences. However, exploratory analyses suggested infants with Turner syndrome have altered connectivity between right supramarginal gyrus and left insula and right putamen. To assess anatomical connectivity, we examined diffusivity indices along the superior longitudinal fasciculus and found no differences. However, an exploratory analysis of 46 additional white matter tracts revealed significant group differences in nine tracts. Results suggest that the first year of life is a window in which interventions might prevent connectivity differences observed at later ages, and by extension, some of the cognitive challenges associated with Turner syndrome.
Collapse
Affiliation(s)
- Reid Blanchett
- Genetics and Genome Sciences, Michigan State University, Biomedical & Physical Sciences, Room 2165, East Lansing, MI 48824, United States
- Department of Epigenetics, Van Andel Research Institute, 33 Bostwick Ave NE, Grand Rapids, MI 49503, United States
| | - Haitao Chen
- Biomedical Imaging Research Institute, Department of Biomedical Sciences and Imaging, 8700 Beverly Blvd, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Roza M Vlasova
- Department of Psychiatry, 333 S. Columbia Street, Suite 304 MacNider Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, United States
| | - Emil Cornea
- Department of Psychiatry, 333 S. Columbia Street, Suite 304 MacNider Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, United States
| | - Maria Maza
- Department of Psychology and Neuroscience, Campus Box #3270, 235 E. Cameron Avenue, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - Marsha Davenport
- Department of Pediatrics, 333 South Columbia Street, Suite 260 MacNider Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - Debra Reinhartsen
- Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, 101 Renee Lynn Ct, Carrboro, NC 27510, United States
| | - Margaret DeRamus
- Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, 101 Renee Lynn Ct, Carrboro, NC 27510, United States
| | - Rebecca Edmondson Pretzel
- Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, 101 Renee Lynn Ct, Carrboro, NC 27510, United States
| | - John H Gilmore
- Department of Psychiatry, 333 S. Columbia Street, Suite 304 MacNider Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, United States
| | - Stephen R Hooper
- Department of Psychiatry, 333 S. Columbia Street, Suite 304 MacNider Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, United States
- Department of Health Sciences, Bondurant Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - Martin A Styner
- Department of Psychiatry, 333 S. Columbia Street, Suite 304 MacNider Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, United States
- Department of Computer Science, Campus Box 3175, Brooks Computer Science Building, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - Wei Gao
- Biomedical Imaging Research Institute, Department of Biomedical Sciences and Imaging, 8700 Beverly Blvd, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
| | - Rebecca C Knickmeyer
- Department of Pediatrics and Human Development, Life Sciences Bldg. 1355 Bogue, #B240B, Michigan State University, East Lansing, MI 48824, United States
- Institute for Quantitative Health Sciences and Engineering, Room 2114, 775 Woodlot Dr., East Lansing, MI 48824, United States
| |
Collapse
|
|
3
|
Peranzoni F, De Castro R, Merlini E, Nguyen YL. 46 XX Ovotesticular Disorder of Sex Development with Gonadotropin-Releasing Hormone Receptor, Autosomal Recessive Heterozygous Missense Mutation and Autosomal Dominant Heterozygous Missense Mutation of the PROKR2 Gene: A Case Report. Glob Med Genet 2024; 11:220-224. [PMID: 38988852 PMCID: PMC11233268 DOI: 10.1055/s-0044-1788060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/12/2024] Open
Abstract
True hermaphroditism is a disorder of sex development (DSD), accounting for less than 5% of all DSD cases, defined by the simultaneous presence of testicular tissue and ovarian tissue in the same individual. In the reported case, the patient presented two genetic mutations involved in the pathogenic pathway of the DSD condition associated with the clinical features of Kallmann syndrome (KS), a developmental disease that associates hypogonadotropic hypogonadism (HH), due to gonadotropin-releasing hormone deficiency, and anosmia, related to the absence or hypoplasia of the olfactory bulbs. Given the variable degree of hyposmia in KS, the distinction between KS and normosmic idiopathic HH is currently unclear, especially as HH patients do not always undergo detailed olfactory testing. This syndrome is very rare, with an estimated prevalence of 1:80,000 in males and 1:40,000 in females. This is the only case report concerning a patient with 46 XX true hermaphroditism affected by HH and digenic inheritance of Kallmann syndrome.
Collapse
Affiliation(s)
- Francesca Peranzoni
- Department of Pediatric Surgery, Lausanne University Hospital, Lausanne, Switzerland
| | | | - Emilio Merlini
- Department of Pediatric Surgery, Hospital of Alexandria, Italy
| | - Yen Le Nguyen
- Department of Pediatric Urology, Vietnam National Hospital of Pediatric 2, Ho Chi Minh City, Vietnam
| |
Collapse
|
|
4
|
Rohayem J, Alexander EC, Heger S, Nordenström A, Howard SR. Mini-Puberty, Physiological and Disordered: Consequences, and Potential for Therapeutic Replacement. Endocr Rev 2024; 45:460-492. [PMID: 38436980 PMCID: PMC11244267 DOI: 10.1210/endrev/bnae003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Indexed: 03/05/2024]
Abstract
There are 3 physiological waves of central hypothalamic-pituitary-gonadal (HPG) axis activity over the lifetime. The first occurs during fetal life, the second-termed "mini-puberty"-in the first months after birth, and the third at puberty. After adolescence, the axis remains active all through adulthood. Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by a deficiency in hypothalamic gonadotropin-releasing hormone (GnRH) secretion or action. In cases of severe CHH, all 3 waves of GnRH pulsatility are absent. The absence of fetal HPG axis activation manifests in around 50% of male newborns with micropenis and/or undescended testes (cryptorchidism). In these boys, the lack of the mini-puberty phase accentuates testicular immaturity. This is characterized by a low number of Sertoli cells, which are important for future reproductive capacity. Thus, absent mini-puberty will have detrimental effects on later fertility in these males. The diagnosis of CHH is often missed in infants, and even if recognized, there is no consensus on optimal therapeutic management. Here we review physiological mini-puberty and consequences of central HPG axis disorders; provide a diagnostic approach to allow for early identification of these conditions; and review current treatment options for replacement of mini-puberty in male infants with CHH. There is evidence from small case series that replacement with gonadotropins to mimic "mini-puberty" in males could have beneficial outcomes not only regarding testis descent, but also normalization of testis and penile sizes. Moreover, such therapeutic replacement regimens in disordered mini-puberty could address both reproductive and nonreproductive implications.
Collapse
Affiliation(s)
- Julia Rohayem
- Department of Pediatric Endocrinology and Diabetology, Children's Hospital of Eastern Switzerland, 9006 St. Gallen, Switzerland
- University of Muenster, 48149 Muenster, Germany
| | - Emma C Alexander
- Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK
| | - Sabine Heger
- Department of Pediatric Endocrinology, Children's Hospital Auf der Bult, 30173 Hannover, Germany
| | - Anna Nordenström
- Pediatric Endocrinology, Karolinska Institutet, Astrid Lindgren Children's Hospital, Karolinska University Hospital, 17176 Stockholm, Sweden
| | - Sasha R Howard
- Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK
- Department of Paediatric Endocrinology, Royal London Children's Hospital, Barts Health NHS Trust, London E1 1FR, UK
| |
Collapse
|
|
5
|
Jiang K, Jorgensen JS. Fetal Leydig cells: What we know and what we don't. Mol Reprod Dev 2024; 91:e23739. [PMID: 38480999 PMCID: PMC11135463 DOI: 10.1002/mrd.23739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 02/12/2024] [Accepted: 02/24/2024] [Indexed: 05/24/2024]
Abstract
During male fetal development, testosterone plays an essential role in the differentiation and maturation of the male reproductive system. Deficient fetal testosterone production can result in variations of sex differentiation that may cause infertility and even increased tumor incidence later in life. Fetal Leydig cells in the fetal testis are the major androgen source in mammals. Although fetal and adult Leydig cells are similar in their functions, they are two distinct cell types, and therefore, the knowledge of adult Leydig cells cannot be directly applied to understanding fetal Leydig cells. This review summarizes our current knowledge of fetal Leydig cells regarding their cell biology, developmental biology, and androgen production regulation in rodents and human. Fetal Leydig cells are present in basement membrane-enclosed clusters in between testis cords. They originate from the mesonephros mesenchyme and the coelomic epithelium and start to differentiate upon receiving a Desert Hedgehog signal from Sertoli cells or being released from a NOTCH signal from endothelial cells. Mature fetal Leydig cells produce androgens. Human fetal Leydig cell steroidogenesis is LHCGR (Luteinizing Hormone Chronic Gonadotropin Receptor) dependent, while rodents are not, although other Gαs -protein coupled receptors might be involved in rodent steroidogenesis regulation. Fetal steroidogenesis ceases after sex differentiation is completed, and some fetal Leydig cells dedifferentiate to serve as stem cells for adult testicular cell types. Significant gaps are acknowledged: (1) Why are adult and fetal Leydig cells different? (2) What are bona fide progenitor and fetal Leydig cell markers? (3) Which signaling pathways and transcription factors regulate fetal Leydig cell steroidogenesis? It is critical to discover answers to these questions so that we can understand vulnerable targets in fetal Leydig cells and the mechanisms for androgen production that when disrupted, leads to variations in sex differentiation that range from subtle to complete sex reversal.
Collapse
Affiliation(s)
- Keer Jiang
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
- Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Joan S. Jorgensen
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
| |
Collapse
|
|
6
|
Adibi JJ, Zhao Y, Koistinen H, Mitchell RT, Barrett ES, Miller R, O'Connor TG, Xun X, Liang HW, Birru R, Smith M, Moog NK. Molecular pathways in placental-fetal development and disruption. Mol Cell Endocrinol 2024; 581:112075. [PMID: 37852527 PMCID: PMC10958409 DOI: 10.1016/j.mce.2023.112075] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/11/2023] [Accepted: 09/24/2023] [Indexed: 10/20/2023]
Abstract
The first trimester of pregnancy ranks high in priority when minimizing harmful exposures, given the wide-ranging types of organogenesis occurring between 4- and 12-weeks' gestation. One way to quantify potential harm to the fetus in the first trimester is to measure a corollary effect on the placenta. Placental biomarkers are widely present in maternal circulation, cord blood, and placental tissue biopsied at birth or at the time of pregnancy termination. Here we evaluate ten diverse pathways involving molecules expressed in the first trimester human placenta based on their relevance to normal fetal development and to the hypothesis of placental-fetal endocrine disruption (perturbation in development that results in abnormal endocrine function in the offspring), namely: human chorionic gonadotropin (hCG), thyroid hormone regulation, peroxisome proliferator activated receptor protein gamma (PPARγ), leptin, transforming growth factor beta, epiregulin, growth differentiation factor 15, small nucleolar RNAs, serotonin, and vitamin D. Some of these are well-established as biomarkers of placental-fetal endocrine disruption, while others are not well studied and were selected based on discovery analyses of the placental transcriptome. A literature search on these biomarkers summarizes evidence of placenta-specific production and regulation of each biomarker, and their role in fetal reproductive tract, brain, and other specific domains of fetal development. In this review, we extend the theory of fetal programming to placental-fetal programming.
