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Best Practice & Research. Clinical... Jan 2022Cryptorchidism, i.e., undescended testis, is one of the most common genital malformations in newborn male babies. The birth rate of cryptorchidism varies from 1.6 to 9.0... (Review)
Review
Cryptorchidism, i.e., undescended testis, is one of the most common genital malformations in newborn male babies. The birth rate of cryptorchidism varies from 1.6 to 9.0 %. Etiology of disrupted testicular descent is complex and predisposing causes include genetic, hormonal, environmental, lifestyle and maternal factors. Testicular descent occurs in two major steps and testicular hormones and normal function of hypothalamic-pituitary-testicular axis are important for normal descent. Several gene mutations are associated with syndromic cryptorchidism but they are rarely found in boys with isolated undescended testis. Testicular regression can also cause an empty scrotum. Normal male genital phenotype indicates that the boy has had functioning testis during development. Torsion of the testis can cause testicular regression but in many cases the reason for vanishing testis remains elusive. In this narrative review we discuss genetics of cryptorchidism and testicular regression.
Topics: Cryptorchidism; Female; Gonadal Dysgenesis, 46,XY; Humans; Male; Mutation; Testis
PubMed: 35193821
DOI: 10.1016/j.beem.2022.101619 -
Frontiers in Endocrinology 2022Turner syndrome (TS) is a chromosomal disorder affecting females characterized by short stature and gonadal dysgenesis. Untreated girls with TS reportedly are... (Review)
Review
Turner syndrome (TS) is a chromosomal disorder affecting females characterized by short stature and gonadal dysgenesis. Untreated girls with TS reportedly are approximately 20-cm shorter than normal girls within their respective populations. The growth patterns of girls with TS also differ from those of the general population. They are born a little smaller than the normal population possibly due to a mild developmental delay in the uterus. After birth, their growth velocity declines sharply until 2 years of age, then continues to decline gradually until the pubertal age of normal children and then drops drastically around the pubertal period of normal children because of the lack of a pubertal spurt. After puberty, their growth velocity increases a little because of the lack of epiphyseal closure. A secular trend in height growth has been observed in girls with TS so growth in excess of the secular trend should be used wherever available in evaluating the growth in these girls. Growth hormone (GH) has been used to accelerate growth and is known to increase adult height. Estrogen replacement treatment is also necessary for most girls with TS because of hypergonadotropic hypogonadism. Therefore, both GH therapy and estrogen replacement treatment are essential in girls with TS. An optimal treatment should be determined considering both GH treatment and age-appropriate induction of puberty. In this review, we discuss the growth in girls with TS, including overall growth, pubertal growth, the secular trend, growth-promoting treatment, and sex hormone replacement treatment.
Topics: Child; Female; Humans; Turner Syndrome; Human Growth Hormone; Growth Hormone; Puberty; Hormone Replacement Therapy
PubMed: 36714599
DOI: 10.3389/fendo.2022.1068128 -
The Journal of Clinical Investigation Nov 2015The oocyte is the sole source of the female genetic material that will be fertilized by sperm to form an embryo. Many extrinsic and intrinsic factors are critical for...
The oocyte is the sole source of the female genetic material that will be fertilized by sperm to form an embryo. Many extrinsic and intrinsic factors are critical for oocyte development and survival; however, these mediators are incompletely understood. In this issue of the JCI, Weinberg-Shukron et al. uncover a novel recessive missense mutation in the gene encoding nucleoporin-107 (NUP107) that results in abnormal ovarian development. Recapitulation of the human mutation in the Drosophila NUP107 ortholog resulted in poor follicular development and demonstrated an evolutionarily conserved and ovary-specific role of NUP107. While NUP107 is required for nuclear pore complex function in somatic cells of flies and women, this specific amino acid change appears only to be disruptive in the ovary. All together, these findings imply that missense mutations in other genes could be specifically disruptive of ovarian or testicular function, while leaving extragonadal function intact.
