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Nathalie Josso

Publications and source records attributed to Nathalie Josso.

10 recordsLinked to original sources
PubMed2006

Long-term surgical results and patient satisfaction with male pseudohermaphroditism or true hermaphroditism: a cohort of 63 patients.

PURPOSE: To improve treatment policy, we retrospectively evaluated the results of early corrective genital surgery in 63 sexually ambiguous patients 14 to 38 years old. MATERIALS AND METHODS: We analyzed all records classified under male pseudohermaphroditism and true hermaphroditism. Anatomical and functional results and data on self-reported satisfaction were recorded by the managing physician at the last routine followup visit. RESULTS: A total of 38 patients were raised female and 25 were raised male. Basal procedures for external genital reconstruction were initiated shortly after birth, when gender was assigned. Complementary surgical procedures were usually required later. In both sexes there was a significant negative correlation between the number of basal, but not complementary, procedures required and year of birth, due to the adoption of 1-stage procedures in the early 1980s. Most patients with gonadal dysgenesis were raised as females and menstruated under treatment but breast development was abnormal in 30%. Spontaneous puberty was observed in true hermaphrodites raised as either sex. In females with partial androgen insensitivity the main problem was shortness of the vagina. Amenorrhea and infertility often led to transient distress. In males results were poor due to intractable micropenis and minimal virilization. Results were good in 5alpha-reductase deficiency. CONCLUSIONS: Results of intersex surgery have clearly improved with time, and apart from a patient with 5alpha-reductase deficiency who underwent a successful sex change, no patient expressed dissatisfaction with sex of rearing. However, in the absence of an in-depth psychological survey, these optimistic conclusions are valid only in the settings of our study.

Adolescent↗
PubMed2006

Testicular anti-Müllerian hormone: history, genetics, regulation and clinical applications.

Anti-Müllerian hormone (AMH), also called MUllerian inhibiting substance (MIS) is a product of supporting gonadal Sertoli and granulosa cells. Its main physiological role is the induction of regression of Müllerian ducts in male fetuses but it also plays a role in Leydig cell steroidogenesis and in follicular development. It is a member of the transforming growth factor B family and signals through two serine/threonine kinase receptors, only one of whom, type II, is specific. Type I receptors and the intracytoplasmic signaling molecules are shared with the bone morphogenetic family. AMH is positively regulated by SF1, SOX9 and FSH. Testosterone is a powerful downregulator. Males lacking functional AMH or AMH receptor genes do not undergo regression of MUllerian derivatives during fetal life. AMH is an excellent marker of prepubertal testicular function and has gained recognition as a valuable marker of follicular reserve in adult women.

Animals↗
PubMed2005

Role of type I receptors for anti-Müllerian hormone in the SMAT-1 Sertoli cell line.

Anti-Müllerian hormone (AMH) is a member of the transforming growth factor-beta family responsible for regression of Müllerian ducts during male sexual differentiation and for regulation of gonadal steroidogenesis. AMH is also a gonadal tumor suppressor which mediates its effects through a specific type II receptor and the bone morphogenetic protein (BMP)-specific Smad proteins, suggesting that AMH and BMPs could also share type I receptors, namely activin-like kinases (ALKs)2, 3 or 6. However, attempts to identify a unique AMH type I receptor among them were unsuccessful. Here, using kinase-deficient type I receptors and small interfering RNA technology, we demonstrate that, in an AMH Sertoli target cell line, ALK3 mediates AMH effects on both Smad1 activation and P450 side-chain cleavage enzyme. In addition, transfecting a combination of normal and kinase-deficient receptors, we show that ALK2 can compensate for the absence of ALK3 and probably acts in synergy with ALK3 at high concentrations of AMH to activate Smad1, whereas ALK6 has a competitive inhibitory effect. These results are a first step in understanding how AMH transduces its effects in immature Sertoli cells.

Animals↗
PubMed2005

AMH and AMH receptor defects in persistent Müllerian duct syndrome.