Collapse
Affiliation(s)
- Jennifer J Adibi
- Department of Epidemiology, University of Pittsburgh School of Public Health, USA; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Yaqi Zhao
- St. Jude's Research Hospital, Memphis, TN, USA
| | - Hannu Koistinen
- Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland
| | - Rod T Mitchell
- Department of Paediatric Endocrinology, Royal Hospital for Children and Young People, Edinburgh BioQuarter, Edinburgh, UK
| | - Emily S Barrett
- Environmental and Population Health Bio-Sciences, Rutgers University School of Public Health, Piscataway, NJ, USA
| | - Richard Miller
- Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY, USA
| | - Thomas G O'Connor
- Department of Psychiatry, University of Rochester Medical Center, Rochester, NY, USA
| | - Xiaoshuang Xun
- Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA
| | - Hai-Wei Liang
- Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA
| | - Rahel Birru
- Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA
| | - Megan Smith
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA
| | - Nora K Moog
- Department of Medical Psychology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| |
Collapse
|
|
7
|
Baines KJ, West RC. Sex differences in innate and adaptive immunity impact fetal, placental, and maternal health†. Biol Reprod 2023; 109:256-270. [PMID: 37418168 DOI: 10.1093/biolre/ioad072] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 06/29/2023] [Accepted: 06/30/2023] [Indexed: 07/08/2023] Open
Abstract
The differences between males and females begin shortly after birth, continue throughout prenatal development, and eventually extend into childhood and adult life. Male embryos and fetuses prioritize proliferation and growth, often at the expense of the fetoplacental energy reserves. This singular focus on growth over adaptability leaves male fetuses and neonates vulnerable to adverse outcomes during pregnancy and birth and can have lasting impacts throughout life. Beyond this prioritization of growth, male placentas and fetuses also respond to infection and inflammation differently than female counterparts. Pregnancies carrying female fetuses have a more regulatory immune response, whereas pregnancies carrying male fetuses have a stronger inflammatory response. These differences can be seen as early as the innate immune response with differences in cytokine and chemokine signaling. The sexual dimorphism in immunity then continues into the adaptive immune response with differences in T-cell biology and antibody production and transfer. As it appears that these sex-specific differences are amplified in pathologic pregnancies, it stands to reason that differences in the placental, fetal, and maternal immune responses in pregnancy contribute to increased male perinatal morbidity and mortality. In this review, we will describe the genetic and hormonal contributions to the sexual dimorphism of fetal and placental immunity. We will also discuss current research efforts to describe the sex-specific differences of the maternal-fetal interface and how it impacts fetal and maternal health.
Collapse
Affiliation(s)
- Kelly J Baines
- Anatomy, Physiology, Pharmacology Department, Auburn University, Auburn, AL 36849, USA
| | - Rachel C West
- Anatomy, Physiology, Pharmacology Department, Auburn University, Auburn, AL 36849, USA
| |
Collapse
|
|
8
|
Alex AM, Ruvio T, Xia K, Jha SC, Girault JB, Wang L, Li G, Shen D, Cornea E, Styner MA, Gilmore JH, Knickmeyer RC. Influence of gonadal steroids on cortical surface area in infancy. Cereb Cortex 2022; 32:3206-3223. [PMID: 34952542 PMCID: PMC9340392 DOI: 10.1093/cercor/bhab410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 09/13/2021] [Accepted: 09/14/2021] [Indexed: 12/27/2022] Open
Abstract
Sex differences in the human brain emerge as early as mid-gestation and have been linked to sex hormones, particularly testosterone. Here, we analyzed the influence of markers of early sex hormone exposure (polygenic risk score (PRS) for testosterone, salivary testosterone, number of CAG repeats, digit ratios, and PRS for estradiol) on the growth pattern of cortical surface area in a longitudinal cohort of 722 infants. We found PRS for testosterone and right-hand digit ratio to be significantly associated with surface area, but only in females. PRS for testosterone at the most stringent P value threshold was positively associated with surface area development over time. Higher right-hand digit ratio, which is indicative of low prenatal testosterone levels, was negatively related to surface area in females. The current work suggests that variation in testosterone levels during both the prenatal and postnatal period may contribute to cortical surface area development in female infants.
Collapse
Affiliation(s)
- Ann Mary Alex
- Neuroengineering Division, Institute for Quantitative Health Sciences and Engineering, Michigan State University, East Lansing, MI 48824, USA
| | - Tom Ruvio
- Neuroengineering Division, Institute for Quantitative Health Sciences and Engineering, Michigan State University, East Lansing, MI 48824, USA
| | - Kai Xia
- Department of Psychiatry, University of North Carolina Chapel Hill, Chapel Hill, NC 27599, USA
| | - Shaili C Jha
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Jessica B Girault
- Department of Psychiatry, University of North Carolina Chapel Hill, Chapel Hill, NC 27599, USA
- Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Li Wang
- Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Gang Li
- Department of Radiology and Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Dinggang Shen
- School of Biomedical Engineering, ShanghaiTech University, Shanghai 201210, China
- Department of Artificial Intelligence, Korea University, Seoul 02841, Republic of Korea
| | - Emil Cornea
- Department of Psychiatry, University of North Carolina Chapel Hill, Chapel Hill, NC 27599, USA
| | - Martin A Styner
- Department of Psychiatry, University of North Carolina Chapel Hill, Chapel Hill, NC 27599, USA
- Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - John H Gilmore
- Department of Psychiatry, University of North Carolina Chapel Hill, Chapel Hill, NC 27599, USA
| | - Rebecca C Knickmeyer
- Neuroengineering Division, Institute for Quantitative Health Sciences and Engineering, Michigan State University, East Lansing, MI 48824, USA
- Department of Psychiatry, University of North Carolina Chapel Hill, Chapel Hill, NC 27599, USA
- Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI 48824, USA
- Center for Research in Autism, Intellectual, and Other Neurodevelopmental Disabilities, Michigan State University, East Lansing, MI 48824, USA
| |
Collapse
|
|
9
|
Pletcher A, Shibata M. Prostate organogenesis. Development 2022; 149:275758. [DOI: 10.1242/dev.200394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
ABSTRACT
Prostate organogenesis begins during embryonic development and continues through puberty when the prostate becomes an important exocrine gland of the male reproductive system. The specification and growth of the prostate is regulated by androgens and is largely a result of cell-cell communication between the epithelium and mesenchyme. The fields of developmental and cancer biology have long been interested in prostate organogenesis because of its relevance for understanding prostate diseases, and research has expanded in recent years with the advent of novel technologies, including genetic-lineage tracing, single-cell RNA sequencing and organoid culture methods, that have provided important insights into androgen regulation, epithelial cell origins and cellular heterogeneity. We discuss these findings, putting them into context with what is currently known about prostate organogenesis.
Collapse
Affiliation(s)
- Andrew Pletcher
- The George Washington University School of Medicine and Health Sciences 1 Department of Anatomy and Cell Biology , , Washington, DC 20052, USA
- The George Washington University Cancer Center, The George Washington University School of Medicine and Health Sciences 2 , Washington, DC 20052, USA
| | - Maho Shibata
- The George Washington University School of Medicine and Health Sciences 1 Department of Anatomy and Cell Biology , , Washington, DC 20052, USA
- The George Washington University Cancer Center, The George Washington University School of Medicine and Health Sciences 2 , Washington, DC 20052, USA
| |
Collapse
|
|
10
|
Planinić A, Marić T, Bojanac AK, Ježek D. Reinke crystals: Hallmarks of adult Leydig cells in humans. Andrology 2022; 10:1107-1120. [DOI: 10.1111/andr.13201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 04/26/2022] [Accepted: 05/23/2022] [Indexed: 11/30/2022]
Affiliation(s)
- Ana Planinić
- Department of Histology and Embryology University of Zagreb School of Medicine
- Scientific Centre of Excellence for Reproductive and Regenerative Medicine University of Zagreb School of Medicine
| | - Tihana Marić
- Scientific Centre of Excellence for Reproductive and Regenerative Medicine University of Zagreb School of Medicine
- Department of Medical Biology University of Zagreb School of Medicine
| | - Ana Katušić Bojanac
- Scientific Centre of Excellence for Reproductive and Regenerative Medicine University of Zagreb School of Medicine
- Department of Medical Biology University of Zagreb School of Medicine
| | - Davor Ježek
- Department of Histology and Embryology University of Zagreb School of Medicine
- Scientific Centre of Excellence for Reproductive and Regenerative Medicine University of Zagreb School of Medicine
| |
Collapse
|
|
11
|
The Roles of Luteinizing Hormone, Follicle-Stimulating Hormone and Testosterone in Spermatogenesis and Folliculogenesis Revisited. Int J Mol Sci 2021; 22:ijms222312735. [PMID: 34884539 PMCID: PMC8658012 DOI: 10.3390/ijms222312735] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/11/2021] [Accepted: 11/12/2021] [Indexed: 12/17/2022] Open
Abstract
Spermatogenesis and folliculogenesis involve cell–cell interactions and gene expression orchestrated by luteinizing hormone (LH) and follicle-stimulating hormone (FSH). FSH regulates the proliferation and maturation of germ cells independently and in combination with LH. In humans, the requirement for high intratesticular testosterone (T) concentration in spermatogenesis remains both a dogma and an enigma, as it greatly exceeds the requirement for androgen receptor (AR) activation. Several data have challenged this dogma. Here we report our findings on a man with mutant LH beta subunit (LHβ) that markedly reduced T production to 1–2% of normal., but despite this minimal LH stimulation, T production by scarce mature Leydig cells was sufficient to initiate and maintain complete spermatogenesis. Also, in the LH receptor (LHR) knockout (LuRKO) mice, low-dose T supplementation was able to maintain spermatogenesis. In addition, in antiandrogen-treated LuRKO mice, devoid of T action, the transgenic expression of a constitutively activating follicle stimulating hormone receptor (FSHR) mutant was able to rescue spermatogenesis and fertility. Based on rodent models, it is believed that gonadotropin-dependent follicular growth begins at the antral stage, but models of FSHR inactivation in women contradict this claim. The complete loss of FSHR function results in the complete early blockage of folliculogenesis at the primary stage, with a high density of follicles of the prepubertal type. These results should prompt the reassessment of the role of gonadotropins in spermatogenesis, folliculogenesis and therapeutic applications in human hypogonadism and infertility.
Collapse
|
|
12
|
Connan-Perrot S, Léger T, Lelandais P, Desdoits-Lethimonier C, David A, Fowler PA, Mazaud-Guittot S. Six Decades of Research on Human Fetal Gonadal Steroids. Int J Mol Sci 2021; 22:ijms22136681. [PMID: 34206462 PMCID: PMC8268622 DOI: 10.3390/ijms22136681] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 06/14/2021] [Accepted: 06/18/2021] [Indexed: 11/16/2022] Open
Abstract
Human fetal gonads acquire endocrine steroidogenic capabilities early during their differentiation. Genetic studies show that this endocrine function plays a central role in the sexually dimorphic development of the external genitalia during fetal development. When this endocrine function is dysregulated, congenital malformations and pathologies are the result. In this review, we explain how the current knowledge of steroidogenesis in human fetal gonads has benefited from both the technological advances in steroid measurements and the assembly of detailed knowledge of steroidogenesis machinery and its expression in human fetal gonads. We summarise how the conversion of radiolabelled steroid precursors, antibody-based assays, mass spectrometry, ultrastructural studies, and the in situ labelling of proteins and mRNA have all provided complementary information. In this review, our discussion goes beyond the debate on recommendations concerning the best choice between the different available technologies, and their degrees of reproducibility and sensitivity. The available technologies and techniques can be used for different purposes and, as long as all quality controls are rigorously employed, the question is how to maximise the generation of robust, reproducible data on steroid hormones and their crucial roles in human fetal development and subsequent functions.