Topics: Animals; Aquaporins; Drosophila Proteins; Female; Gonadal Dysgenesis, 46,XX; Humans; Male; Mutation, Missense; Nuclear Pore Complex Proteins; Ovary
PubMed: 26485282
DOI: 10.1172/JCI84692 -
Sexual Development : Genetics,... 2022Recently, a series of recurrent missense variants in the RNA-helicase DHX37 have been reported associated with either 46,XY gonadal dysgenesis, 46,XY testicular... (Review)
Review
Recently, a series of recurrent missense variants in the RNA-helicase DHX37 have been reported associated with either 46,XY gonadal dysgenesis, 46,XY testicular regression syndrome (TRS), or anorchia. All affected children have non-syndromic forms of disorders/differences of sex development (DSD). These variants, which involve highly conserved amino acids within known functional domains of the protein, are predicted by in silico tools to have a deleterious effect on helicase function. DHX37 is required for ribosome biogenesis in eukaryotes, and how these variants cause DSD is unclear. The relationship between DHX37 and human congenital disorders is complex as compound heterozygous as well as de novo heterozygous missense variants in DHX37 are also associated with a complex congenital developmental syndrome (NEDBAVC, neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies; OMIM 618731), consisting of microcephaly, global developmental delay, seizures, facial dysmorphia, and kidney and cardiac anomalies. Here, we will give a brief overview of ribosome biogenesis and the role of DHX37 in this process. We will discuss variants in DHX37, their contribution to human disease in the general context of human ribosomopathies, and the possible disease mechanisms that may be involved.
Topics: Humans; Gonadal Dysgenesis, 46,XY; Heterozygote; Mutation, Missense; RNA Helicases
PubMed: 35835064
DOI: 10.1159/000522004 -
Sexual Development : Genetics,... 2022Pathogenic variants in the MAP3K1 gene are an important cause of 46,XY non-syndromic partial and complete gonadal dysgenesis, accounting for at least 4% of cases.... (Review)
Review
Pathogenic variants in the MAP3K1 gene are an important cause of 46,XY non-syndromic partial and complete gonadal dysgenesis, accounting for at least 4% of cases. Inheritance occurs in a sex-limited, autosomal dominant fashion with virtually complete penetrance in 46,XY individuals. 46,XX carriers appear to have normal fertility and no developmental abnormalities. Pathogenic variants occur almost exclusively within known domains of the MAP3K1 protein, facilitating annotation when identified. Where studied, these variants have been modeled to alter the local MAP3K1 folding and surface domains and have been shown to alter interactions with known binding partners. The net effect of these variants is to increase phosphorylation of downstream targets ERK1, ERK2, and p38, resulting in multiple gain-of-function effects interfering with testis determination and enabling ovarian determination.
Topics: Male; Humans; MAP Kinase Kinase Kinase 1; Gonadal Dysgenesis, 46,XY; Gonadal Dysgenesis; Heterozygote; Testis
PubMed: 35290982
DOI: 10.1159/000522428 -
Nihon Hinyokika Gakkai Zasshi. the... Aug 1994Male pseudohermaphroditism (MPH) is a complex variety of sexual differentiation disorders characterized by deficiency of masculinization of the internal and/or external... (Review)
Review
Male pseudohermaphroditism (MPH) is a complex variety of sexual differentiation disorders characterized by deficiency of masculinization of the internal and/or external genital organs in the presence of testicular development as the male gonad. This condition is caused by embryonic failure in the processes of male sexual development, which is a sequence of mechanisms originating from the genetic sex determination triggered by the SRY gene on the Y chromosome, followed by genital sex differentiation influenced by the fetal testis. Resulting phenotypical features of MPH vary from complete female to mostly normal but with some ambiguity in the maleness. Pubertal changes are also important factors related to etiology. Recent elucidation of detailed mechanisms of male differentiation and its derangements has been achieved in the era of molecular genetics. Classical classification of MPH, mainly based on anatomical and endocrinological findings obviously needs to subject to a complete revision. The newest version of MPH classification is reviewed and discussed in relation to etiological backgrounds of each type of the disorder. Main etiological factors are: failure of the SRY and its related genes involved in the testis determination; failure of anti-mülerian hormone (AMH) for normal involution of the female duct system; disordered production or function of androgen receptors essential for the fetal differentiation of the male genital organs; 5 alpha-reductase deficiency syndrome; defective responsiveness of the testis to gonadotropin due to Leydig cell agenesis; various types of enzyme defects involved in testicular androgen biosynthesis; fetal testicular dysgenesis syndromes occurring at various stages of embryogenesis; and other less clearly defined entities of MPH. Implications are that other types of sexual differentiation disorders than MPH, such as true hermaphroditism, gonadal dysgenesis and some other disorders that have been considered to be distinct entities, may have close linkage to MPH through dysgenetic process of gonadal development with subsequent degeneration and/or tumorigenesis. Molecular basis of these probably related disorders should be elucidated in the near future and some clues to preventive measures for these genetically determined malformations are awaited.
Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Androgens; Animals; Disorders of Sex Development; Gonadal Dysgenesis; Humans; Male; Receptors, Androgen; Sex Differentiation
PubMed: 7933752
DOI: 10.5980/jpnjurol1989.85.1189 -
Sexual Development : Genetics,... 2022Transcriptional regulators related to the invertebrate sexual regulators doublesex and mab-3 occur throughout metazoans and control sex in most animal groups. Seven of... (Review)
Review
Transcriptional regulators related to the invertebrate sexual regulators doublesex and mab-3 occur throughout metazoans and control sex in most animal groups. Seven of these DMRT genes are found in mammals, and mouse genetics has shown that one, Dmrt1, plays a crucial role in testis differentiation, both in germ cells and somatic cells. Deletions and, more recently, point mutations affecting human DMRT1 have demonstrated that its heterozygosity is associated with 46,XY complete gonadal dysgenesis. Most of our detailed knowledge of DMRT1 function in the testis, the focus of this review, derives from mouse studies, which have revealed that DMRT1 is essential for male somatic and germ cell differentiation and maintenance of male somatic cell fate after differentiation. Moreover, ectopic DMRT1 can reprogram differentiated female granulosa cells into male Sertoli-like cells. The ability of DMRT1 to control sexual cell fate likely derives from at least 3 properties. First, DMRT1 functionally collaborates with another key male sex regulator, SOX9, and possibly other proteins to maintain and reprogram sexual cell fate. Second, and related, DMRT1 appears to function as a pioneer transcription factor, binding "closed" inaccessible chromatin and promoting its opening to allow binding by other regulators including SOX9. Third, DMRT1 binds DNA by a highly unusual form of interaction and can bind with different stoichiometries.
Topics: Animals; Female; Humans; Male; Mice; Germ Cells; Gonadal Dysgenesis; Sex Differentiation; Testis; Transcription Factors
PubMed: 34515237
DOI: 10.1159/000518272 -
Frontiers in Endocrinology 2021Insulin-like factor 3 (INSL3) is produced in the testes and has been proposed as a circulating biomarker of Leydig cell capacity, but remains undescribed in 45,X/46,XY...
OBJECTIVE
Insulin-like factor 3 (INSL3) is produced in the testes and has been proposed as a circulating biomarker of Leydig cell capacity, but remains undescribed in 45,X/46,XY mosaicism. The aim was to examine serum concentrations and gonadal expression of INSL3 in 45,X/46,XY mosaicism.
METHODS
Retrospectively collected data from medical records, gonadal tissue samples, and prospectively analyzed serum samples from eighteen male patients with 45,X/46,XY mosaicism (one prepubertal, four testosterone-treated, 13 untreated) were included. Biochemical, clinical, and histological outcomes were evaluated according to serum INSL3 concentrations, quantified by LC-MS/MS methodology, and gonadal INSL3 immunohistochemical expression.
