AMH Regulation by Steroids in the Mammalian Testis: Underlying Mechanisms and Clinical Implications.

Anti-Müllerian hormone (AMH) is a distinctive biomarker of the immature Sertoli cell. AMH expression, triggered by specific transcription factors upon fetal Sertoli cells differentiation independently of gonadotropins or sex steroids, drives Müllerian duct regression in the male, preventing the development of the uterus and Fallopian tubes. AMH continues to be highly expressed by Sertoli until the onset of puberty, when it is downregulated to low adult levels. FSH increases testicular AMH output by promoting immature Sertoli cell proliferation and individual cell expression. AMH secretion also showcases a differential regulation exerted by intratesticular levels of androgens and estrogens. In the fetus and the newborn, Sertoli cells do not express the androgen receptor, and the high androgen concentrations do not affect AMH expression. Conversely, estrogens can stimulate AMH production because estrogen receptors are present in Sertoli cells and aromatase is stimulated by FSH. During childhood, sex steroids levels are very low and do not play a physiological role on AMH production. However, hyperestrogenic states upregulate AMH expression. During puberty, testosterone inhibition of AMH expression overrides stimulation by estrogens and FSH. The direct effects of sex steroids on AMH transcription are mediated by androgen receptor and estrogen receptor α action on AMH promoter sequences. A modest estrogen action is also mediated by the membrane G-coupled estrogen receptor GPER. The understanding of these complex regulatory mechanisms helps in the interpretation of serum AMH levels found in physiological or pathological conditions, which underscores the importance of serum AMH as a biomarker of intratesticular steroid concentrations.

Molecular mechanisms underlying AMH elevation in hyperoestrogenic states in males.

Anti-Müllerian hormone (AMH) is secreted by Sertoli cells of the testes from early fetal life until puberty, when it is downregulated by androgens. In conditions like complete androgen insensitivity syndrome (CAIS), AMH downregulation does not occur and AMH increases at puberty, due in part to follicle-stimulating hormone (FSH) effect. However, other conditions like Peutz-Jeghers syndrome (PJS), characterised by low FSH, also have increased AMH. Because both CAIS and PJS may present as hyperoestrogenic states, we tested the hypothesis that oestradiol (E2) upregulates AMH expression in peripubertal Sertoli cells and explored the molecular mechanisms potentially involved. The results showed that E2 is capable of inducing an upregulation of endogenous AMH and of the AMH promoter activity in the prepubertal Sertoli cell line SMAT1, signalling through ERα binding to a specific ERE sequence present on the hAMH promoter. A modest action was also mediated through the membrane oestrogen receptor GPER. Additionally, the existence of ERα expression in Sertoli cells in patients with CAIS was confirmed by immunohistochemistry. The evidence presented here provides biological plausibility to the hypothesis that testicular AMH production increases in clinical conditions in response to elevated oestrogen levels.

A mutation inactivating the distal SF1 binding site on the human anti-Müllerian hormone promoter causes persistent Müllerian duct syndrome.

The persistent Müllerian duct syndrome (PMDS) is a 46,XY disorder of sexual development characterized by the persistence of Müllerian duct derivatives, uterus and tubes, in otherwise normally masculinized males. The condition, transmitted as a recessive autosomal trait, is usually due to mutations in either the anti-Müllerian hormone (AMH) gene or its main receptor. Many variants of these genes have been described, all targeting the coding sequences. We report the first case of PMDS due to a regulatory mutation. The AMH promoter contains two binding sites for steroidogenic factor 1 (SF1), one at -102 and the other at -228. Our patient carries a single base deletion at -225, significantly decreasing its capacity for binding SF1, as measured by the electrophoresis mobility shift assay. Furthermore, by linking the AMH promoter to the luciferase gene, we show that the transactivation capacity of the promoter is significantly decreased by the mutation, in contrast to the disruption of the -102 binding site. To explain the difference in impact we hypothesize that SF1 could partially overcome the lack of binding to the -102 binding site by interacting with a GATA4 molecule linked to a nearby response element. We show that disruption of both the -102 SF1 and the -84 GATA response elements significantly decreases the transactivation capacity of the promoter. In conclusion, we suggest that the distance between mutated SF1 sites and potentially rescuing GATA binding motifs might play a role in the development of PMDS.

Spreading the clinical window for diagnosing fetal-onset hypogonadism in boys.

