Safety of standardised treatments for haematologic malignancies as regards to testicular endocrine function in children and teenagers.

STUDY QUESTION: Does standardised treatments used in children and adolescents with haematologic malignancies, including acute lymphoblastic (ALL) or myeloid leukaemia (AML) and non-Hodgkin lymphoma (NHL), affect endocrine function of the developing testes? SUMMARY ANSWER: Therapy of haematologic malignancies do not provoke an overt damage of Sertoli and Leydig cell populations, as revealed by normal levels of anti-Müllerian hormone (AMH) and testosterone, but a mild primary testicular dysfunction may be observed, compensated by moderate gonadotropin elevation, during pubertal development. WHAT IS KNOWN ALREADY: Evidence exists on the deleterious effect that chemotherapy and radiotherapy have on germ cells, and some attention has been given to the effects on Leydig and Sertoli cells of the adult gonads, but information is virtually non-existent on the effects of oncologic treatment on testicular somatic cell components during childhood and adolescence. STUDY DESIGN, SIZE, DURATION: A retrospective, analytical, observational study included 97 boys with haematological malignancies followed at two tertiary paediatric public hospitals in Buenos Aires, Argentina, between 2002 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: Clinical records of males aged 1-18 years, referred with the diagnoses of ALL, AML or NHL for the assessment of gonadal function, were eligible. We assessed serum levels of AMH and FSH as biomarkers of Sertoli cell endocrine function and testosterone and LH as biomarkers of Leydig cell function. MAIN RESULTS AND THE ROLE OF CHANCE: All hormone levels were normal in the large majority of patients until early pubertal development. From Tanner stage G3 onwards, while serum AMH and testosterone kept within the normal ranges, gonadotropins reached mildly to moderately elevated values in up to 35.9% of the cases, indicating a compensated Sertoli and/or Leydig cell dysfunction, which generally did not require hormone replacement therapy. LIMITATIONS, REASONS FOR CAUTION: Serum inhibin B determination and semen analysis were not available for most patients; therefore, we could not conclude on potential fertility impairment or identify whether primary Sertoli cell dysfunction resulted in secondary depleted spermatogenesis or whether primary germ cell damage impacted Sertoli cell function. WIDER IMPLICATIONS OF THE FINDINGS: The regimens used in the treatment of boys and adolescents with ALL, AML or NHL in the past two decades seem relatively safe for endocrine testicular function; nonetheless, a mild primary testicular endocrine dysfunction may be observed, usually compensated by slightly elevated gonadotropin secretion by the pituitary in adolescents, and not requiring hormone replacement therapy. No clinically relevant risk factor, such as severity of the disease or treatment protocol, could be identified in association with the compensated endocrine dysfunction. STUDY FUNDING/COMPETING INTEREST(S): This work was partially funded by grants PIP 11220130100687 of Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and PICT 2016-0993 of Fondo para la Investigación Científica y Tecnológica (FONCYT), Argentina. R.A.R., R.P.G. and P.B. have received honoraria from CONICET (Argentina) for technology services using the AMH ELISA. L.A.A. is part-time employee of CSL Behring Argentina. The other authors have no conflicts of interest to disclose.

Gonadotrophin secretion pattern in anorchid boys from birth to pubertal age: pathophysiological aspects and diagnostic usefulness.

CONTEXT: The biphasic ontogeny of serum gonadotrophins observed in normal children also exists in girls with gonadal dysgenesis, although with higher levels. However, limited data exist in prepubertal boys with anorchia. OBJECTIVE: To investigate whether the existence of testicular tissue is required for gonadotrophin downregulation in boys. Secondarily, we analysed the prevalence of high gonadotrophins and its diagnostic value to assess the presence or absence of testes in childhood. STUDY DESIGN: In a retrospective, semi-longitudinal study, we compared serum gonadotrophin levels in 35 boys with anorchia aged 0-18 years, in 29 bilaterally cryptorchid boys with abdominal testes and in 236 normal boys. RESULTS: In anorchid boys, follicle stimulating hormone (FSH) and luteinizing hormone (LH) were abnormally high in the first months after birth, then decreased progressively. LH decreased more readily than FSH and dropped to normal values in up to 70% of anorchid patients before the usual age of pubertal onset, when both gonadotrophins increased again to very high levels. In cryptorchid boys, FSH was elevated in a significantly (P < 0·0001) lower proportion of cases. Below the age of 6 years, FSH below 2 IU/l ruled out anorchia and LH above 5 IU/l confirmed anorchia with high accuracy. Between 6 and 11 years, FSH or LH levels above 5 IU/l were highly specific for the absence of testes. CONCLUSIONS: The U-shaped pattern of serum gonadotrophins observed in normal males from birth to puberty was also found in anorchid boys, but with gonadotrophin levels considerably elevated. Serum gonadotrophin levels may normalize in anorchid boys during late childhood only to rise again at puberty. The presence of testicular tissue results in restrain of gonadotrophin secretion in most patients, even if the testes are cryptorchid.

