Anti-Müllerian hormone, testicular descent and cryptorchidism

Anti-Müllerian hormone (AMH) is a Sertoli cell-secreted glycoprotein involved in male fetal sex differentiation: it provokes the regression of Müllerian ducts, which otherwise give rise to the Fallopian tubes, the uterus and the upper part of the vagina. In the first trimester of fetal life, AMH is expressed independently of gonadotropins, whereas from the second trimester onwards AMH testicular production is stimulated by FSH and oestrogens; at puberty, AMH expression is inhibited by androgens. AMH has also been suggested to participate in testicular descent during fetal life, but its role remains unclear. Serum AMH is a well-recognized biomarker of testicular function from birth to the first stages of puberty. Especially in boys with nonpalpable gonads, serum AMH is the most useful marker of the existence of testicular tissue. In boys with cryptorchidism, serum AMH levels reflect the mass of functional Sertoli cells: they are lower in patients with bilateral than in those with unilateral cryptorchidism. Interestingly, serum AMH increases after testis relocation to the scrotum, suggesting that the ectopic position result in testicular dysfunction, which may be at least partially reversible. In boys with cryptorchidism associated with micropenis, low AMH and FSH are indicative of central hypogonadism, and serum AMH is a good marker of effective FSH treatment. In patients with cryptorchidism in the context of disorders of sex development, low serum AMH is suggestive of gonadal dysgenesis, whereas normal or high AMH is found in patients with isolated androgen synthesis defects or with androgen insensitivity. In syndromic disorders, assessment of serum AMH has shown that Sertoli cell function is preserved in boys with Klinefelter syndrome until mid-puberty, while it is affected in patients with Noonan, Prader-Willi or Down syndromes

Anti-Müllerian Hormone and Testicular Function in Prepubertal Boys With Cryptorchidism

IntroductionThe functional capacity of the testes in prepubertal boys with cryptorchidism before treatment has received very little attention. The assessment of testicular function at diagnosis could be helpful in the understanding of the pathophysiology of cryptorchidism and in the evaluation of the effect of treatment. Anti-Müllerian hormone is a well-accepted Sertoli cell biomarker to evaluate testicular function during childhood without the need for stimulation tests.ObjectiveThe aim of the study was to assess testicular function in prepubertal children with cryptorchidism before orchiopexy, by determining serum anti-Müllerian hormone (AMH). We also evaluated serum gonadotropins and testosterone and looked for associations between testicular function and the clinical characteristics of cryptorchidism.Materials and methodsWe performed a retrospective, cross-sectional, analytical study at a tertiary pediatric public hospital. All clinical charts of patients admitted at the outpatient clinic, and recorded in our database with the diagnosis of cryptorchidism, were eligible. The main outcome measure of the study was the serum concentration of AMH. Secondary outcome measures were serum LH, FSH, and testosterone. For comparison, serum hormone levels from a normal population of 179 apparently normal prepubertal boys were used.ResultsOut of 1,557 patients eligible in our database, 186 with bilateral and 124 with unilateral cryptorchidism were selected using a randomization software. Median AMH standard deviation score was below 0 in both the bilaterally and the unilaterally cryptorchid groups, indicating that testicular function was overall decreased in patients with cryptorchidism. Serum AMH was significantly lower in boys with bilateral cryptorchidism as compared with controls and unilaterally cryptorchid patients between 6 months and 1.9 years and between 2 and 8.9 years of age. Serum AMH below the normal range reflected testicular dysfunction in 9.5–36.5% of patients according to the age group in bilaterally cryptorchid boys and 6.3–16.7% in unilaterally cryptorchid boys. FSH was elevated in 8.1% and LH in 9.1% of boys with bilateral cryptorchidism, most of whom were anorchid. In patients with present testes, gonadotropins were only mildly elevated in less than 5% of the cases. Basal testosterone was mildly decreased in patients younger than 6 months old, and uninformative during childhood.ConclusionPrepubertal boys with cryptorchidism, especially those with bilaterally undescended gonads, have decreased AMH production. Although serum AMH may fall within the normal range, there is a considerable prevalence of testicular dysfunction during childhood in this frequent condition

Male Central Precocious Puberty: Serum Profile of Anti-Müllerian Hormone and Inhibin B before, during, and after Treatment with GnRH Analogue