Collapse
Affiliation(s)
- Stéphane Connan-Perrot
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, 35000 Rennes, France; (S.C.-P.); (P.L.); (C.D.-L.); (A.D.)
| | - Thibaut Léger
- Fougères Laboratory, French Agency for Food, Environmental and Occupational Health & Safety (ANSES), CEDEX, 35306 Fougères, France;
| | - Pauline Lelandais
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, 35000 Rennes, France; (S.C.-P.); (P.L.); (C.D.-L.); (A.D.)
| | - Christèle Desdoits-Lethimonier
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, 35000 Rennes, France; (S.C.-P.); (P.L.); (C.D.-L.); (A.D.)
| | - Arthur David
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, 35000 Rennes, France; (S.C.-P.); (P.L.); (C.D.-L.); (A.D.)
| | - Paul A. Fowler
- Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK;
| | - Séverine Mazaud-Guittot
- Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, 35000 Rennes, France; (S.C.-P.); (P.L.); (C.D.-L.); (A.D.)
- Correspondence: ; Tel.: +33-2-23-23-58-86
| |
Collapse
|
|
13
|
Hornig NC, Holterhus PM. Molecular basis of androgen insensitivity syndromes. Mol Cell Endocrinol 2021; 523:111146. [PMID: 33385475 DOI: 10.1016/j.mce.2020.111146] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 12/17/2020] [Accepted: 12/21/2020] [Indexed: 02/07/2023]
Abstract
Individuals with complete androgen insensitivity syndrome show a female genital phenotype despite 46, XY gonosomes and the presence of androgen producing testes. This clinical observation indicates the resistance of the body and its cells to androgens like testosterone. At the molecular level, this hormone resistance is caused by hemizygous loss of function mutations in the X-chromosomal androgen receptor (AR) gene. Partial forms of androgen insensitivity syndrome (PAIS) show different degrees of virilisation largely depending on the remaining activity of the AR. Nevertheless, the phenotypic outcome can be variable even in presence of the same mutation and in the same kindred indicating the presence of further influencing factors. Importantly, the majority of clinically diagnosed PAIS individuals do not bear a mutation in their AR gene. A recent assay using the androgen regulated gene apolipoprotein D as biomarker is able to detect androgen insensitivity on the cellular level even in absence of an AR gene mutation. Using this assay a class of AIS without an AR-gene mutation was defined as AIS type II and suggests that unidentified cofactors of the AR are responsible for the PAIS phenotype. Here we outline the scientific progress made from the first clinical definition of AIS over biochemical and molecular characterizations to the concept of AIS type II. This review is based on publications in the PubMed database of the National Institutes of Health using the search terms androgen insensitivity syndrome and androgen receptor mutation.
Collapse
Affiliation(s)
- Nadine C Hornig
- Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Kiel, Germany.
| | - Paul-Martin Holterhus
- Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Kiel, Germany
| |
Collapse
|
|
14
|
Mason KA, Schoelwer MJ, Rogol AD. Androgens During Infancy, Childhood, and Adolescence: Physiology and Use in Clinical Practice. Endocr Rev 2020; 41:5770947. [PMID: 32115641 DOI: 10.1210/endrev/bnaa003] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Accepted: 02/28/2020] [Indexed: 12/29/2022]
Abstract
We provide an in-depth review of the role of androgens in male maturation and development, from the fetal stage through adolescence into emerging adulthood, and discuss the treatment of disorders of androgen production throughout these time periods. Testosterone, the primary androgen produced by males, has both anabolic and androgenic effects. Androgen exposure induces virilization and anabolic body composition changes during fetal development, influences growth and virilization during infancy, and stimulates development of secondary sexual characteristics, growth acceleration, bone mass accrual, and alterations of body composition during puberty. Disorders of androgen production may be subdivided into hypo- or hypergonadotropic hypogonadism. Hypogonadotropic hypogonadism may be either congenital or acquired (resulting from cranial radiation, trauma, or less common causes). Hypergonadotropic hypogonadism occurs in males with Klinefelter syndrome and may occur in response to pelvic radiation, certain chemotherapeutic agents, and less common causes. These disorders all require testosterone replacement therapy during pubertal maturation and many require lifelong replacement. Androgen (or gonadotropin) therapy is clearly beneficial in those with persistent hypogonadism and self-limited delayed puberty and is now widely used in transgender male adolescents. With more widespread use and newer formulations approved for adults, data from long-term randomized placebo-controlled trials are needed to enable pediatricians to identify the optimal age of initiation, route of administration, and dosing frequency to address the unique needs of their patients.
Collapse
Affiliation(s)
- Kelly A Mason
- Department of Pediatrics, University of Virginia, Charlottesville, Virginia
| | | | - Alan D Rogol
- Department of Pediatrics, University of Virginia, Charlottesville, Virginia
| |
Collapse
|
|
15
|
A review of the intriguing interaction between testosterone and neurocognitive development in males with 47,XXY. Curr Opin Obstet Gynecol 2020; 32:140-146. [PMID: 32004174 DOI: 10.1097/gco.0000000000000612] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Although 47,XXY (Klinefelter syndrome) was first discovered more than 50 years ago, there have been limited comprehensive studies on this disorder. The present review explains the study of neurodevelopmental dysfunction and the impact of testosterone replacement at specific junctions in the life of males with 47,XXY. The intricate relationship between testosterone, neurodevelopment, health, and well being warrants an in-depth investigation in order to achieve optimal outcomes. RECENT FINDINGS Current literature suggests that the implementation of biological treatment has a positive impact on numerous areas of neurodevelopment. Further research is needed to determine ideal dosage, timing, and frequency of biological treatment for efficacy and safety of the child with 47,XXY. SUMMARY As noninvasive prenatal screening has detected increasing numbers of fetuses with 47,XXY, parents may benefit from both prenatal and postnatal counseling, including the latest innovative biological treatment, that may further optimize the child's outcome, especially when coupled with targeted early intervention services.
Collapse
|
|
16
|
Baskin L, Cao M, Sinclair A, Li Y, Overland M, Isaacson D, Cunha GR. Androgen and estrogen receptor expression in the developing human penis and clitoris. Differentiation 2020; 111:41-59. [PMID: 31655443 PMCID: PMC6926156 DOI: 10.1016/j.diff.2019.08.005] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 08/28/2019] [Accepted: 08/28/2019] [Indexed: 12/21/2022]
Abstract
To better understand how the human fetal penis and clitoris grows and remodels, we undertook an investigation to define active areas of cellular proliferation and programmed cell death spatially and temporally during development of human fetal external genitalia from the indifferent stage (8 weeks) to 18 weeks of gestation. Fifty normal human fetal penile and clitoral specimens were examined using macroscopic imaging, scanning electron microscopy and immunohistochemical localization for the cellular proliferation and apoptotic markers, Ki67 and Caspase-3. A number of hot spots of cellular proliferation characterized by Ki67 localization are present in the penis and clitoris especially early in development, most notably in the corporal body, glans, remodeling glanular urethra, the urethral plate, the roof of the urethral groove and the fully formed penile urethra. The 12-fold increase in penile length over 10 weeks of growth from 8 to 18 weeks of gestation based on Ki67 labelling appears to be driven by cellular proliferation in the corporal body and glans. Throughout all ages in both the developing penis and clitoris Ki67 labeling was consistently elevated in the ventral epidermis and ventral mesenchyme relative to the dorsal counterparts. This finding is consistent with the intense morphogenetic activity/remodeling in the ventral half of the genital tubercle in both sexes involving formation of the urethral/vestibular plates, canalization of the urethral/vestibular plates and fusion of the urethral folds to form the penile urethra. Areas of reduced or absent Ki67 staining include the urethral fold epithelium that fuses to form the penile tubular urethra. In contrast, the urethral fold mesenchyme is positive for Ki67. Apoptosis was rarely noted in the developing penis and clitoris; the only area of minimal Caspase-3 localization was in the epithelium of the ventral epithelial glanular channel remodeling.
Collapse
Affiliation(s)
- Laurence Baskin
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Division of Pediatric Urology, University of California San Francisco Benioff Children's Hospital, San Francisco, CA, USA.
| | - Mei Cao
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Division of Pediatric Urology, University of California San Francisco Benioff Children's Hospital, San Francisco, CA, USA
| | - Adriane Sinclair
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Division of Pediatric Urology, University of California San Francisco Benioff Children's Hospital, San Francisco, CA, USA
| | - Yi Li
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Division of Pediatric Urology, University of California San Francisco Benioff Children's Hospital, San Francisco, CA, USA
| | - Maya Overland
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Division of Pediatric Urology, University of California San Francisco Benioff Children's Hospital, San Francisco, CA, USA
| | - Dylan Isaacson
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Division of Pediatric Urology, University of California San Francisco Benioff Children's Hospital, San Francisco, CA, USA
| | - Gerald R Cunha
- Department of Urology, University of California, San Francisco, San Francisco, CA, USA; Division of Pediatric Urology, University of California San Francisco Benioff Children's Hospital, San Francisco, CA, USA
| |
Collapse
|
|
17
|
Cunha GR, Liu G, Sinclair A, Cao M, Glickman S, Cooke PS, Baskin L. Androgen-independent events in penile development in humans and animals. Differentiation 2020; 111:98-114. [DOI: 10.1016/j.diff.2019.07.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Revised: 07/11/2019] [Accepted: 07/12/2019] [Indexed: 01/28/2023]
|
|
18
|
Bhattacharya I, Sen Sharma S, Majumdar SS. Pubertal orchestration of hormones and testis in primates. Mol Reprod Dev 2019; 86:1505-1530. [DOI: 10.1002/mrd.23246] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Accepted: 07/15/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Indrashis Bhattacharya
- Department of Zoology & BiotechnologyHNB Garhwal University, Srinagar CampusSrinagar India
- Cellular Endocrinology LabNational Institute of ImmunologyNew Delhi India
| | - Souvik Sen Sharma
- Cellular Endocrinology LabNational Institute of ImmunologyNew Delhi India
| | - Subeer S. Majumdar
- Cellular Endocrinology LabNational Institute of ImmunologyNew Delhi India
- Gene and Protein Engineering LabNational Institute of Animal BiotechnologyHyderabad India
| |
Collapse
|
|
19
|
Savchuk I, Morvan ML, Antignac JP, Kurek M, Le Bizec B, Söder O, Svechnikov K. Ontogenesis of human fetal testicular steroidogenesis at early gestational age. Steroids 2019; 141:96-103. [PMID: 30529237 DOI: 10.1016/j.steroids.2018.12.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/28/2018] [Accepted: 12/02/2018] [Indexed: 11/29/2022]
Abstract
The onset of steroidogenesis in human fetal testes (HFT) during the first trimester is poorly investigated. One important unresolved question is the ontogeny of steroidogenic enzymes and formation of steroidogenic pathways in the HFT at early pregnancy. Our aim was to explore steroidogenesis, the expression of steroidogenic enzymes and their maturation in the HFT at gestational weeks (GW) 8-12. Steroids in the HFT were analyzed by gas chromatography/coupled to tandem mass spectrometry. The expression of steroidogenic enzymes in the HFT at GW8-12 was investigated by qPCR, automated Western blotting and immunohistochemistry. We demonstrated that the HFT at GW8-9 produced low level of testosterone via the Δ4 pathway and progesterone was the major steroid found in the testicular tissue. In contrast, more mature Leydig cells from the HFT at GW11-12 synthesized high levels of androgens via the Δ5 pathway. We also observed a significant upregulation of the expression of StAR, CYP11A1, CYP17A1 and its accessory proteins, P450 oxidoreductase (POR) and cytochrome b5 in the HFT at GW11-12 compared to GW8-9. Altogether, our data suggest that that human fetal Leydig cells differentiate rapidly at the end of the first trimester by acquiring capacity to express high levels of steroidogenic enzymes and switch from the Δ4 to the Δ5 pathways to synthesize high levels of androgens due to maturation of the CYP17-POR-b5 complex.