Sertoli cell markers in the diagnosis of paediatric male hypogonadism.

During childhood, the pituitary-testicular axis is partially dormant: testosterone secretion decreases following a drop in luteinising hormone levels; follicle-stimulating hormone (FSH) levels also go down. Conversely, Sertoli cells are most active, as revealed by the circulating levels of anti-Müllerian hormone (AMH) and inhibin B. Therefore, hypogonadism can best be evidenced, without stimulation tests, if Sertoli cell function is assessed. Serum AMH is high from fetal life until mid-puberty. Testicular AMH production increases in response to FSH and is potently inhibited by androgens. Inhibin B is high in the first years of life, then decreases partially while remaining clearly higher than in females, and increases again at puberty. Serum AMH and inhibin B are undetectable in anorchid patients. In primary or central hypogonadism affecting the whole gonad established in fetal life or childhood, all testicular markers are low. Conversely, when hypogonadism only affects Leydig cells, serum AMH and inhibin B are normal. In males of pubertal age with central hypogonadism, AMH and inhibin B are low. Treatment with FSH provokes an increase in serum levels of both Sertoli cell markers, whereas human chorionic gonadotrophin (hCG) administration increases testosterone levels. In conclusion, measurement of serum AMH and inhibin B is helpful in assessing testicular function, without need for stimulation tests, and orientates the aetiological diagnosis of paediatric male hypogonadism.

Are Klinefelter boys hypogonadal?

UNLABELLED: Male hypogonadism implies decreased function of one or more testicular cell population, i.e. germ, Leydig and/or Sertoli cells. In the normal prepubertal boy, Sertoli cells are very active, as indicated by high anti-Müllerian hormone (AMH) and inhibin B secretion, whereas the functional activity of Leydig cells is minimal, as evidenced by low testosterone production, and germ cells do not undergo the full spermatogenic process. Klinefelter syndrome is the most frequent cause of hypogonadism in the adult male. In this review, we discuss whether the gonadal failure is already established during infancy and childhood. In Klinefelter syndrome, there is increased germ cells degeneration from mid-foetal life - resulting in a decreased number at birth - which persists during infancy and childhood and becomes dramatic during puberty. Controversial results exist in the literature regarding Leydig cell function in Klinefelter boys: while some authors have found normal to low testosterone levels in infancy and childhood, others have reported normal to high values. Sertoli cell products AMH and inhibin B are normal in prepubertal boys and only decline during mid- to late puberty. CONCLUSION: Klinefelter syndrome is a primary hypogonadism affecting all testicular cell populations. Germ cells are affected from foetal life, and a severe depletion occurs at puberty. Leydig cell function may be normal or mildly affected in foetal and early postnatal life. Sertoli cell function is not impaired until mid- to late puberty, as reflected by normal AMH and inhibin B in Klinefelter boys.

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

INTRODUCTION: The 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. OBJECTIVE: The 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 METHODS: We 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. RESULTS: Out 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. CONCLUSION: Prepubertal 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.

Clinical and Etiological Aspects of Gynecomastia in Adult Males: A Multicenter Study.