In early fetal development, the testis secretes - independent of pituitary gonadotropins - androgens and anti-Müllerian hormone (AMH) that are essential for male sex differentiation. In the second half of fetal life, the hypothalamic-pituitary axis gains control of testicular hormone secretion. Follicle-stimulating hormone (FSH) controls Sertoli cell proliferation, responsible for testis volume increase and AMH and inhibin B secretion, whereas luteinizing hormone (LH) regulates Leydig cell androgen and INSL3 secretion, involved in the growth and trophism of male external genitalia and in testis descent. This differential regulation of testicular function between early and late fetal periods underlies the distinct clinical presentations of fetal-onset hypogonadism in the newborn male: primary hypogonadism results in ambiguous or female genitalia when early fetal-onset, whereas it becomes clinically undistinguishable from central hypogonadism when established later in fetal life. The assessment of the hypothalamic-pituitary-gonadal axis in male has classically relied on the measurement of gonadotropin and testosterone levels in serum. These hormone levels normally decline 3-6 months after birth, thus constraining the clinical evaluation window for diagnosing male hypogonadism. The advent of new markers of gonadal function has spread this clinical window beyond the first 6 months of life. In this review, we discuss the advantages and limitations of old and new markers used for the functional assessment of the hypothalamic-pituitary-testicular axis in boys suspected of fetal-onset hypogonadism.

The prepubertal testis: biomarkers and functions.

PURPOSE OF REVIEW: Biomarkers of prepubertal testicular function have become widely available only in recent years. The aim of this review is to update the knowledge on key biomarkers used to assess hypogonadism in boys. RECENT FINDINGS: Sertoli cells are the most representative cells of the prepubertal testis. Anti-Müllerian hormone and inhibin B are essential biomarkers of Sertoli cell function. Also, INSL3 arises as an additional marker of Leydig cell dysfunction. SUMMARY: The widespread use of these biomarkers has enhanced our knowledge on the pathophysiology and diagnosis of prepubertal male hypogonadism. Beyond their well known germ-cell toxicity, oncologic treatments may also affect Sertoli cell function. Pathophysiology is not the same in all aneuploidies leading to infertility: while hypogonadism is not evident until mid-puberty in Klinefelter syndrome, it is established in early infancy in Down syndrome. In Noonan syndrome, the occurrence of primary hypogonadism depends on the existence of cryptorchidism, and Prader-Willi syndrome may present with either primary or combined forms of hypogonadism. Prepubertal testicular markers have also provided insights into the effects of environmental disruptors on gonadal function from early life, and helped dissipate concerns about testicular function in boys born preterm or small for gestational age or conceived by assisted reproductive technique procedures.

Virus sincicial respiratorio y adenovirus. Un estudio clínico comparativo en pacientes internados y sin factores de riesgo / Respiratory syncytial virus and adenovirus. A comparative clinical study in hospitalized patients without risk factors

Las infecciones respiratorias agudas constituyenlas enfermedades infecciosas más frecuentes de losniños. Los agentes etiológicos asociados con mayorfrecuencia a infecciones respiratorias agudas bajasson los virus respiratorios, principalmente el virussincicial respiratorio (60 por ciento), adenovirus (8 por ciento) y parainfluenza(3 por ciento). El adenovirus es el agente etiológicocon peor pronóstico, con una mortalidad de hasta10 por ciento, contra 2 por ciento del virus sincicial respiratorio.Objetivo. Comparar la evolución clínica de pacientesen los cuales se obtuvieron identificaciones viralesde secreciones nasofaríngeas positivas para adenovirusy VSR.Población, material y métodos. Estudio retrospectivo,analítico y transversal en el que se analizaronhistorias clínicas de pacientes internadosen el Hospital General de Niños "Dr. Pedro deElizalde" entre enero y diciembre de 2003 conidentificación viral de secreciones nasofaríngeaspositiva para adenovirus o virus sincicial respiratoriorealizados con el método de inmunofluorescenciaindirecta, sin antecedentes patológicos. Lasvariables a incluir en el estudio fueron virussincicial respiratorio y adenovirus, tiempo de internaciónen días, requerimiento de oxigenoterapiaen días, ingreso a asistencia respiratoria mecánica,óbito, edad y sexo.Resultados. Del total de pacientes estudiados, en27,5 por ciento se identificó adenovirus en el aspirado desecreciones nasofaríngeas (44 niños) y en 72,5 por ciento,virus sincicial respiratorio (116 niños). No hubodiferencias significativas para ninguna de las variablesanalizadas.Conclusión. No se encontró diferencia significativaentre las evoluciones clínicas de los pacientes conidentificaciones virales positivas para adenovirus yvirus sincicial respiratorio(AU)