Anti-Müllerian hormone (AMH) produced by fetal Sertoli cells is responsible for regression of Müllerian ducts, the anlage for uterus and Fallopian tubes, during male sex differentiation. A member of the transforming growth factor-beta superfamily, AMH signals through two transmembrane receptors, type II which is specific and type I receptors, shared with the bone morphogenetic protein family. Mutations of the AMH and AMH receptor type II (AMHR-II) genes lead to persistence of the uterus and Fallopian tubes in males. Both conditions are transmitted according to a recessive autosomal pattern and are symptomatic only in males. Affected individuals are otherwise normally virilized, undergo normal male puberty; and may be fertile if testes, tightly attached to the Fallopian tubes, can be replaced in the scrotum. Approximately 85% of the cases are due, in similar proportions, to mutations of the AMH or AMHR-II gene. The genetic background does not influence the phenotype, the only difference is the level of circulating AMH which is normal for age in AMHR-II mutants and usually low or undetectable in AMH gene defects. This is due to lack of secretion, explained by the localization of the mutations in critical regions, based on the assumed 3D structure of the molecule. Similarly, lack of translocation to the surface membrane is responsible for the inactivity of AMHR-II molecules bearing mutations in the extracellular domain. In 15% of cases, the cause of the persistent Mullerian duct syndrome is unknown and could be related to complex malformations of the urogenital region, unrelated to AMH physiology.

Animals↗
PubMed2004

[Hermaphroditism pathology].

Hermaphroditism is a general term referring to all discrepancies between phenotype and genotype of sex development. It must be preferred to sexual ambiguity which refers mainly to external genitalia anomalies. Hermaphroditism is studied on an historical and pathogenetical perspective. Short embryological summaries are integrated. The defects of sexual differentiation due to hormone deficiency are first studied: androgen insensitivity, steroid 5 alpha-reductase 2 deficiency, defects of testosterone synthesis, persistant mullerian ducts syndrome. Sexual determinism deficiencies are then presented: Turner syndrome, XX males, pure gonadal dysgenesis, true hermaphroditism, mixed gonadal dysgenesis, Drash and Frasier syndrome. Tumors of dysgenetic gonads followed. Mixed tumors developed in dysgenetic gonads are gonadoblastoma and dysgerminoma. Sex cord tumors are androgen insensitivity associated tumors, Leydig cells tumors and adrenal cell inclusion tumors. Sex reversion genes open new perspectives.

Disorders of Sex Development↗
PubMed2003

Mutations of the anti-mullerian hormone gene in patients with persistent mullerian duct syndrome: biosynthesis, secretion, and processing of the abnormal proteins and analysis using a three-dimensional model.

Anti-Müllerian hormone (AMH), a TGF-beta family member, determines whether an individual develops a uterus and Fallopian tubes. Mutations in the AMH gene lead to persistent Müllerian duct syndrome in males. The wild-type human AMH protein is synthesized as a disulfide-linked dimer of two identical 70-kDa polypeptides, which undergoes proteolytic processing to generate a 110-kDa N-terminal dimer and a bioactive 25-kDa TGF-beta-like C-terminal dimer. We have studied the biosynthesis and secretion of wild-type AMH and of seven persistent Müllerian duct syndrome proteins, containing mutations in either the N- or C-terminal domain. Mutant proteins lacking the C-terminal domain are secreted more rapidly than full-length AMH, whereas single amino acid changes in both domains can have profound effects on protein stability and folding. The addition of a cysteine in an N-terminal domain mutant, R194C, prevents proper folding, whereas the elimination of the cysteine involved in forming the interchain disulfide bond, in a C-terminal domain mutant, C525Y, leads to a truncation at the C terminus. A molecular model of the AMH C-terminal domain provides insights into how some mutations could affect biosynthesis and function.

Amino Acid Sequence↗
PubMed2003

Follicle-stimulating hormone increases testicular Anti-Mullerian hormone (AMH) production through sertoli cell proliferation and a nonclassical cyclic adenosine 5'-monophosphate-mediated activation of the AMH Gene.