OBJECTIVES: To evaluate the characteristics of presentation, biochemical profile, and etiology of gynecomastia in adults. METHODS: Medical records of 237 men aged 18-85 years with gynecomastia were evaluated. RESULTS: Highest prevalence of gynecomastia was observed between 21 and 30 years (n = 74; 31.2%). The most common presenting complaints were aesthetic concerns (62.8%) and breast pain (51.2%). 25.3% of the subjects had a history of pubertal gynecomastia. 56.5% had bilateral gynecomastia. 39.9% were overweight and 22.8% were obese. The etiology could not be identified in 45.1% of the cases; the most frequent identified causes were anabolic steroids consumption (13.9%), hypogonadism (11.1%), and use of pharmaceutical drugs (7.8%). Patients with bilateral gynecomastia had a longer history of disease, higher BMI, and lower testosterone levels. CONCLUSIONS: Patients with gynecomastia presented more often with aesthetic concerns and secondarily with breast pain. The most frequent final diagnosis was idiopathic gynecomastia, whereas the most frequent identified etiologies were anabolic steroids consumption, hypogonadism, and use of pharmaceutical drugs. Despite the low frequency of etiologies such as thyroid dysfunction or adrenal carcinoma, we emphasize the importance of a thorough assessment of the patient, as gynecomastia may be the tip of the iceberg for the diagnosis of treatable diseases.

Establishment of testicular endocrine function impairment during childhood and puberty in boys with Klinefelter syndrome.

OBJECTIVE: To precisely characterize the chronology of testicular endocrine function impairment during childhood and adolescence in patients with Klinefelter syndrome. Design Retrospective chart review. Patients A total of 29 boys with Klinefelter syndrome with up to 12.3 years follow-up. MEASUREMENTS: Clinical features and serum hormone levels were analysed during follow-up. RESULTS: Of the 29 patients, 16 were prepubertal and 13 had already entered puberty at their first visit. Fifteen patients were followed up through late puberty. Before puberty, LH, FSH, testosterone, anti-Müllerian hormone (AMH) and inhibin B were within the expected range in almost all cases. However, levels of the inhibin alpha-subunit precursor Pro-alphaC were in the lowest levels of the normal range in most cases. During puberty, FSH levels increased earlier and more markedly than LH. Inhibin B and AMH declined to abnormally low or undetectable levels in advanced pubertal stages. Although testosterone and Pro-alphaC levels were within the reference ranges in most cases, they were abnormally low for the observed LH values. CONCLUSIONS: In Klinefelter syndrome, a mild Leydig cell dysfunction is present from early childhood in most cases and persists throughout puberty. Sertoli cell function is normal until mid puberty, when a dramatic impairment is observed.

Time course of the serum gonadotropin surge, inhibins, and anti-Müllerian hormone in normal newborn males during the first month of life.

CONTEXT: Newborns with ambiguous genitalia or males with nonpalpable gonads usually require an early assessment of the presence and functional state of testicular tissue. OBJECTIVE: Our objective was to characterize the precise ontogeny of the serum patterns of gonadotropins, testosterone, anti-Müllerian hormone (AMH), and inhibins in normal newborn boys. DESIGN: We conducted a cross-sectional and longitudinal study. SUBJECTS: Serum samples were obtained in 57 boys and 13 girls on d 2 of life. A second sample was obtained on d 7, 10, 15, 20, and 30 (boys) and on d 30 (girls). MAIN OUTCOME MEASURES: Serum levels of gonadotropins, testosterone, AMH, and inhibins were measured. RESULTS: In males, LH and FSH were undetectable or very low on d 2. By d 7, LH increased to 3.94 +/- 3.19 IU/liter (mean +/- sd) and FSH to 2.04 +/- 1.67 IU/liter. LH/FSH ratios were 0.40 +/- 0.11 (d 2) and 2.02 +/- 0.20 (d 30). AMH rose from 371 +/- 168 pmol/liter (d 2) to 699 +/- 245 pmol/liter (d 30), and inhibin B rose from 214 +/- 86 ng/liter (d 2) to 361 +/- 93 ng/liter (d 30). The inhibin alpha-subunit precursor (pro-alphaC) remained stable during the first month of life. Testosterone levels were 66 +/- 42 ng/dl (d 2), 82 +/- 24 ng/dl (d 20), and 210 +/- 130 ng/dl (d 30). A sexual dimorphism was observed in AMH and inhibin B (lower in girls on d 2 and 30), in LH/FSH ratio (lower in girls on d 30) and in testosterone (lower in girls on d 30). CONCLUSIONS: Sertoli cell markers AMH and inhibin B are the earliest useful markers indicating the existence of normal testicular tissue.

Compensatory function of the remaining testis is dissociated in boys and adolescents with monorchidism.