Collapse
Affiliation(s)
- I Savchuk
- Department of Women's and Children's Health, Pediatric Endocrinology Unit, Karolinska Institute & University Hospital, Stockholm, Sweden
| | - M L Morvan
- École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (Oniris), Laboratoire d'Étude des Résidus et Contaminants dans les aliments (LABERCA), UMR INRA 1329, Nantes, France
| | - J P Antignac
- École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (Oniris), Laboratoire d'Étude des Résidus et Contaminants dans les aliments (LABERCA), UMR INRA 1329, Nantes, France
| | - M Kurek
- Department of Women's and Children's Health, Pediatric Endocrinology Unit, NORDFERTIL Research Lab, Karolinska Institute & University Hospital, Stockholm, Sweden
| | - B Le Bizec
- École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (Oniris), Laboratoire d'Étude des Résidus et Contaminants dans les aliments (LABERCA), UMR INRA 1329, Nantes, France
| | - O Söder
- Department of Women's and Children's Health, Pediatric Endocrinology Unit, Karolinska Institute & University Hospital, Stockholm, Sweden
| | - K Svechnikov
- Department of Women's and Children's Health, Pediatric Endocrinology Unit, Karolinska Institute & University Hospital, Stockholm, Sweden.
| |
Collapse
|
|
20
|
Rotgers E, Jørgensen A, Yao HHC. At the Crossroads of Fate-Somatic Cell Lineage Specification in the Fetal Gonad. Endocr Rev 2018; 39:739-759. [PMID: 29771299 PMCID: PMC6173476 DOI: 10.1210/er.2018-00010] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 05/09/2018] [Indexed: 01/07/2023]
Abstract
The reproductive endocrine systems are vastly different between males and females. This sexual dimorphism of the endocrine milieu originates from sex-specific differentiation of the somatic cells in the gonads during fetal life. Most gonadal somatic cells arise from the adrenogonadal primordium. After separation of the adrenal and gonadal primordia, the gonadal somatic cells initiate sex-specific differentiation during gonadal sex determination with the specification of the supporting cell lineages: Sertoli cells in the testis vs granulosa cells in the ovary. The supporting cell lineages then facilitate the differentiation of the steroidogenic cell lineages, Leydig cells in the testis and theca cells in the ovary. Proper differentiation of these cell types defines the somatic cell environment that is essential for germ cell development, hormone production, and establishment of the reproductive tracts. Impairment of lineage specification and function of gonadal somatic cells can lead to disorders of sexual development (DSDs) in humans. Human DSDs and processes for gonadal development have been successfully modeled using genetically modified mouse models. In this review, we focus on the fate decision processes from the initial stage of formation of the adrenogonadal primordium in the embryo to the maintenance of the somatic cell identities in the gonads when they become fully differentiated in adulthood.
Collapse
Affiliation(s)
- Emmi Rotgers
- Reproductive Developmental Biology Group, National Institute of Environmental Health Sciences, Durham, North Carolina
| | - Anne Jørgensen
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.,International Research and Research Training Center in Endocrine Disruption of Male Reproduction and Child Health, Copenhagen, Denmark
| | - Humphrey Hung-Chang Yao
- Reproductive Developmental Biology Group, National Institute of Environmental Health Sciences, Durham, North Carolina
| |
Collapse
|
|
21
|
Lanciotti L, Cofini M, Leonardi A, Penta L, Esposito S. Up-To-Date Review About Minipuberty and Overview on Hypothalamic-Pituitary-Gonadal Axis Activation in Fetal and Neonatal Life. Front Endocrinol (Lausanne) 2018; 9:410. [PMID: 30093882 PMCID: PMC6070773 DOI: 10.3389/fendo.2018.00410] [Citation(s) in RCA: 127] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Accepted: 07/02/2018] [Indexed: 11/13/2022] Open
Abstract
Minipuberty consists of activation of the hypothalamic-pituitary-gonadal (HPG) axis during the neonatal period, resulting in high gonadotropin and sex steroid levels, and occurs mainly in the first 3-6 months of life in both sexes. The rise in the levels of these hormones allows for the maturation of the sexual organs. In boys, the peak testosterone level is associated with penile and testicular growth and the proliferation of gonadic cells. In girls, the oestradiol levels stimulate breast tissue, but exhibit considerable fluctuations that probably reflect the cycles of maturation and atrophy of the ovarian follicles. Minipuberty allows for the development of the genital organs and creates the basis for future fertility, but further studies are necessary to understand its exact role, especially in girls. Nevertheless, no scientific study has yet elucidated how the HPG axis turns itself off and remains dormant until puberty. Additional future studies may identify clinical implications of minipuberty in selected cohorts of patients, such as premature and small for gestational age infants. Finally, minipuberty provides a fundamental 6-month window of the possibility of making early diagnoses in patients with suspected sexual reproductive disorders to enable the prompt initiation of treatment rather than delaying treatment until pubertal failure.
Collapse
Affiliation(s)
| | | | | | | | - Susanna Esposito
- Pediatric Clinic, Department of Surgical and Biomedical Sciences, Università degli Studi di Perugia, Perugia, Italy
| |
Collapse
|
|
22
|
Bell MR. Comparing Postnatal Development of Gonadal Hormones and Associated Social Behaviors in Rats, Mice, and Humans. Endocrinology 2018; 159:2596-2613. [PMID: 29767714 PMCID: PMC6692888 DOI: 10.1210/en.2018-00220] [Citation(s) in RCA: 174] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 05/08/2018] [Indexed: 12/20/2022]
Abstract
Postnatal development includes dramatic changes in gonadal hormones and the many social behaviors they help regulate, both in rodents and humans. Parental care-seeking is the most salient social interaction in neonates and infants, play and prosocial behaviors are commonly studied in juveniles, and the development of aggression and sexual behavior begins in peripubertal stages but continues through late adolescence into adulthood. Although parental behaviors are shown after reproductive success in adulthood, alloparenting behaviors are actually high in juveniles as well. These behaviors are sensitive to both early-life organizational effects of gonadal hormones and later-life activational regulation. However, changes in circulating gonadal hormones and the display of the previous behaviors over development differ between rats, mice, and humans. These endpoints are of interest to endocrinologist, toxicologists, and neuroscientists because of their relevance to mental health disorders and their vulnerability to effects of endocrine-disrupting chemical exposure. As such, the goal of this mini-review is to succinctly describe and relate the postnatal development of gonadal hormones and social behaviors to each other, over time, and across animal models. Ideally, this will help identify appropriate animal models and age ranges for continued study of both normative development and in contexts of environmental disruption.
Collapse
Affiliation(s)
- Margaret R Bell
- Department of Biological Sciences, DePaul University, Chicago, Illinois
- Department of Health Sciences, DePaul University, Chicago, Illinois
| |
Collapse
|
|
23
|
Kuiri-Hänninen T, Dunkel L, Sankilampi U. Sexual dimorphism in postnatal gonadotrophin levels in infancy reflects diverse maturation of the ovarian and testicular hormone synthesis. Clin Endocrinol (Oxf) 2018; 89:85-92. [PMID: 29668033 DOI: 10.1111/cen.13716] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 03/27/2018] [Accepted: 04/06/2018] [Indexed: 12/26/2022]
Abstract
BACKGROUND The postnatal gonadotrophin surge is sexually dimorphic: FSH levels predominate in girls and LH levels in boys. However, in preterm (PT) girls, both gonadotrophin levels are higher than in PT boys. OBJECTIVE To evaluate how gonadal maturation contributes to the sex differences in FSH and LH. DESIGN Monthly follow-up of 58 full-term (FT, 29 boys) and 67 PT (33 boys) infants from 1 week (D7) to 6 months of age (M1-M6). Analyses were also carried out according to postmenstrual (PM) age in PT infants. METHODS Urinary LH, FSH, oestradiol (E2), testosterone (T) and serum inhibin B (InhB) levels. RESULTS High gonadotrophin levels in PT girls abruptly decreased (P < .001) by M2, corresponding to a PM age of 38-42 weeks, and LH levels fell below the levels found in boys. This decrease was parallel to a steep increase in E2 levels (P < .001), and, from M4 to M6, LH and E2 correlated positively in PT girls (P < .01). T levels in PT boys increased earlier than E2 levels in PT girls. In addition, InhB levels were high in PT boys already at D7, in contrast to low InhB in PT girls. InhB and FSH correlated negatively in the whole group (P < .001). CONCLUSIONS Ovarian hormone synthesis is immature and incapable of responding to gonadotrophin stimulus before 38-42 PM weeks in PT girls, which may explain their highly elevated FSH and LH levels. The higher InhB levels in boys compared to girls may explain sexual dimorphism in FSH levels.