RESULTS
Serum INSL3 concentrations spanned from below to above the reference range. In untreated patients, the median serum INSL3 SD score was -0.80 (IQR: -1.65 to 0.55) and no significant difference was observed between INSL3 and testosterone. There was no clear association between serum INSL3 and External Genitalia Score at diagnosis, spontaneous puberty, or sperm concentration. INSL3 and CYP11A1 expression overlapped, except for less pronounced INSL3 expression in areas with severe Leydig cell hyperplasia. No other apparent links between INSL3 expression and histological outcomes were observed.
CONCLUSIONS
In this pilot study, serum INSL3 concentrations ranged and seemed independent of other reproductive hormones and clinical features in males with 45,X/46,XY mosaicism. Discordant expression of INSL3 and CYP11A1 may explain low INSL3 and normal testosterone concentrations in some patients. Further studies are needed to elucidate the divergence between serum INSL3 and testosterone and the potential clinical use of INSL3.
Topics: Adolescent; Adult; Child; Follow-Up Studies; Gonadal Dysgenesis, 46,XY; Humans; Insulin; Male; Middle Aged; Mosaicism; Pilot Projects; Prognosis; Prospective Studies; Proteins; Retrospective Studies; Young Adult
PubMed: 34447353
DOI: 10.3389/fendo.2021.709954 -
Science Advances Jan 2023During embryonic development, mutually antagonistic signaling cascades determine gonadal fate toward a testicular or ovarian identity. Errors in this process result in...
During embryonic development, mutually antagonistic signaling cascades determine gonadal fate toward a testicular or ovarian identity. Errors in this process result in disorders of sex development (DSDs), characterized by discordance between chromosomal, gonadal, and anatomical sex. The absence of an appropriate, accessible in vitro system is a major obstacle in understanding mechanisms of sex-determination/DSDs. Here, we describe protocols for differentiation of mouse and human pluripotent cells toward gonadal progenitors. Transcriptomic analysis reveals that the in vitro-derived murine gonadal cells are equivalent to embryonic day 11.5 in vivo progenitors. Using similar conditions, Sertoli-like cells derived from 46,XY human induced pluripotent stem cells (hiPSCs) exhibit sustained expression of testis-specific genes, secrete anti-Müllerian hormone, migrate, and form tubular structures. Cells derived from 46,XY DSD female hiPSCs, carrying an variant, show aberrant gene expression and absence of tubule formation. CRISPR-Cas9-mediated variant correction rescued the phenotype. This is a robust tool to understand mechanisms of sex determination and model DSDs.
Topics: Male; Animals; Mice; Humans; Female; Cellular Reprogramming; Induced Pluripotent Stem Cells; Gonads; Gonadal Dysgenesis, 46,XY
PubMed: 36598988
DOI: 10.1126/sciadv.abn9793 -
Veterinary Medicine and Science Mar 2023Abnormalities of the external genitals are an important issue in dog breeding because of the unfavourable qualities and characteristics of breeds, resulting in... (Review)
Review
Abnormalities of the external genitals are an important issue in dog breeding because of the unfavourable qualities and characteristics of breeds, resulting in consistent economic losses. Despite their significance, little scientific attention has been given to these problems. Although there are several reviews on cryptorchidism in dogs, none have described anorchia. Testicular agenesis is a rare reproductive disorder with a congenital origin. Moreover, no author has described the diagnostic procedure for making a definitive diagnosis of anorchia in dogs. It is important to have a well-structured diagnostic scheme to help practical veterinarians make a confirmatory diagnosis. This review article aims to provide an update on canine anorchia diagnosis based on the poor research studies published in recent years. We have also contributed to the pathogenesis of this disorder using human medicine studies. Finally, the review includes therapeutic hypotheses that can be expanded in future studies.
Topics: Male; Humans; Dogs; Animals; Cryptorchidism; Gonadal Dysgenesis, 46,XY; Dog Diseases
PubMed: 36597410
DOI: 10.1002/vms3.1033