OBJECTIVE: Compensatory hypertrophy has been classically described in patients with monorchidism. However, it remains unclear whether there is a functional compensatory activity of the different cell populations. Our aim was to assess the functional capacity of the solitary testis in monorchid males from infancy through puberty in order to determine whether the remaining gonad is capable of compensating the functional activity of Sertoli and Leydig cells of the absent gonad. DESIGN: In a retrospective, cross-sectional, analytical study performed at a tertiary paediatric public hospital, we included 89 boys with monorchidism and 358 healthy controls, aged 6 months-18 years. Testicular volume and circulating levels of reproductive hormones were compared between patients with monorchidism and normal boys. Serum anti-Müllerian hormone (AMH) and FSH were used as biomarkers of the functional mass of prepubertal Sertoli cells, whereas serum testosterone and LH were used as biomarkers of Leydig cells. RESULTS: In the vast majority of the cases, the testicular volume of monorchid boys was smaller than the sum of the volume of both testes of healthy controls. Serum AMH was lower and FSH was higher in patients with monorchidism than in controls aged <3 and >13 years. Serum testosterone and LH did not differ significantly between patients and controls. CONCLUSION: In boys and adolescents with monorchidism, there is a dissociated capacity of the remaining testis to compensate for the absence of the other gonad: while Leydig cell function is largely compensated, Sertoli cell proliferation and function was lower than in controls.

Low risk of impaired testicular Sertoli and Leydig cell functions in boys with isolated hypospadias.

CONTEXT: Isolated hypospadias may result from impaired testicular function or androgen end-organ defects or, alternatively, from hormone-independent abnormalities of morphogenetic events responsible for urethral seam. OBJECTIVE: The objective was to evaluate the relative prevalence of hormone-dependent etiologies in boys with isolated hypospadias. DESIGN, PATIENTS, AND MAIN OUTCOME MEASURES: We studied endocrine testicular capacity in 61 patients with isolated hypospadias and 28 with hypospadias associated with micropenis, cryptorchidism, or ambiguous genitalia. Serum anti-Müllerian hormone and inhibin B were used as Sertoli cell markers. A human chorionic gonadotropin test was performed to evaluate Leydig cell function. RESULTS: Testicular dysfunction was observed in 57.1% and androgen end-organ defects in 7.2% of patients with hypospadias associated with cryptorchidism, micropenis, or ambiguous genitalia. In the remaining 35.7%, the disorder was idiopathic. The presence of ambiguous genitalia predicted the existence of testicular or end-organ dysfunction with 81.8% specificity. Isolated hypospadias was associated in 14.8% of patients with testicular dysfunction and in 6.5% of cases with end-organ defects; in 78.7% of cases, the condition was idiopathic. The occurrence of isolated hypospadias ruled out the existence of testicular or end-organ disorders with 80.0% sensitivity. Altogether our data indicate that the risk for the existence of an underlying testicular or end-organ dysfunction is low in patients with isolated hypospadias (odds ratio, 0.13; 95% confidence interval, 0.05-0.36; P < 0.001). CONCLUSIONS: Boys with isolated hypospadias are more likely to have normal endocrine testicular and androgen end-organ functions, suggesting that transient disruption of morphogenetic events in early fetal life may be the predominant underlying cause.

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.

Afectación de la función testicular en niños con criptorquidia / Testicular dysfuntion in boys with cryptorchidism

Introducción: La capacidad funcional del testículo en los niños con criptorquidia ha recibido poca atención. La hormona anti-mülleriana (AMH), producida por la célula de Sertoli, es el marcador ideal para evaluar la función testicular durante la infancia. Objetivo: Caracterizar la función testicular en niños prepuberales antes de la orquidopexia. Investigar la asociación entre función testicular y las características de la criptorquidia. Pacientes y métodos: Estudio de corte transversal y analítico, retrospectivo. Medida de resultado principal: concentración de AMH. Medidas de resultados secundarias: concentraciones de gonadotrofinas y testosterona. Para comparación, se utilizaron los niveles hormonales de 179 niños normales. Resultados: Se seleccionaron 186 pacientes con criptorquidia bilateral y 124 con criptorquidia unilateral. La mediana de SDS de AMH fue menor a 0 en ambos grupos. La concentración sérica de AMH fue más baja en pacientes con criptorquidia bilateral que en niños controles y en niños con criptorquidia unilateral. La testosterona estuvo disminuida en niños menores de 6 meses. Las gonadotrofinas estuvieron aumentadas en un bajo porcentaje de los casos. Conclusión: Los niños prepuberales con criptorquidia, especialmente aquellos con criptorquidia bilateral, tienen menor producción de AMH y una considerable prevalencia de disfunción testicular