Collapse
Affiliation(s)
| | - Leo Dunkel
- William Harvey Research Institute, Barts and the London, Queen Mary University of London, London, UK
| | - Ulla Sankilampi
- Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland
| |
Collapse
|
|
24
|
Harada N. Role of androgens in energy metabolism affecting on body composition, metabolic syndrome, type 2 diabetes, cardiovascular disease, and longevity: lessons from a meta-analysis and rodent studies. Biosci Biotechnol Biochem 2018; 82:1667-1682. [PMID: 29957125 DOI: 10.1080/09168451.2018.1490172] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Testosterone is a sex hormone produced by testicular Leydig cells in males. Blood testosterone concentrations increase at three time-periods in male life-fetal, neonatal (which can be separated into newborn and infant periods), and pubertal stages. After peaking in the early 20s, the blood bioactive testosterone level declines by 1-2% each year. It is increasingly apparent that a low testosterone level impairs general physical and mental health in men. Here, this review summarizes recent systematic reviews and meta-analyses of epidemiological studies in males (including cross-sectional, longitudinal, and androgen deprivation studies, and randomized controlled testosterone replacement trials) in relation to testosterone and obesity, body composition, metabolic syndrome, type 2 diabetes, cardiovascular disease, and longevity. Furthermore, underlying mechanisms are discussed using data from rodent studies involving castration or androgen receptor knockout. This review provides an update understanding of the role of testosterone in energy metabolism. Abbreviations AR: androgen receptor; CV: cardiovascular; FDA: US Food and Drug Administration; HFD: high-fat diet; KO: knockout; MetS: metabolic syndrome; RCT: randomized controlled trial; SHBG: sex hormone binding globulin; SRMA: systematic review and meta-analysis; TRT: testosterone replacement therapy; T2DM:type 2 diabetes mellitus.
Collapse
Affiliation(s)
- Naoki Harada
- a Division of Applied Life Sciences , Graduate School of Life and Environmental Sciences, Osaka Prefecture University , Sakai , Osaka , Japan
| |
Collapse
|
|
25
|
Tharmalingam MD, Jorgensen A, Mitchell RT. Experimental models of testicular development and function using human tissue and cells. Mol Cell Endocrinol 2018; 468:95-110. [PMID: 29309804 DOI: 10.1016/j.mce.2017.12.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 12/21/2017] [Accepted: 12/21/2017] [Indexed: 12/17/2022]
Abstract
The mammalian testis has two main roles, production of gametes for reproduction and synthesis of steroid- and peptide hormones for masculinization. These processes are tightly regulated and involve complex interactions between a number of germ and somatic cell-types that comprise a unique microenvironment known as the germ stem cell niche. In humans, failure of normal testicular development or function is associated with susceptibility to a variety of male reproductive disorders including disorders of sex development, infertility and testicular cancer. Whilst studies in rodent models have provided detailed insight into the signaling pathways and molecular mechanisms that regulate the testis, there are important species differences in testicular development, function and reproductive disorders that highlight the need for suitable experimental models utilising human testicular tissues or cells. In this review, we outline experimental approaches used to sustain cells and tissue from human testis at different developmental time-points and discuss relevant end-points. These include survival, proliferation and differentiation of cell lineages within the testis as well as autocrine, paracrine and endocrine function. We also highlight the utility of these experimental approaches for modelling the effects of environmental exposures on testicular development and function.
Collapse
Affiliation(s)
- Melissa D Tharmalingam
- MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK
| | - Anne Jorgensen
- Department of Growth and Reproduction, University Hospital of Copenhagen, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
| | - Rod T Mitchell
- MRC Centre for Reproductive Health, The University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, Scotland, UK; Department of Endocrinology and Diabetes, Edinburgh Royal Hospital for Sick Children, 9 Sciennes Road, Edinburgh, EH9 1LF, Scotland, UK.
| |
Collapse
|
|
26
|
Kilcoyne KR, Mitchell RT. Assessing the impact of in-utero exposures: potential effects of paracetamol on male reproductive development. Arch Dis Child 2017; 102:1169-1175. [PMID: 28588045 DOI: 10.1136/archdischild-2016-311374] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 05/03/2017] [Accepted: 05/03/2017] [Indexed: 12/21/2022]
Abstract
Human male reproductive disorders (cryptorchidism, hypospadias, testicular cancer and low sperm counts) are common and some may be increasing in incidence worldwide. These associated disorders can arise from subnormal testosterone production during fetal life. This has resulted in a focus on in-utero environmental influences that may result in reproductive effects on the offspring in later life. Over recent years, there has been a dramatic increase in the scientific literature describing associations between in-utero environmental exposures (eg, industrial chemicals and pharmaceuticals) and subsequent reproductive outcomes in male offspring. This includes studies investigating a potential role for in-utero analgesic exposure(s) on the fetal testis; however, providing definitive evidence of such effects presents numerous challenges. In this review, we describe an approach to assessing the potential clinical relevance of in-utero (and postnatal) environmental exposures on subsequent male reproductive function using exposure to the analgesic paracetamol as an example.
Collapse
Affiliation(s)
- Karen R Kilcoyne
- MRC Centre for Reproductive Health, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK
| | - Rod T Mitchell
- MRC Centre for Reproductive Health, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.,Department of Diabetes and Endocrinology, Royal Hospital for Sick Children, Edinburgh, UK
| |
Collapse
|
|
27
|
Wang S, Shi M, Zhu D, Mathews R, Zheng Z. External Genital Development, Urethra Formation, and Hypospadias Induction in Guinea Pig: A Double Zipper Model for Human Urethral Development. Urology 2017; 113:179-186. [PMID: 29155192 DOI: 10.1016/j.urology.2017.11.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 10/31/2017] [Accepted: 11/02/2017] [Indexed: 01/23/2023]
Abstract
OBJECTIVE To determine whether the guinea pig phallus would be an appropriate model of human penile development, we characterized the embryology and sexual differentiation of guinea pig external genitalia and attended to induce hypospadias in males and tubular urethra formation in females pharmacologically. MATERIALS AND METHODS The external genitalia of guinea pig were collected from genital swelling initiation to newborn stages, and scanning electronic microscopy and histology were performed to visualize the morphology and structure. Immunohistochemistry was used to determine the androgen receptor localization. Bicalutamide and methyltestosterone were given to pregnant dams to reveal the role and timing of androgen in guinea pig penile masculinization. RESULTS Canalization and dorsal-to-ventral movement of the urethral canal develops the urethral groove in both sexes, and then the males perform distal-opening-proximal-closing to form tubular urethra. More nuclear-localized androgen receptor is found in proximal genital tubercles of males than in females at (E) 29. Antiandrogen treatment at E26-E30 can cause hypospadias, and methyltestosterone administration at E27-E31 can induce tubular urethra formation in females. CONCLUSION Fetal development of the guinea pig phallus is homologous to that of humans. Although guinea pig has structures similar to mouse, the urethral groove and the tubular urethra formation are more similar to humans. Antiandrogen treatment causes hypospadias in males and additional androgen induces tubular urethra formation in females. Thus, guinea pig is an appropriate model for further study of cellular and molecular mechanisms involved in distal-opening-proximal-closing in tubular urethra formation and the evaluation of the pathophysiological processes of hypospadias.
Collapse
Affiliation(s)
- Shanshan Wang
- Department of Physiology, School of Medicine, Southern Illinois University Carbondale, Carbondale, IL
| | - Mingxin Shi
- Department of Physiology, School of Medicine, Southern Illinois University Carbondale, Carbondale, IL
| | - Dongqing Zhu
- Department of Physiology, School of Medicine, Southern Illinois University Carbondale, Carbondale, IL; Department of Pharmacy, Jiangsu Food & Pharmaceutical Science College, Huai'an, Jiangsu Province, China
| | - Ranjiv Mathews
- Department of Urology, School of Medicine, Southern Illinois University, Springfield, IL
| | - Zhengui Zheng
- Department of Physiology, School of Medicine, Southern Illinois University Carbondale, Carbondale, IL.
| |
Collapse
|
|
28
|
Picut CA, Ziejewski MK, Stanislaus D. Comparative Aspects of Pre- and Postnatal Development of the Male Reproductive System. Birth Defects Res 2017; 110:190-227. [PMID: 29063715 DOI: 10.1002/bdr2.1133] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 08/29/2017] [Accepted: 08/30/2017] [Indexed: 01/01/2023]
Abstract
This review describes pre- and postnatal development of the male reproductive system in humans and laboratory animals, and highlights species differences in the timing and control of hormonal and morphologic events. Major differences are that the fetal testis is dependent on gonadotropins in humans, but is independent of such in rats; humans have an extended postnatal quiescent period, whereas rats exhibit no quiescence; and events such as secretion by the prostate and seminal vesicles, testicular descent, and the appearance of spermatogonia are all prenatal events in humans, but are postnatal events in rats. Major differences in the timing of the developmental sequence between rats and humans include: gonocyte transformation period (rat: postnatal day 0-9; human: includes gestational week 22 to 9 months of age); masculinization programming window (rat: gestational day 15.5-17.5; human: gestational week 9-14); and mini-puberty (rat: 0-6 hr after birth; human: 3-6 months of age). Endocrine disruptors can cause unique lesions in the prenatal and early postnatal testis; therefore, it is important to consider the differences in the timing of the developmental sequence when designing preclinical studies as identification of windows of sensitivity for endocrine disruption or toxicants will aid in interpretation of results and provide clues to a mode of action. Birth Defects Research 110:190-227, 2018. © 2017 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Catherine A Picut
- Charles River Laboratories, Pathology Associates, Durham, North Carolina
| | - Mary K Ziejewski
- GlaxoSmithKline Research & Development, King of Prussia, Pennsylvania
| | - D Stanislaus
- GlaxoSmithKline Research & Development, King of Prussia, Pennsylvania
| |
Collapse
|
|
29
|
Obesity during pregnancy affects sex steroid concentrations depending on fetal gender. Int J Obes (Lond) 2017; 41:1636-1645. [PMID: 28676682 DOI: 10.1038/ijo.2017.159] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2017] [Revised: 06/08/2017] [Accepted: 06/25/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND/OBJECTIVE It is not clear whether maternal obesity along with fetal gender affect sex steroid metabolism during pregnancy. Therefore, we compared sex steroid concentrations and placental expression of steroidogenic enzymes between non-obese and obese pregnant women with non-pathological pregnancies, and investigated the influence of fetal gender on these parameters. METHODS In 35 normal weight (body mass index (BMI) 20-24.9 kg m-2) (controls) and 36 obese women (BMI 30-36 kg m-2) (obese), a fasting blood sample was obtained at first and at third trimester of gestation to measure progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate, androstenedione, testosterone and estradiol by liquid chromatography-tandem mass spectrometry and estrone by radioimmunoassay. In a subset of women, placental mRNA and protein expression of steroidogenic enzymes was measured by quantitative PCR and western blot, respectively. The comparisons were primarily made between controls and obese, and then separately according to fetal gender. RESULTS At first and third trimesters of gestation serum progesterone was lower whereas testosterone was higher in obese women (P<0.05, respectively). Upon analyzing according to fetal gender, lower progesterone levels were present in obese pregnant women with male fetuses at first trimester and with female fetuses at third trimester (P<0.05, respectively). Testosterone was higher in obese women with male fetuses compared to control women with male fetuses (P<0.05). The placental protein expression of P450scc was higher in obese women compared to controls (P<0.05). P450 aromatase was higher in obese women with female fetuses (P=0.009), whereas in obese women with male fetuses P450 aromatase was lower compared to control women (P=0.026). CONCLUSIONS Obesity in non-pathological pregnancies alters the maternal serum progesterone and testosterone concentrations depending on fetal gender. These changes can be attributed to gender-related placental adaptations, as the expression of P450 aromatase is different in placentas from females compared to males.
Collapse
|
|
30
|
Lottrup G, Belling K, Leffers H, Nielsen JE, Dalgaard MD, Juul A, Skakkebæk NE, Brunak S, Rajpert-De Meyts E. Comparison of global gene expression profiles of microdissected human foetal Leydig cells with their normal and hyperplastic adult equivalents. Mol Hum Reprod 2017; 23:339-354. [DOI: 10.1093/molehr/gax012] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 03/07/2017] [Indexed: 01/05/2023] Open
Affiliation(s)
- Grete Lottrup
- Department of Growth and Reproduction, Copenhagen University Hospital(Rigshospitalet), International Center for Research and Training in Endocrine Disruption of Male Reproduction & Child Health (EDMaRC), 9 Blegdamsvej, DK-2100 Copenhagen, Denmark
| | - Kirstine Belling
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Henrik Leffers
- Department of Growth and Reproduction, Copenhagen University Hospital(Rigshospitalet), International Center for Research and Training in Endocrine Disruption of Male Reproduction & Child Health (EDMaRC), 9 Blegdamsvej, DK-2100 Copenhagen, Denmark
| | - John E. Nielsen
- Department of Growth and Reproduction, Copenhagen University Hospital(Rigshospitalet), International Center for Research and Training in Endocrine Disruption of Male Reproduction & Child Health (EDMaRC), 9 Blegdamsvej, DK-2100 Copenhagen, Denmark
| | - Marlene D. Dalgaard
- Department of Growth and Reproduction, Copenhagen University Hospital(Rigshospitalet), International Center for Research and Training in Endocrine Disruption of Male Reproduction & Child Health (EDMaRC), 9 Blegdamsvej, DK-2100 Copenhagen, Denmark
- Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark (DTU), DK-2800 Lyngby, Denmark
- DTU Multi-Assay Core (DMAC), Department of Biotechnology and Biomedicine, DTU Bioengineering, Technical University of Denmark, DK-2800 Lyngby, Denmark
| | - Anders Juul
- Department of Growth and Reproduction, Copenhagen University Hospital(Rigshospitalet), International Center for Research and Training in Endocrine Disruption of Male Reproduction & Child Health (EDMaRC), 9 Blegdamsvej, DK-2100 Copenhagen, Denmark
| | - Niels E. Skakkebæk
- Department of Growth and Reproduction, Copenhagen University Hospital(Rigshospitalet), International Center for Research and Training in Endocrine Disruption of Male Reproduction & Child Health (EDMaRC), 9 Blegdamsvej, DK-2100 Copenhagen, Denmark
| | - Søren Brunak
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark (DTU), DK-2800 Lyngby, Denmark
| | - Ewa Rajpert-De Meyts
- Department of Growth and Reproduction, Copenhagen University Hospital(Rigshospitalet), International Center for Research and Training in Endocrine Disruption of Male Reproduction & Child Health (EDMaRC), 9 Blegdamsvej, DK-2100 Copenhagen, Denmark
| |
Collapse
|
|
31
|
Peak TC, Haney NM, Wang W, DeLay KJ, Hellstrom WJ. Stem cell therapy for the treatment of Leydig cell dysfunction in primary hypogonadism. World J Stem Cells 2016; 8:306-315. [PMID: 27822338 PMCID: PMC5080638 DOI: 10.4252/wjsc.v8.i10.306] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 07/07/2016] [Accepted: 08/29/2016] [Indexed: 02/06/2023] Open
Abstract
The production of testosterone occurs within the Leydig cells of the testes. When production fails at this level from either congenital, acquired, or systemic disorders, the result is primary hypogonadism. While numerous testosterone formulations have been developed, none are yet fully capable of replicating the physiological patterns of testosterone secretion. Multiple stem cell therapies to restore androgenic function of the testes are under investigation. Leydig cells derived from bone marrow, adipose tissue, umbilical cord, and the testes have shown promise for future therapy for primary hypogonadism. In particular, the discovery and utilization of a group of progenitor stem cells within the testes, known as stem Leydig cells (SLCs), has led not only to a better understanding of testicular development, but of treatment as well. When combining this with an understanding of the mechanisms that lead to Leydig cell dysfunction, researchers and physicians will be able to develop stem cell therapies that target the specific step in the steroidogenic process that is deficient. The current preclinical studies highlight the complex nature of regenerating this steroidogenic process and the problems remain unresolved. In summary, there appears to be two current directions for stem cell therapy in male primary hypogonadism. The first method involves differentiating adult Leydig cells from stem cells of various origins from bone marrow, adipose, or embryonic sources. The second method involves isolating, identifying, and transplanting stem Leydig cells into testicular tissue. Theoretically, in-vivo re-activation of SLCs in men with primary hypogonadism due to age would be another alternative method to treat hypogonadism while eliminating the need for transplantation.
Collapse
|
|
32
|
Heikkinen T, Harila V, Ollikkala A, Alvesalo L. Primary tooth size asymmetry in twins and singletons. Orthod Craniofac Res 2016; 19:145-53. [PMID: 26898820 DOI: 10.1111/ocr.12122] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/23/2016] [Indexed: 12/01/2022]
Abstract
OBJECTIVES To explore asymmetry values of antimeric deciduous tooth crown dimensions in three types of twins: monozygotic (MZ), dizygotic same-sex (DZ) and opposite-sex (OS) vs. single-born controls. SETTING AND SAMPLE POPULATION Mesiodistal and labio-lingual crown dimensions of second deciduous molars and mesiodistal canine and first molar crown dimensions of 2159 children at 6-12 years of age were evaluated, originating from the US cross-sectional Collaborative Perinatal Study from the 1970s, including altogether MZ (n = 28), DZ same-sex (n = 33) and OS (n = 39) pairs. Single born (n = 1959) were used as controls. MATERIAL AND METHODS Dental casts were measured for comparison of variance relationships calculated from antimeric teeth, exhibiting fluctuating (FA), and directional (DA) asymmetry using anova. RESULTS Significant differences appeared in MZ and OS girls in DA of deciduous canines, which gain size in the first and second trimester, and deciduous second molars, which finally stop crown growth during the early post-natal period. Significantly, increased FA values appeared for lower deciduous canines and second molars, indicating greatest environmental stress in OS girls, MZ girls and DZ boys. Twin girls had more fluctuating and directional crown asymmetry than twin boys, but in some dimensions, the twins were more symmetric than controls. CONCLUSIONS Transmembrane hormonal influence between opposite-sex twins, and late gestational stress factors, caused by placental malfunction and/or monochorionicity, may be involved in asymmetric growth of antimers, during critical periods of crown size gain.
Collapse
Affiliation(s)
- T Heikkinen
- Oral Development and Orthodontics, Unit of Oral Health Sciences, University of Oulu, Oulu, Finland.,Medical Research Center, Oulu, Oulu, Finland.,Oulu University Hospital, Oulu, Finland
| | - V Harila
- Oral Development and Orthodontics, Unit of Oral Health Sciences, University of Oulu, Oulu, Finland.,Medical Research Center, Oulu, Oulu, Finland.,Oulu University Hospital, Oulu, Finland
| | - A Ollikkala
- Oral Development and Orthodontics, Unit of Oral Health Sciences, University of Oulu, Oulu, Finland.,Medical Research Center, Oulu, Oulu, Finland.,Oulu University Hospital, Oulu, Finland
| | - L Alvesalo
- Oral Development and Orthodontics, Unit of Oral Health Sciences, University of Oulu, Oulu, Finland.,Medical Research Center, Oulu, Oulu, Finland.,Oulu University Hospital, Oulu, Finland
| |
Collapse
|
|
33
|
Suzuki H, Suzuki K, Yamada G. Systematic analyses of murine masculinization processes based on genital sex differentiation parameters. Dev Growth Differ 2015; 57:639-47. [DOI: 10.1111/dgd.12247] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Revised: 10/08/2015] [Accepted: 10/09/2015] [Indexed: 11/28/2022]
Affiliation(s)
- Hiroko Suzuki
- Department of Developmental Genetics; Institute of Advanced Medicine; Wakayama Medical University; 811-1 Kimiidera Wakayama 641-8509 Japan
| | - Kentaro Suzuki
- Department of Developmental Genetics; Institute of Advanced Medicine; Wakayama Medical University; 811-1 Kimiidera Wakayama 641-8509 Japan
| | - Gen Yamada
- Department of Developmental Genetics; Institute of Advanced Medicine; Wakayama Medical University; 811-1 Kimiidera Wakayama 641-8509 Japan
| |
Collapse
|
|
34
|
Li X, Li H, Jia L, Li X, Rahman N. Oestrogen action and male fertility: experimental and clinical findings. Cell Mol Life Sci 2015; 72:3915-30. [PMID: 26160724 PMCID: PMC11113595 DOI: 10.1007/s00018-015-1981-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 06/05/2015] [Accepted: 06/29/2015] [Indexed: 12/24/2022]
Abstract
A proper balance between androgen and oestrogen is fundamental for normal male reproductive development and function in both animals and humans. This balance is governed by the cytochrome P450 aromatase, which is expressed also under spatio-temporal control. Oestrogen receptors ERα and/or ERβ, together with the membrane-associated G-protein-coupled functional ER (GPER), mediate the effects of oestrogen in the testis. Oestrogen action in male reproduction is more complex than previously predicted. The androgen/oestrogen balance and its regulation in the masculinisation programming window (MPW) during foetal life is the most critical period for the development of the male reproductive system. If this balance is impaired during the MPW, the male reproductive system may be negatively affected. Recent data from genetically modified mice and human infertile patients have shown that oestrogens may promote the engulfment of live Leydig cells by macrophages leading to male infertility. We also discuss recent data on environmental oestrogen exposure in men and rodents, where a rodent-human distinction is crucial and analyse some aspects of male fertility potentially related to impaired oestrogen/androgen balance.