Anti-Müllerian hormone (AMH) production by testicular Sertoli cells is high before puberty and can be further induced by FSH. Our objective was to delineate the mechanisms by which FSH stimulates AMH production. Assay of serum AMH levels and histological morphometric analysis in prepubertal FSH-deficient transgenic mice showed that serum AMH and testicular mass were decreased owing to reduced Sertoli cell number. All parameters resumed normal values in mice treated with recombinant FSH. We also analyzed the ability of FSH and the factors involved in its signaling pathway to activate AMH transcription by transfecting AMH promoter-luc reporter constructs of different lengths in a prepubertal Sertoli cell line. Our results showed that FSH activates AMH transcription via adenylate cyclase, cAMP, and protein kinase A but involving a nonclassical cAMP-response pathway requiring nuclear factor-kappaB and activating protein 2 binding sites, which lie more than 1.9 kb upstream of the AMH transcription start site. This is the first report showing the importance of distant sequences in the regulation of AMH expression. We conclude that prepubertal testicular AMH production is increased by FSH stimulation through Sertoli cell proliferation and an enhancement of AMH gene transcription.

Animals↗
PubMed2003

Transduction pathway of anti-Müllerian hormone, a sex-specific member of the TGF-beta family.

Anti-Müllerian hormone (AMH), also called Müllerian inhibiting substance, is a member of the transforming growth factor beta (TGF-beta) family that represses the development and function of reproductive organs. Not for nothing did Professor Alfred Jost, who first discovered its existence, christen it 'hormone inhibitrice'! Anti-Müllerian hormone is thought to exert its effects through two membrane-bound serine/threonine kinase receptors, type 2 and type 1. Upon ligand binding, these drive receptor-specific cytoplasmic substrates, the Smad molecules, into the nucleus where they act as transcription factors. A type 2 receptor specific for AMH was cloned through its homology with receptors of TGF-beta family members; the identity of the type 1 receptor(s) is controversial. Three type 1 receptors for bone morphogenetic proteins (BMPs) are possible candidates, each, not surprisingly, activating BMP-specific Smad molecules, Smads 1, 5 and 8. Each receptor could be involved, depending on the cellular context. To date, AMH signaling has been explored through BMP-specific genes, because a reporter gene related to a physiological AMH function and upregulated by the hormone has not yet been tested in a cell line strongly expressing the AMH receptor(s).

Animals↗
PubMed2002

Aetiological diagnosis of male sex ambiguity: a collaborative study.

UNLABELLED: A collaborative study, supported by the Biomed2 Programme of the European Community, was initiated to optimise the aetiological diagnosis in genetic or gonadal males with intersex disorders, a total of 67 patients with external sexual ambiguity, testicular tissue and/or a XY karyotype. In patients with gonadal dysgenesis or true hermaphroditism, the incidence of vaginal development was 100%, a uterus was present in 60%; uni or bilateral cryptorchidism was seen in nearly all cases of testicular dysgenesis (99%) but in only 57% of true hermaphrodites. Mean serum levels of anti-mullerian hormone and of serum testosterone response to chorionic gonadotropin stimulation were significantly decreased in both conditions, by comparison with patients with unexplained male pseudohermaphroditism or partial androgen insensitivity (PAIS). Mutations in the androgen receptor, 90% within exons 2-8, were detected in patients with PAIS. Clinically, a vaginal pouch was present in 90%, cryptorchidism in 36%. In 52% of cases, no diagnosis could be reached, despite an exhaustive clinical and laboratory work-up, including routine sequencing of exons 2-8 of the androgen receptor. By comparison with PAIS, unexplained male pseudohermaphroditism was characterised by a lower incidence of vaginal pouch (55%) and cryptorchidism (22%) but a high incidence of prematurity/intrauterine growth retardation (30%) or mild malformations (14%). CONCLUSION: reaching an aetiological diagnosis in cases of male intersex is difficult because of the variability of individual cases. Hormonal tests may help to discriminate between partial androgen insensitivity and gonadal dysgenesis/true hermaphroditism but are of less use for differentiating from unexplained male pseudohermaphroditism. Sequencing of exons 2-8 of the androgen receptor after study of testosterone precursors following human chorionic gonadotrophin stimulation is recommended when gonadal dysgenesis and true hermaphroditism can be excluded.

Anti-Mullerian Hormone↗