Introduction: Little information is available on testicular function in boys with cryptorchidism. Anti-müllerian hormone (AMH) is a good marker of testicular functionin childhood. Objective: the aim of this study was to assess testicular function in boys with cryptorchidism before orchiopexy, and to look for an association between testicular function and features of cryptorchidism. Patients and methods: We performed a cross-sectional, retrospective study. Main outcome measure was serum AMH concentration, and secondary variables were gonadotropin and testosterone concentrations. For comparison, levels in 179 normal boys were compared. Results: 186 boys with bilateral cryptorchidism and 124 with unilateral cryptorchidism were included. Mean SDS AMH was below 0 in both groups. Mean serum AMH was lower in boys with bilateral cryptorchidism, as compared to unilateral cryptorchidism and controls between 6 months and 8.9 years of age. Testosterone was lower than normal in boys < 6 months of age. Gonadotropins were rarely affected. Conclusions: Prepubertal boys with cryptorchidism, especially those with bilateral forms, have a lower AMH production, reflecting testicular dysfunction

Clinical Presentation of Klinefelter's Syndrome: Differences According to Age.

The aim of the study was to establish the characteristics of presentation of 94 patients with Kinelfelter's syndrome (KS) referred to the endocrinologist at different ages. The diagnosis of KS was more frequent in the age group between 11 and 20 years (46.8%). Most of the patients (83.7%) showed the classic 47,XXY karyotype and 7.1% showed a 47,XXY/46,XY mosaicism. Half of the patients younger than 18 years presented mild neurodevelopmental disorders. The most frequent clinical findings were cryptorchidism in prepubertal patients, and small testes, cryptorchidism, and gynecomastia in pubertal patients. FSH, LH, AMH, and inhibin B levels were normal in prepubertal patients and became abnormal from midpuberty. Most adults were referred for small testes, infertility, and gynecomastia; 43.6% had sexual dysfunction. Testosterone levels were low in 45%. Mean stature was above the 50th percentile, and 62.5% had BMI ≥25.0 kg/m(2). In conclusion, the diagnosis of Klinefelter syndrome seems to be made earlier nowadays probably because pediatricians are more aware that boys and adolescents with neuro-developmental disorders and cryptorchidism are at increased risk. The increasing use of prenatal diagnosis has also decreased the mean age at diagnosis and allowed to get insight into the evolution of previously undiagnosed cases, which probably represent the mildest forms. In adults average height and weight are slightly higher than those in the normal population. Bone mineral density is mildly affected, more at the spine than at the femoral neck level, in less than half of cases.

Criptorquidia: desde la embriología al tratamiento / Cryptorchidism: from embryology to treatment

La criptorquidia es la anomalía genital más común en el recién nacido varón y a pesar de que su evaluación y tratamiento han progresado con las décadas, siguen existiendo muchas controversias al respecto. En todo niño, el examen físico genital debe buscar la presencia de las gónadas en el escroto, en su ausencia, debe tratar de distinguirse si la anomalía es unilateral o bilateral, definiéndose con la mayor precisión posible la posición de estas y distinguiéndose entre testículo criptórquido, ectópico y retráctil junto con la valoración de la existencia de tejido testicular funcional a través de estudios hormonales. El tratamiento puede ser hormonal o quirúrgico, este último no se recomienda antes del año de edad además corresponde a la terapia más exitosa para reubicar el testículo en el escroto en aquellos pacientes con gónadas en posición inguinal alta, abdominal o en posición ectópica, o en aquellos en los que la terapia hormonal ha fallado. Por otro lado, la terapia hormonal se recomienda en mayor medida cuando las gónadas están en posición inguinal media, baja o escrotal alta. El tratamiento apunta a reducir, aunque no siempre logra evitar los posibles problemas a largo plazo de infertilidad y cáncer de testículo. MÉD UIS. 2015;28(3):371-80.

Cryptorchidism is the most frequent genital anomaly in the newborn male. Although significant progress has been made in the assessment and treatment of cryptorchidism, several controversies still exist. In every boy, the physical examination should seek the presence of the gonads in the scrotum. Otherwise, it should be made clear whether cryptorchidism is unilateral or bilateral, the position of the gonad should be defined as precisely as possible, distinguishing between cryptorchidism, ectopia and retractile testes. Hormonal laboratory studies help assessing the existence of functional testicular tissue. Treatment may be hormonal or surgical. The latter is not recommended before the age of 1 year. Surgery has the highest rates of success in patients with gonads in high inguinal, abdominal or ectopic position, or when hormonal treatment has failed. Hormonal treatment may be successful in patients with gonads in low inguinal or high scrotal position. Treatment aims to reduce, although it does not always avoids, the risks of infertility and of testicular cancer in the long term. MÉD UIS. 2015;28(3):371-80.