We aimed to describe the functional changes of Sertoli cells, based on the measurement of serum anti-Müllerian hormone (AMH) and inhibin B during treatment with GnRHa and after its withdrawal in boys with central precocious puberty. Six boys aged 0.8 to 5.5 yr were included. AMH was low at diagnosis in patients >1 yr but within the normal range in younger patients. AMH increased to normal prepubertal levels during treatment. After GnRHa withdrawal, AMH declined concomitantly with the rise in serum testosterone. At diagnosis, inhibin B was elevated and decreased throughout therapy, remaining in the upper normal prepubertal range. In patients with testicular volume above 4 mL AMH remained higher in spite of suppressed FSH. After treatment withdrawal, inhibin B rose towards normal pubertal levels. In conclusion, AMH did not decrease in patients <1 yr reflecting the lack of androgen receptor expression in Sertoli cells in early infancy. Serum inhibin B might result from the contribution of two sources: the mass of Sertoli cells and the stimulation exerted by FSH. Sertoli cell markers might provide additional tools for the diagnosis and treatment followup of boys with central precocious puberty

Usefulness of the Anti-Mullerian Hormone (AMH) and Inhibin B in the diagnosis of Hypogonadism in the child

Durante la infancia, el eje hipotálamo-hipófiso-testicular se encuentra parcialmente quiescente: bajan los niveles de gonadotrofinas y la secreción de testosterona disminuye siguiendo a la caída de la LH. Por el contrario, las células de Sertoli están activas, como lo demuestran los niveles séricos de hormona anti-mülleriana (AMH) e inhibina B. Por lo tanto, el hipogonadismo en la infancia puede ser puesto en evidencia, sin necesidad de pruebas de estímulo, si se evalúa la función de las células de Sertoli. La AMH sérica es alta desde la vida fetal hasta el inicio de la pubertad. La producción testicular de AMH aumenta en respuesta a la FSH pero es potentemente inhibida por los andrógenos. La inhibina B es alta en los primeros años de la vida, luego disminuye parcialmente aunque permanece claramente más alta que en las mujeres, y aumenta nuevamente en la pubertad. Las concentraciones séricas de AMH e inhibina B son indetectables en pacientes anórquidos. En el hipogonadismo primario que afecta a todo el testículo, establecido durante la vida fetal o la infancia, todos los marcadores testiculares están bajos. Cuando en el hipogonadismo están afectadas sólo las células de Leydig, la AMH y la inhibina B sérica son normales y/o altas, mientras que están bajas cuando se ven afectadas las células de Sertoli. La AMH y la inhibina B están bajas en varones con hipogonadismo central en edad prepuberal y continúan bajas en edad puberal. El tratamiento con FSH induce un aumento en los niveles séricos de los marcadores de la célula de Sertoli. En conclusión, la determinación de los niveles séricos de AMH e inhibina B es útil para evaluar la función testicular, sin necesidad de pruebas de estímulo, y orientar el diagnóstico etiológico en el hipogonadismo masculino en pediatrí[email protected] childhood, the hypothalamic-pituitary-gonadal axis is partially quiescent: gonadotropin and testosterone levels decrease, but Sertoli cells remain active, as shown by serum anti-Müllerian hormone (AMH) and inhibin B levels. Therefore, hypogonadism may be diagnosed during childhood, without the need for stimulation tests, provided Sertoli cell function is assessed. Serum AMH levels are high from fetal life until the onset of puberty. Testicular AMH production increases in response to FSH but is potently inhibited by androgens. Serum inhibin B levels are high until the age of 3-4 years in boys; although they decrease thereafter, they remain clearly higher than in girls of the same age. During the early stage of puberty, serum inhibin B increases again to reach adult values. AMH and inhibin B are undetectable in the serum of anorchid patients. In boys with fetalonset primary hypogonadism affecting the whole testicular parenchyma, AMH and inhibin B are low in serum. Conversely, they are normal or high when only the interstitial tissue of the gonads is impaired. AMH and inhibin B are low in children with central hypogonadism and persist low during pubertal age. FSH treatment induces an increase in both Sertoli cell markers. In conclusion, the determination of serum AMH and inhibin B levels is useful for the assessment of testicular function, without the need for stimulation tests, in pediatric patients

Hipogonadismo masculino: una clasificación ampliada basada en la fisiología endocrina del desarrollo