Virus sincicial respiratorio y adenovirus. Un estudio clínico comparativo en pacientes internados y sin factores de riesgo / Respiratory syncytial virus and adenovirus. A comparative clinical study in hospitalized patients without risk factors

Las infecciones respiratorias agudas constituyenlas enfermedades infecciosas más frecuentes de losniños. Los agentes etiológicos asociados con mayorfrecuencia a infecciones respiratorias agudas bajasson los virus respiratorios, principalmente el virussincicial respiratorio (60 por ciento), adenovirus (8 por ciento) y parainfluenza(3 por ciento). El adenovirus es el agente etiológicocon peor pronóstico, con una mortalidad de hasta10 por ciento, contra 2 por ciento del virus sincicial respiratorio.Objetivo. Comparar la evolución clínica de pacientesen los cuales se obtuvieron identificaciones viralesde secreciones nasofaríngeas positivas para adenovirusy VSR.Población, material y métodos. Estudio retrospectivo,analítico y transversal en el que se analizaronhistorias clínicas de pacientes internadosen el Hospital General de Niños "Dr. Pedro deElizalde" entre enero y diciembre de 2003 conidentificación viral de secreciones nasofaríngeaspositiva para adenovirus o virus sincicial respiratoriorealizados con el método de inmunofluorescenciaindirecta, sin antecedentes patológicos. Lasvariables a incluir en el estudio fueron virussincicial respiratorio y adenovirus, tiempo de internaciónen días, requerimiento de oxigenoterapiaen días, ingreso a asistencia respiratoria mecánica,óbito, edad y sexo.Resultados. Del total de pacientes estudiados, en27,5 por ciento se identificó adenovirus en el aspirado desecreciones nasofaríngeas (44 niños) y en 72,5 por ciento,virus sincicial respiratorio (116 niños). No hubodiferencias significativas para ninguna de las variablesanalizadas.Conclusión. No se encontró diferencia significativaentre las evoluciones clínicas de los pacientes conidentificaciones virales positivas para adenovirus yvirus sincicial respiratorio(AU)

Virus sincicial respiratorio y adenovirus. Un estudio clínico comparativo en pacientes internados y sin factores de riesgo / Respiratory syncytial virus and adenovirus. A comparative clinical study in hospitalized patients without risk factors

Las infecciones respiratorias agudas constituyenlas enfermedades infecciosas más frecuentes de losniños. Los agentes etiológicos asociados con mayorfrecuencia a infecciones respiratorias agudas bajasson los virus respiratorios, principalmente el virussincicial respiratorio (60 por ciento), adenovirus (8 por ciento) y parainfluenza(3 por ciento). El adenovirus es el agente etiológicocon peor pronóstico, con una mortalidad de hasta10 por ciento, contra 2 por ciento del virus sincicial respiratorio.Objetivo. Comparar la evolución clínica de pacientesen los cuales se obtuvieron identificaciones viralesde secreciones nasofaríngeas positivas para adenovirusy VSR.Población, material y métodos. Estudio retrospectivo,analítico y transversal en el que se analizaronhistorias clínicas de pacientes internadosen el Hospital General de Niños "Dr. Pedro deElizalde" entre enero y diciembre de 2003 conidentificación viral de secreciones nasofaríngeaspositiva para adenovirus o virus sincicial respiratoriorealizados con el método de inmunofluorescenciaindirecta, sin antecedentes patológicos. Lasvariables a incluir en el estudio fueron virussincicial respiratorio y adenovirus, tiempo de internaciónen días, requerimiento de oxigenoterapiaen días, ingreso a asistencia respiratoria mecánica,óbito, edad y sexo.Resultados. Del total de pacientes estudiados, en27,5 por ciento se identificó adenovirus en el aspirado desecreciones nasofaríngeas (44 niños) y en 72,5 por ciento,virus sincicial respiratorio (116 niños). No hubodiferencias significativas para ninguna de las variablesanalizadas.Conclusión. No se encontró diferencia significativaentre las evoluciones clínicas de los pacientes conidentificaciones virales positivas para adenovirus yvirus sincicial respiratorio