Basal follicle-stimulating hormone and peak gonadotropin levels after gonadotropin-releasing hormone infusion show high diagnostic accuracy in boys with suspicion of hypogonadotropic hypogonadism.

CONTEXT: Differential diagnosis between hypogonadotropic hypogonadism (HH) and constitutional delay of puberty in boys is challenging. Most tests use an acute GnRH stimulus, allowing only the release of previously synthesized gonadotropins. A constant GnRH infusion, inducing de novo gonadotropin synthesis, may allow a better discrimination. OBJECTIVE: We evaluated the diagnostic accuracy of basal and peak gonadotropins after GnRH infusion, measured by ultrasensitive assays, to confirm the diagnosis in boys with suspected HH. DESIGN AND SETTING: We conducted a validation study following Standards for Reporting of Diagnostic Accuracy criteria at a tertiary public hospital. PATIENTS AND METHODS: A GnRH i.v. infusion test was performed in 32 boys. LH and FSH were determined by immunofluorometric assay at 0-120 min. DIAGNOSIS ASCERTAINMENT: The following diagnoses were ascertained: complete HH (n = 19; testes < 4 ml at 18 yr), partial HH (n = 6; testes enlargement remained arrested for > or = 1 yr or did not reach 15 ml), and constitutional delay of puberty (n = 7; testes > or = 15 ml at 18 yr). MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative predictive values, and diagnostic efficiency were assessed. RESULTS: Basal FSH less than 1.2 IU/liter confirmed HH with specificity of 1.00 (95% confidence interval = 0.59-1.00), rendering GnRH infusion unnecessary. In patients with basal FSH of at least 1.2 IU/liter, the coexistence of peak FSH less than 4.6 IU/liter and peak LH less than 5.8 IU/liter after GnRH infusion had high specificity (1.00; 95% confidence interval = 0.59-1.00) and diagnostic efficiency (76.9%) for HH. CONCLUSIONS: Basal FSH less than 1.2 IU/liter confirms HH, which precludes from further testing, reducing patient discomfort and healthcare system costs. In patients with basal FSH of at least 1.2 IU/liter, a GnRH infusion test has a high diagnostic efficiency.

Utilidad de la hormona anti-Mülleriana (AMH) y la inhibina B en el diagnóstico del hipogonadismo en el niño

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 pediatría.

During 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.

Altered serum profile of inhibin B, Pro-alphaC and anti-Müllerian hormone in prepubertal and pubertal boys with varicocele.

OBJECTIVE: Anti-Müllerian hormone (AMH) and inhibin B are reliable markers of Sertoli cell function. The aim of the present study was to assess the functional state of Sertoli cells in order to detect early changes in the testicular function of prepubertal and pubertal patients with untreated grade II or III varicocele. DESIGN AND PATIENTS: Seven prepubertal and 55 pubertal boys with untreated grade II or III varicocele were studied. Seven prepubertal and 43 pubertal normal boys were considered as controls. MEASUREMENTS: Serum levels of gonadotrophins, testosterone, inhibin B and Pro-alphaC and AMH were determined by time-resolved immunofluorometric assays, radioimmunoassay (RIA) and specific enzyme-linked immunosorbent assays (ELISAs), respectively. RESULTS: Inhibin B and Pro-alphaC serum levels were higher in prepubertal patients with varicocele than in controls (P < 0.001). No further increment in inhibin B and Pro-alphaC levels was observed in pubertal patients with varicocele. Higher levels of AMH were found in patients in Tanner stages I, III, IV and V when compared to normal boys by Tanner stage (P < 0.05, P < 0.01, P < 0.01, P < 0.001, respectively). The direct correlation found in normal boys between inhibin B levels and LH, testosterone and testicular volume was not observed in patients with varicocele. CONCLUSIONS: The altered serum profile of gonadal hormones observed in untreated prepubertal and pubertal patients with varicocele may indicate an early abnormal regulation of the seminiferous epithelium function.