Collapse
Affiliation(s)
- Xiangdong Li
- State Key Laboratory of the Agro-Biotechnology, Faculty of Biological Sciences, China Agricultural University, Beijing, China.
| | - Haiwen Li
- Department of Nutrition and Food Science, University of Maryland, College Park, MD, USA
| | - Lina Jia
- State Key Laboratory of the Agro-Biotechnology, Faculty of Biological Sciences, China Agricultural University, Beijing, China
| | - Xiru Li
- Department of General Surgery, The 301th Hospital of PLA, Beijing, China
| | - Nafis Rahman
- Department of Physiology, Institute F Biomedicine, University of Turku, Turku, Finland
| |
Collapse
|
|
35
|
Teerds KJ, Huhtaniemi IT. Morphological and functional maturation of Leydig cells: from rodent models to primates. Hum Reprod Update 2015; 21:310-28. [PMID: 25724971 DOI: 10.1093/humupd/dmv008] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2014] [Accepted: 01/15/2015] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Leydig cells (LC) are the sites of testicular androgen production. Development of LC occurs in the testes of most mammalian species as two distinct growth phases, i.e. as fetal and pubertal/adult populations. In primates there are indications of a third neonatal growth phase. LC androgen production begins in embryonic life and is crucial for the intrauterine masculinization of the male fetal genital tract and brain, and continues until birth after which it rapidly declines. A short post-natal phase of LC activity in primates (including human) termed 'mini-puberty' precedes the period of juvenile quiescence. The adult population of LC evolves, depending on species, in mid- to late-prepuberty upon reawakening of the hypothalamic-pituitary-testicular axis, and these cells are responsible for testicular androgen production in adult life, which continues with a slight gradual decline until senescence. This review is an updated comparative analysis of the functional and morphological maturation of LC in model species with special reference to rodents and primates. METHODS Pubmed, Scopus, Web of Science and Google Scholar databases were searched between December 2012 and October 2014. Studies published in languages other than English or German were excluded, as were data in abstract form only. Studies available on primates were primarily examined and compared with available data from specific animal models with emphasis on rodents. RESULTS Expression of different marker genes in rodents provides evidence that at least two distinct progenitor lineages give rise to the fetal LC (FLC) population, one arising from the coelomic epithelium and the other from specialized vascular-associated cells along the gonad-mesonephros border. There is general agreement that the formation and functioning of the FLC population in rodents is gonadotrophin-responsive but not gonadotrophin-dependent. In contrast, although there is in primates some controversy on the role of gonadotrophins in the formation of the FLC population, there is consensus about the essential role of gonadotrophins in testosterone production. Like the FLC population, adult Leydig cells (ALC) in rodents arise from stem cells, which have their origin in the fetal testis. In contrast, in primates the ALC population is thought to originate from FLC, which undergo several cycles of regression and redifferentiation before giving rise to the mature ALC population, as well as from differentiation of stem cells/precursor cells. Despite this difference in origin, both in primates and rodents the formation of the mature and functionally active ALC population is critically dependent on the pituitary gonadotrophin, LH. From studies on rodents considerable knowledge has emerged on factors that are involved besides LH in the regulation of this developmental process. Whether the same factors also play a role in the development of the mature primate LC population awaits further investigation. CONCLUSION Distinct populations of LC develop along the life span of males, including fetal, neonatal (primates) and ALC. Despite differences in the LC lineages of rodents and primates, the end product is a mature population of LC with the main function to provide androgens necessary for the maintenance of spermatogenesis and extra-gonadal androgen actions.
Collapse
Affiliation(s)
- Katja J Teerds
- Human and Animal Physiology, Wageningen University, De Elst 1, 6709 WD, Wageningen, The Netherlands
| | - Ilpo T Huhtaniemi
- Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, Du Cane Road, W12 0NN London, UK Department of Physiology, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland
| |
Collapse
|
|
36
|
Bertoldo MJ, Faure M, Dupont J, Froment P. Impact of metformin on reproductive tissues: an overview from gametogenesis to gestation. ANNALS OF TRANSLATIONAL MEDICINE 2014; 2:55. [PMID: 25333030 DOI: 10.3978/j.issn.2305-5839.2014.06.04] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Accepted: 05/21/2014] [Indexed: 12/29/2022]
Abstract
Metformin is an oral anti-hyperglycemic drug that acts as an insulin sensitizer in the treatment of diabetes mellitus type 2. It has also been widely used in the treatment of polycystic ovary syndrome (PCOS) and gestational diabetes. This drug has been shown to activate a protein kinase called 5' AMP-activated protein kinase or AMPK. AMPK is present in many tissues making metformin's effect multi factorial. However as metformin crosses the placenta, its use during pregnancy raises concerns regarding potential adverse effects on the mother and fetus. The majority of reports suggest no significant adverse effects or teratogenicity. However, disconcerting reports of male mouse offspring that were exposed to metformin in utero that present with a reduction in testis size, seminiferous tubule size and in Sertoli cell number suggest that we do not understand the full suite of effects of metformin. In addition, recent molecular evidence is suggesting an epigenetic effect of metformin which could explain some of the long-term effects reported. Nevertheless, the data are still insufficient to completely confirm or disprove negative effects of metformin. The aims of this review are to provide a summary of the safety of metformin in various aspects of sexual reproduction, the use of metformin by gestating mothers, and its possible side-effects on offspring from women who are administered metformin during pregnancy.
Collapse
Affiliation(s)
- Michael J Bertoldo
- Unité de Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique, Centre Val de Loire, UMR85, 37380 Nouzilly, France
| | - Melanie Faure
- Unité de Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique, Centre Val de Loire, UMR85, 37380 Nouzilly, France
| | - Joelle Dupont
- Unité de Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique, Centre Val de Loire, UMR85, 37380 Nouzilly, France
| | - Pascal Froment
- Unité de Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique, Centre Val de Loire, UMR85, 37380 Nouzilly, France
| |
Collapse
|
|
37
|
Habert R, Livera G, Rouiller-Fabre V. Man is not a big rat: concerns with traditional human risk assessment of phthalates based on their anti-androgenic effects observed in the rat foetus. Basic Clin Androl 2014; 24:14. [PMID: 25780587 PMCID: PMC4349750 DOI: 10.1186/2051-4190-24-14] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Accepted: 08/15/2014] [Indexed: 11/10/2022] Open
Abstract
Phthalates provide one of the most documented example evidencing how much we must be cautious when using the traditional paradigm based on extrapolation of experimental data from rodent studies for human health risk assessment of endocrine disruptors (EDs). Since foetal testis is known as one of the most sensitive targets of EDs, phthalate risk assessment is routinely based on the capacity of such compounds to decrease testosterone production by the testis or to impair masculinization in the rat during foetal life. In this paper, the well-established inhibiting effects of phthalates of the foetal Leydig cells function in the rat are briefly reviewed. Then, data obtained in humans and other species are carefully analysed. Already in January 2009, using the organotypic culture system named Fetal Testis Assay (FeTA) that we developed, we reported that phthalates might not affect testosterone production in human foetal testes. Several recent experimental studies using xenografts confirm the absence of detectable anti-androgenic effect of phthalates in the human foetal testes. Epidemiological studies led to contradictory results. Altogether, these findings suggest that phthalates effects on foetal Leydig cells are largely species-specific. Consequently, the phthalate threshold doses that disturb foetal steroidogenesis in rat testes and that are presently used to define the acceptable daily intake levels for human health protection must be questioned. This does not mean that phthalates are safe because these compounds have many deleterious effects upon germ cell development that may be common to the different studied species including human. More generally, the identification of common molecular, cellular or/and phenotypic targets in rat and human testes should precede the choice of the toxicological endpoint in rat to accurately assess the safety threshold of any ED in humans.
Collapse
Affiliation(s)
- René Habert
- Sorbonne Paris Cité, Laboratory of Development of the Gonads, Unit of Stem Cells and Radiation, University Paris Diderot, BP 6, 92265 Fontenay-aux-Roses, France ; CEA, DSV, iRCM, SCSR, LDG, 92265 Fontenay-aux-Roses, France ; INSERM, Unité 967, F-92265 Fontenay aux Roses, France ; Stem Cells and Radiation Unit, LDG / SCSR / iRCM / DSV, Centre CEA, BP6, F-92265 Fontenay aux Roses, France
| | - Gabriel Livera
- Sorbonne Paris Cité, Laboratory of Development of the Gonads, Unit of Stem Cells and Radiation, University Paris Diderot, BP 6, 92265 Fontenay-aux-Roses, France ; CEA, DSV, iRCM, SCSR, LDG, 92265 Fontenay-aux-Roses, France ; INSERM, Unité 967, F-92265 Fontenay aux Roses, France
| | - Virginie Rouiller-Fabre
- Sorbonne Paris Cité, Laboratory of Development of the Gonads, Unit of Stem Cells and Radiation, University Paris Diderot, BP 6, 92265 Fontenay-aux-Roses, France ; CEA, DSV, iRCM, SCSR, LDG, 92265 Fontenay-aux-Roses, France ; INSERM, Unité 967, F-92265 Fontenay aux Roses, France
| |
Collapse
|
|
38
|
O'Shaughnessy PJ, Fowler PA. Development of the human fetal testis. ANNALES D'ENDOCRINOLOGIE 2014; 75:48-53. [DOI: 10.1016/j.ando.2014.03.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Accepted: 03/25/2014] [Indexed: 10/25/2022]
|
|
39
|
Bay K, Anand-Ivell R. Human Testicular Insulin-Like Factor 3 and Endocrine Disrupters. VITAMINS & HORMONES 2014; 94:327-48. [DOI: 10.1016/b978-0-12-800095-3.00012-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
|
|
40
|
Heikkinen T, Harila V, Tapanainen JS, Alvesalo L. Masculinization of the eruption pattern of permanent mandibular canines in opposite sex twin girls. AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY 2013; 151:566-72. [PMID: 23754587 DOI: 10.1002/ajpa.22298] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Accepted: 04/24/2013] [Indexed: 11/06/2022]
Abstract
The aim of this study is to explore the effect of prenatal androgenization on the clinical eruption of permanent teeth expressing dimorphism and bimaturism. The eruption curves of permanent teeth (except third molars), including those that make up the canine complex (permanent canines, lower first premolars), are compared among opposite sex twins (OS twins) relative to single-born boys and girls. The comparisons are made with regard to three phases of eruption (pierced mucosa, half- erupted, and completely erupted) from a cross-sectional sample of dental casts, using Kaplan-Meier survival and Cox regression analyzes. The casts were collected from 2159 school children from the US Collaborative Perinatal Project, including 39 pairs of OS-twins, of which 12 pairs (30.8%) were Euro-Americans and 27 pairs (69.2%) were of African-American ancestry. The eruption patterns of the incisors, upper first molars, and lower canines were found to be significantly masculinized (delayed) among OS twin girls. The differences in most other teeth were either not significant, or the number of observations of active eruption phases were too few, such as in the upper first molars and incisors, to yield strong evidence and meaningful results. The masculinization of the tooth eruption pattern in OS twin girls is intriguing because of the lower canine responses during puberty, as well as canine primordial formation during early fetal androgenization of their co-twin during the 8th to 14th gestational weeks. The present results offer a challenge for future research exploring tooth eruption mechanisms, and may also highlight some cases of delayed or ectopic canines, which are biased toward females.
Collapse
Affiliation(s)
- Tuomo Heikkinen
- Oral Development and Orthodontics, Institute of Dentistry, University of Oulu, Oulu, Finland.
| | | | | | | |
Collapse
|
|
41
|
Tartarin P, Moison D, Guibert E, Dupont J, Habert R, Rouiller-fabre V, Frydman N, Pozzi S, Frydman R, Lecureuil C, Froment P. Metformin exposure affects human and mouse fetal testicular cells. Hum Reprod 2012; 27:3304-14. [DOI: 10.1093/humrep/des264] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
|
|
42
|
Järvelä IY, Žáčková T, Laitinen P, Ryynänen M, Tekay A. Effect of parity and fetal sex on placental and luteal hormones during early first trimester. Prenat Diagn 2012; 32:160-7. [DOI: 10.1002/pd.2921] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- Ilkka Y. Järvelä
- Departments of Obstetrics and Gynecology; Oulu University Hospital; Oulu; Finland
| | - Tamara Žáčková
- Institute for the Care of Mother and Child Department of IVF; Charles University; Prague; Czech Republic
| | | | - Markku Ryynänen
- Departments of Obstetrics and Gynecology; Oulu University Hospital; Oulu; Finland
| | - Aydin Tekay
- Departments of Obstetrics and Gynecology; Oulu University Hospital; Oulu; Finland
| |
Collapse
|
|
43
|
Abstract
Disorders of sex development often arise from anomalies in the molecular or cellular networks that guide the differentiation of the embryonic gonad into either a testis or an ovary, two functionally distinct organs. The activation of the Y-linked gene Sry (sex-determining region Y) and its downstream target Sox9 (Sry box-containing gene 9) triggers testis differentiation by stimulating the differentiation of Sertoli cells, which then direct testis morphogenesis. Once engaged, a genetic pathway promotes the testis development while actively suppressing genes involved in ovarian development. This review focuses on the events of testis determination and the struggle to maintain male fate in the face of antagonistic pressure from the underlying female programme.
Collapse
|
|
44
|
Bay K, Andersson AM. Human testicular insulin-like factor 3: in relation to development, reproductive hormones and andrological disorders. ACTA ACUST UNITED AC 2011; 34:97-109. [PMID: 20550598 DOI: 10.1111/j.1365-2605.2010.01074.x] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Knockout of the gene encoding insulin-like factor 3 (INSL3) results in cryptorchidism in mice due to disruption of the transabdominal phase of testicular descent. This finding was essential for understanding the complete course of testis descensus, and wound up years of speculations regarding the endocrine regulation of this process. INSL3 is, along with testosterone, a major secretory product of testicular Leydig cells. In addition to its crucial function in testicular descent, INSL3 is suggested to play a paracrine role in germ cell survival and an endocrine role in bone metabolism. INSL3 is produced in human prenatal and neonatal, and in adult Leydig cells to various extents, and is in a developmental context regulated like testosterone, with production during second trimester, an early postnatal peak and increasing secretion during puberty, resulting in high adult serum levels. INSL3 production is entirely dependent on the state of Leydig cell differentiation, and is stimulated by the long-term trophic effects mediated by luteinizing hormone (LH). Once differentiated, Leydig cells apparently express INSL3 in a constitutive manner, and the hormone is thereby insensitive to the acute, steroidogenic effects of LH, which for example is an important factor in the regulation of testosterone. Clinically, serum INSL3 levels can turn out to be a usable tool to monitor basal Leydig cell function in patients with various disorders affecting Leydig cell function. According to animal studies, foetal INSL3 production is, directly or indirectly, sensitive to oestrogenic or anti-androgenic compounds. This provides important insight into the mechanism by which maternal exposure to endocrine disrupters can result in cryptorchidism in the next generation. Conclusively, INSL3 is an interesting testicular hormone with potential clinical value as a marker for Leydig cell function. It should be considered on a par with testosterone in the evaluation of testicular function and the consequences of Leydig cell dysfunction.
Collapse
Affiliation(s)
- K Bay
- University Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark.
| | | |
Collapse
|
|
45
|
Abstract
Complete testicular descent is a sign of, and a prerequisite for, normal testicular function in adult life. The process of testis descent is dependent on gubernacular growth and reorganization, which is regulated by the Leydig cell hormones insulin-like peptide 3 (INSL3) and testosterone. Investigation of the role of INSL3 and its receptor, relaxin-family peptide receptor 2 (RXFP2), has contributed substantially to our understanding of the hormonal control of testicular descent. Cryptorchidism is a common congenital malformation, which is seen in 2-9% of newborn boys, and confers an increased risk of infertility and testicular cancer in adulthood. Although some cases of isolated cryptorchidism in humans can be ascribed to known genetic defects, such as mutations in INSL3 or RXFP2, the cause of cryptorchidism remains unknown in most patients. Several animal and human studies are currently underway to test the hypothesis that in utero factors, including environmental and maternal lifestyle factors, may be involved in the etiology of cryptorchidism. Overall, the etiology of isolated cryptorchidism seems to be complex and multifactorial, involving both genetic and nongenetic components.
Collapse
|
|
46
|
Abstract
The testes are essential endocrine regulators of fetal masculinization and male development and are, themselves, subject to hormonal regulation during gestation. This review focuses, primarily, on this latter control of testicular function. Data available suggest that, in most mammalian species, the testis goes through a period of independent function before the fetal hypothalamic–pituitary–gonadal axis develops at around 50% of gestation. This pituitary-independent phase coincides with the most critical period of fetal masculinization. Thereafter, the fetal testes appear to become pituitary hormone-dependent, concurrent with declining Leydig cell function, but increasing Sertoli cell numbers. The two orders of mammals most commonly used for these types of studies (rodents and primates) appear to represent special cases within this general hypothesis. In terms of testicular function, rodents are born ‘early’ before the pituitary-dependent phase of fetal development, while the primate testis is dependent upon placental gonadotropin released during the pituitary-independent phase of development.
Collapse
|
|
47
|
Roland AV, Nunemaker CS, Keller SR, Moenter SM. Prenatal androgen exposure programs metabolic dysfunction in female mice. J Endocrinol 2010; 207:213-23. [PMID: 20713501 PMCID: PMC3612271 DOI: 10.1677/joe-10-0217] [Citation(s) in RCA: 141] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Polycystic ovary syndrome (PCOS) is a common fertility disorder with metabolic sequelae. Our laboratory previously characterized reproductive phenotypes in a prenatally androgenized (PNA) mouse model for PCOS. PNA mice exhibited elevated testosterone and LH levels, irregular estrous cycles, and neuroendocrine abnormalities suggesting increased central drive to the reproductive system. In this study, we examined metabolic characteristics of female PNA mice. PNA mice exhibited increased fasting glucose and impaired glucose tolerance (IGT) that were independent of age and were not associated with changes in body composition or peripheral insulin sensitivity. IGT was associated with defects in pancreatic islet function leading to an impaired response to high glucose, consistent with impaired insulin secretion. Exposure of isolated pancreatic islets to androgen in vitro demonstrated an impaired response to glucose stimulation similar to that in PNA mice, suggesting androgens may have activational in addition to organizational effects on pancreatic islet function. PNA mice also exhibited increased size of visceral adipocytes, suggesting androgen-programed differences in adipocyte differentiation and/or function. These studies demonstrate that in addition to causing reproductive axis abnormalities, in utero androgen exposure can induce long-term metabolic alterations in female mice.
Collapse
Affiliation(s)
- Alison V. Roland
- Department of Medicine, University of Virginia, Charlottesville, VA 22908
| | - Craig S. Nunemaker
- Department of Medicine, University of Virginia, Charlottesville, VA 22908
| | - Susanna R. Keller
- Department of Medicine, University of Virginia, Charlottesville, VA 22908
- Department of Cell Biology, University of Virginia, Charlottesville, VA 22908
| | - Suzanne M. Moenter
- Department of Medicine, University of Virginia, Charlottesville, VA 22908
- Department of Cell Biology, University of Virginia, Charlottesville, VA 22908
| |
Collapse
|
|
48
|
Sajjad Y. Development of the genital ducts and external genitalia in the early human embryo. J Obstet Gynaecol Res 2010; 36:929-37. [DOI: 10.1111/j.1447-0756.2010.01272.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
|
|
49
|
Scott HM, Mason JI, Sharpe RM. Steroidogenesis in the fetal testis and its susceptibility to disruption by exogenous compounds. Endocr Rev 2009; 30:883-925. [PMID: 19887492 DOI: 10.1210/er.2009-0016] [Citation(s) in RCA: 244] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Masculinization depends on adequate production of testosterone by the fetal testis within a specific "masculinization programming window." Disorders resulting from subtle deficiencies in this process are common in humans, and environmental exposures/lifestyle could contribute causally because common therapeutic and environmental compounds can affect steroidogenesis. This evidence derives mainly from rodent studies, but because there are major species differences in regulation of steroidogenesis in the fetal testis, this may not always be a guide to potential effects in the human. In addition to direct study of the effects of compounds on steroidogenesis, information also derives from study of masculinization disorders that result from mutations in genes in pathways regulating steroidogenesis. This review addresses this issue by critically reviewing the comparative timing of production and regulation of steroidogenesis in the fetal testis of humans and of rodents and its susceptibility to disruption; where there is limited information for the fetus, evidence from effects on steroidogenesis in the adult testis is considered. There are a number of fundamental regulatory differences between the human and rodent fetal testis, most notably in the importance of paracrine vs. endocrine drives during masculinization such that inactivating LH receptor mutations block masculinization in humans but not in rodents. Other large differences involve the steroidogenic response to estrogens and GnRH analogs and possibly phthalates, whereas for other compounds there may be differences in sensitivity to disruption (ketoconazole). This comparison identifies steroidogenic targets that are either vulnerable (mitochondrial cholesterol transport, CYP11A, CYP17) or not (cholesterol uptake) to chemical interference.
Collapse
Affiliation(s)
- Hayley M Scott
- MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
| | | | | |
Collapse
|
|
50
|
Fowler PA, Bhattacharya S, Gromoll J, Monteiro A, O'Shaughnessy PJ. Maternal smoking and developmental changes in luteinizing hormone (LH) and the LH receptor in the fetal testis. J Clin Endocrinol Metab 2009; 94:4688-95. [PMID: 19837924 PMCID: PMC2848822 DOI: 10.1210/jc.2009-0994] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
CONTEXT The LH receptor (LHCGR) drives fetal testosterone secretion, which is vital for human masculinization. Maternal smoking is associated with defective masculinization, but the relationship between smoking, tropic hormones, testosterone, and functional LHCGR expression is poorly understood. OBJECTIVE This study aimed to investigate developmental changes in fetal gonadotropins, human chorionic gonadotropin (hCG), and expression of fetal testicular LHCGR isoforms and the effects of maternal cigarette smoking. DESIGN We conducted an observational study of the male fetus, comparing pregnancies in which the mothers did or did not smoke. SETTING The study was conducted at the Universities of Aberdeen and Glasgow. PATIENTS/PARTICIPANTS Testes and blood were collected from 54 morphologically normal human male fetuses of women undergoing elective termination of normal second-trimester pregnancies. MAIN OUTCOME MEASURES We measured circulating testosterone, hCG, LH, prolactin, FSH, and testicular LHCGR isoform expression. RESULTS Fetal testosterone and hCG, but not LH, significantly declined between 11 and 19 wk gestation with no significant change in testicular responsiveness. The proportion of nonfunctional LHCGR transcript in fetal testes was 2.3-fold lower than in adults. Fetal hCG was reduced 38% (P = 0.021) and the ratio of inactive vs. active LHCGR isoforms lowered by smoking. CONCLUSIONS Falling second-trimester fetal testosterone is probably due to declining maternal hCG because Leydig cell LH/hCG responsiveness remains constant. Although maternal cigarette smoking reduces fetal hCG, the ratio of inactive LHCGR isoforms is reduced and gonadotropin drive maintains testosterone production near control levels. The lower relative abundance of inactive isoforms compared with the adult testis reflects the importance of LHCGR.
Collapse
Affiliation(s)
- Paul A Fowler
- Division of Applied Medicine, Centre for Reproductive Endocrinology and Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom.
| | | | | | | | | |
Collapse
|