La fisiología testicular normal es el resultado de la función integrada de los compartimientos tubular e intersticial. Los marcadores séricos de la función del tejido intersticial son la testosterona y el factor similar a la insulina 3 (INSL3), mientras que la función tubular puede ser evaluada por el recuento, la morfología y la motilidad espermáticos y los niveles circulantes de hormona anti-Mülleriana (AMH) e inhibina B. La definición clásica de hipogonadismo masculino se refiere a la insuficiencia testicular asociada con la deficiencia de andrógenos, sin tener en cuenta las posibles deficiencias en las poblaciones de células germinales y de Sertoli. Tampoco considera el hecho de que la deficiencia de testosterona sérica basal no se puede equiparar a hipogonadismo en la infancia, ya que las células de Leydig son usualmente inactivas en dicha etapa de la vida. Una definición clínica amplia de hipogonadismo masculino en diferentes períodos de la vida requiere de una consideración global de la fisiología del eje hipotálamo-hipófiso-testicular y de sus posibles alteraciones a lo largo del desarrollo. En este trabajo, proponemos una clasificación ampliada de hipogonadismo masculino basada en la fisiopatología del eje hipotálamo-hipófiso-testicular en los diferentes períodos de la vida. Las características clínicas y bioquímicas del hipogonadismo masculino varían en función de: a) el nivel del eje hipotálamo-hipófiso-testicular afectado inicialmente: central, primario o dual; b) la población de células testiculares inicialmente dañada: disfunción testicular generalizada o disfunción testicular disociada; y c) el período de la vida en que la función gonadal se afecta: fetal o postnatal. En el presente trabajo, destacamos que: la evaluación de la función testicular basal en la infancia y la niñez se basa esencialmente en la evaluación de marcadores de células de Sertoli (AMH e inhibina B); el aumento de las gonadotrofinas no debe ser considerado una condición sine qua non para el diagnóstico de hipogonadismo primario en la infancia; y, por último, que la falta de elevación de gonadotrofinas en adolescentes o adultos con insuficiencia gonadal primaria puede ser indicativa de un hipogonadismo dual por afectación concomitante de las gónadas y del eje hipotálamo-hipofisario.Fil: Rey, Rodolfo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Grinspon, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Gottlieb, S. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Pasqualini, T.. Hospital Italiano de Buenos Aires; ArgentinaFil: Knoblovits, P.. Hospital Italiano de Buenos Aires; ArgentinaFil: Aszpis, S.. Hospital "Carlos G. Durand"; ArgentinaFil: Pacenza, N.. Unidad Asistencial “Dr. César Milstein “; ArgentinaFil: Stewart Usher, J.. Centro Médico Haedo; ArgentinaFil: Bergadá, I.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Campo, Stella Maris. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentin

Male hypogonadism: an extended classification based on a developmental, endocrine physiology-based approach

Normal testicular physiology results from the integrated function of the tubular and interstitial compartments. Serum markers of interstitial tissue function are testosterone and insulin-like factor 3 (INSL3), whereas tubular function can be assessed by sperm count, morphology and motility, and serum anti-Mu¨llerian hormone (AMH) and inhibin B. The classical definition of male hypogonadism refers to testicular failure associated with androgen deficiency, without considering potential deficiencies in germ and Sertoli cells. Furthermore, the classical definition does not consider the fact that low basal serum testosterone cannot be equated to hypogonadism in childhood, because Leydig cells are normally quiescent. A broader clinical definition of hypogonadism that could be applied to male patients in different periods of life requires a comprehensive consideration of the physiology of the hypothalamic- pituitary-testicular axis and its disturbances along development. Here we propose an extended classification of male hypogonadism based on the pathophysiology of the hypothalamic-pituitary-testicular axis in different periods of life. The clinical and biochemical features of male hypogonadism vary according to the following: (i) the level of the hypothalamic-pituitary-testicular axis primarily affected: central, primary or combined; (ii) the testicular cell population initially impaired: whole testis dysfunction or dissociated testicular dysfunction, and: (iii) the period of life when the gonadal function begins to fail: foetal-onset or postnatal-onset. The evaluation of basal testicular function in infancy and childhood relies mainly on the assessment of Sertoli cell markers (AMH and inhibin B). Hypergonadotropism should not be considered a sine qua non condition for the diagnosis of primary hypogonadism in childhood. Finally, the lack of elevation of gonadotropins in adolescents or adults with primary gonadal failure is indicative of a combined hypogonadism involving the gonads and the hypothalamic-pituitary axis.Fil: Rey, Rodolfo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Grinspon, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Gottlieb, Silvia Elisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Pascualini, T.. Hospital Italiano de Buenos Aires; ArgentinaFil: Knoblovits, P.. Hospital Italiano de Buenos Aires; ArgentinaFil: Aszpis, S.. Hospital "Carlos G. Durand"; ArgentinaFil: Pacenza, N.. Unidad Asistencial "Dr. César Milstein"; ArgentinaFil: Stewart Usher, J.. Centro Médico Haedo; ArgentinaFil: Bergadá, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Campo, Stella Maris. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentin