Improving safety in paediatric thyroidectomy by PTH measurements.

OBJETIVE: We followed our previously reported algorithm based on intra and postoperative parathyroid hormone (PTH) levels to predict postthyroidectomy hypoparathyroid hypocalcemia. The objective of the study was to assess if this strategy is useful and safe to reduce hypocalcemia, hospitalisation length and postsurgery calcium sampling. DESIGN, PATIENTS, MEASSUREMENTS: We classified our series of 66 patients according to their risk of hypoparathyroidism based on PTH determinations. We treated high-risk patients with calcium and vitamin D1-25 supplementation and obtained routine daily calcium samples to control low-risk patients until 48 h postsurgery. We compared the outcomes and overall results of this new approach with those of a historical control group of patients with equivalent PTH measurements who were treated only if they presented hypocalcemia. RESULTS: In the high-risk subgroup (n = 30), five patients had hypocalcemia within the first 24 h. Compared with the high-risk control subgroup, the incidence of hypocalcemia fell from 100% to 17% (p < .001), and the median hospitalisation length from 6 to 3 days (p < .001). In the low-risk subgroup (n = 36), 28 patients remained normocalcemic with significantly less calcium sampling (p < .001). Eight patients had hypocalcemia; seven of them required neck dissection, which was the only risk factor related to postsurgical hypoparathyroidism (RR: 2.1 [confidence interval 95%: 1.4-3.1]; p < .001). The overall incidence of hypocalcemia decreased by 58% in our patients compared to the control group. CONCLUSIONS: Assessing PTH levels to classify the risk of hypoparathyroidism and to initiate preventive therapy was an effective approach that improved the safety of our paediatric patients by reducing the incidence of hypocalcemia and the length of hospitalisation after thyroidectomy in paediatric patients.

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.

p.R209H GH1 variant challenges short stature assessment.

OBJECTIVE: to describe the marked variability in clinical and biochemical patterns that are associated with a p.R209H GH1 missense variant in a large Argentinean pedigree, which makes the diagnosis of GHD elusive. DESIGN: We describe a non-consanguineous pedigree composed by several individuals with short stature, including 2 pediatric patients with typical diagnosis of isolated growth hormone deficiency (IGHD) and 4 other siblings with severe short stature, low serum IGF-1 and IGFBP-3, but normal stimulated GH levels, suggesting growth hormone insensitivity (GHI) in the latter group. RESULTS: Patients with classical IGHD phenotype carried a heterozygous variant in GH1: c.626G>A (p.R209H). Data from the extended pedigree suggested GH1 as the initial candidate gene, which showed the same pathogenic heterozygous GH1 variant in the four siblings with short stature and a biochemical pattern of GHI. CONCLUSIONS: We suggest considering GH1 sequencing in children with short stature associated to low IGF-1 and IGFBP-3 serum levels, even in the context of normal response to growth hormone provocative testing (GHPT).

One-year treatment with gonadotropin-releasing hormone analogues does not affect body mass index, insulin sensitivity or lipid profile in girls with central precocious puberty.

Background Puberty is associated with a physiological decline in insulin sensitivity (IS). Overweight (OW) and obesity (OB) are common among girls with central precocious puberty (CPP). CPP is considered a risk factor for metabolic diseases. The aim of this study was to assess surrogate measures of IS, body mass index (BMI) and other metabolic parameters in CPP girls at diagnosis and during treatment with gonadotropin-releasing hormone analogues (GnRHa). Methods We present a prospective longitudinal study of CPP girls. The standard oral glucose tolerance test, homeostatic model assessment of insulin resistance (HOMA-IR), whole-body IS index (ISI) and fasting lipid profiles were evaluated at diagnosis, and at 6 and 12 months of treatment. Results Nineteen CPP girls were included; 17 were evaluable. At baseline, seven patients had normal weight (NW), five were OW and five were OB. During GnRHa treatment no significant changes were observed in BMI, HOMA-IR or ISI when considering the whole group. Whereas, when we analyzed patients according to BMI status, in NW patients, BMI increased significantly with no changes in HOMA-IR or ISI along treatment. In the OW/OB group, no significant differences were observed in BMI, HOMA-IR or ISI. Conclusions Girls with CPP showed a high frequency of OW/OB and a high prevalence of IR. GnRHa did not affect BMI, IS or the lipid profile when considering the whole cohort of patients. However, there was an increase in BMI in NW girls but not in OW/OB patients.

Desarrollo sexual precoz en niñas / Early sexual development in girls

Se define como desarrollo sexual precoz en la niña a la aparición de caracteres sexuales secundarios antes de los 8 años. Existen distintos tipos de desarrollo sexual precoz: Pubertad Precoz Central (PPC) producida por la reactivación prematura del eje hipotálamo-hipófisogonadal (HHG), Pubertad Precoz Periférica producida por actividad ovárica autónoma independiente del eje HHG y variantes del desarrollo sexual (pubarca y telarca precoz aisladas). Recientemente los avances en estudios moleculares y por imágenes han permitido precisar mejor su etiología. El diagnóstico se basa en el examen físico, análisis de laboratorio y estudios por imágenes que permiten diferenciar las formas completas de sus variantes. La PPC produce alteraciones emocionales en las niñas y aceleran la maduración esquelética comprometiendo la talla adulta por lo cual es necesario instituir el tratamiento adecuado. La terapéutica de elección son los análogos de GnRH que mostraron ser seguros y efectivos en las niñas con PPC. Se presenta una revisión del tema enfatizando en las herramientas de utilidad para orientar al pediatra en el diagnóstico y realizar la pronta derivación al especialista en endocrinología infantil para el tratamiento y seguimiento de niñas con distintos tipos de desarrollo sexual precoz

The appearance of secondary sexual characteristics before the age of 8 in girls is defined as early sexual development. There are different types of early sexual development: Central Precocious Puberty (CPP) produced by the premature reactivation of the hypothalamic-pituitary-gonadal axis (HPG), Peripheral Precocious Puberty produced by autonomous ovarian activity independent of the HPG axis and variants of sexual development (premature pubarche and telarche). Recently, advances in molecular studies and imaging have allowed to better define the etiology of early sexual development. The diagnosis is based on physical examination, laboratory analysis and imaging studies that allow differentiation of the complete form from their variants. CPP produces emotional alterations in girls and accelerates skeletal maturation, compromising adult height. After confirming diagnosis it is necessary to institute the appropriate treatment. GnRH analogues have shown to be safe and effective in girls with CPP. A review of the topic is presented, emphasizing on the useful tools to guide the pediatrician in the diagnosis and prompt referral to a pediatric endocrinologist for the treatment and monitoring of girls with different types of early sexual development

Characterization of four Latin American families confirms previous findings and reveals novel features of acid-labile subunit deficiency.

OBJECTIVE: Acid-labile subunit deficiency (ACLSD), caused by inactivating mutations in both IGFALS gene alleles, is characterized by marked reduction in IGF-I and IGFBP-3 levels associated with mild growth retardation. The aim of this study was to expand the known phenotype and genetic characteristics of ACLSD by reporting data from four index cases and their families. DESIGN: Auxological data, biochemical and genetic studies were performed in four children diagnosed with ACLSD and all available relatives. METHODS: Serum levels of IGF-I, IGFBP-3, acid-labile subunit (ALS), and in vitro ternary complex formation (ivTCF) were determined. After sequencing the IGFALS gene, pathogenicity of novel identified variants was evaluated by in vitro expression in transfected Chinese hamster ovarian (CHO) cells. ALS protein was detected in patients' sera and CHO cells conditioned media and lysates by Western immunoblot (WIB). RESULTS: Four index cases and four relatives were diagnosed with ACLSD. The following variants were found: p.Glu35Glyfs*17, p.Glu35Lysfs*87, p.Leu213Phe, p.Asn276Ser, p.Leu409Phe, p.Ala475Val and p.Ser490Trp. ACLSD patients presented low IGF-I and low or undetectable levels of IGFBP-3 and ALS. Seven out of 8 patients did not form ivTCF. CONCLUSIONS: This study confirms previous findings in ACLSD, such as the low IGF-I and a more severe reduction in IGFBP-3 levels, and a gene dosage effect observed in heterozygous carriers (HC). In addition, father-to-son transmission (father compound heterozygous and mother HC), preservation of male fertility, and marginal ALS expression with potential involvement in preserved responsiveness to rhGH treatment, are all novel aspects, not previously reported in this condition.

Concentración de insulina e índices de insulinosensibilidad en niños y adolescentes sanos / Insulin level and insulin sensitivity indices among healthy children and adolescents

Introducción. Existe escasa información acerca de los valores de referencia de la insulina y de los índices de insulinosensibilidad en pediatría. Objetivo. Describir la variación de insulina e índices subrogantes de insulinosensibilidad en la etapa pediátrica. Población y métodos. Variación de la concentración de insulina en ayuno y de los índices subrogantes, como el modelo de evaluación homeostática de resistencia a la insulina (homeostasis model assessment of insulin resistance; HOMA-IR, por sus siglas en inglés), en niños sanos con la edad, el índice de masa corporal, estadio puberal (EP), la concentración de IGF-I, colesterol total y triglicéridos. Resultados. Se incluyeron 226 niños sanos (1-18 años). La insulina aumentó con la edad, el índice de masa corporal, el EP, los niveles de IGF-I y triglicéridos (r²= 0,38; p 7,5 años presentaron mayores valores de insulina [mediana (Pc3 y Pc97) pUI/ mL: 5,0 (1,7-9,6)] que los prepuberales < 7,5 años [2,9 pUI/mL (1,3-10,9); p < 0,01]. En la pubertad (del EP II al EP V), la insulina fue mayor en las niñas que en los varones [(7,4 (1,8-16,9) versus 5,8 (1,8-12,9); p 7,5 años: 1,1 (0,3-2,0) versus niños < 7,5 años: 0,6 (0,3-1,4; p < 0,01). Los grupos puberales presentaron niveles más elevados de insulina y de HOMA-IR respecto de los niños prepuberales (p 2,0 y > 2,6 en prepúberes y púberes, respectivamente, podrían alertar a los pediatras sobre un posible estado de insulinorresistencia.

Introduction. Information on insulin reference values and insulin sensitivity indices in the field of pediatrics is scarce. Objective. To describe insulin range and insulin sensitivity surrogate indices during childhood. Population and methods. Fasting insulin level range and surrogate indices, such as the homeostasis model assessment of insulin resistance (HOMA-IR), among healthy children and adolescents by age, body mass index, pubertal stage (PS), insulin-like growth factor-1 (IGF-1), total cholesterol, and triglycerides. Results. Two hundred and twenty-six healthy children and adolescents (1-18 years old) were included. Insulin increased with age, body mass index, pubertal stage, IGF-1 and triglyceride levels (r²= 0.38, p 7.5 years old had higher insulin levels [median (P3 and P97) pIU/mL: 5.0 (1.7-9.6)] than prepubertal children < 7.5 years old [2.9 pIU/ mL (1.3-10.9), p < 0.01]. During puberty (from PS II to PS V), insulin was higher in girls than in boys [7.4 (1.8-16.9) versus 5.8 (1.8-12.9), p 7.5 years old: 1.1 (0.32.0) versus children < 7.5 years old: 0.6 (0.3-1.4, p < 0.01). The insulin level and HOMA-IR results were higher in pubertal children compared to the prepubertal group (p 2.0 and > 2.6 in prepubertal and pubertal children, respectively, may be considered a warning sign for pediatricians to further investigate insulin resistance.

Insulin level and insulin sensitivity indices among healthy children and adolescents. / Concentración de insulina e índices de insulinosensibilidad en niños y adolescentes sanos.

INTRODUCTION: Information on insulin reference values and insulin sensitivity indices in the field of pediatrics is scarce. OBJECTIVE: To describe insulin range and insulin sensitivity surrogate indices during childhood. MATERIALS AND METHODS: Fasting insulin level range and surrogate indices, such as the homeostasis model assessment of insulin resistance (HOMA-IR), among healthy children and adolescents by age, body mass index, pubertal stage (PS), insulin-like growth factor-1 (IGF-1), total cholesterol, and triglycerides. RESULTS: Two hundred and twenty-six healthy children and adolescents (1-18 years old) were included. Insulin increased with age, body mass index, pubertal stage, IGF-1 and triglyceride levels (r2= 0.38, p 〈 0.0001). Prepubertal children 〉 7.5 years old had higher insulin levels [median (P3 and P97) pIU/mL: 5.0 (1.7-9.6)] than prepubertal children 〈 7.5 years old [2.9 pIU/ mL (1.3-10.9), p 〈 0.01]. During puberty (from PS II to PS V), insulin was higher in girls than in boys [7.4 (1.8-16.9) versus 5.8 (1.8-12.9), p 〈 0.01]. The HOMA-IR index increased in the group of prepubertal children 〉 7.5 years old: 1.1 (0.32.0) versus children 〈 7.5 years old: 0.6 (0.3-1.4, p 〈 0.01). The insulin level and HOMA-IR results were higher in pubertal children compared to the prepubertal group (p 〈 0.001). CONCLUSIONS: Known physiological changes were observed inboth insulin levels and the HOMA-IR index among children and adolescents. A fasting blood insulin level of 10 pIU/mL in prepubertal children and of 17 pIU/mL and 13 pIU/mL in pubertal girls and boys, respectively, may be considered as an acceptable cut-off value in healthy children. A HOMA-IR value 〉 2.0 and 〉 2.6 in prepubertal and pubertal children, respectively, may be considered a warning sign for pediatricians to further investigate insulin resistance.

INTRODUCCIÓN: Existe escasa información acerca de los valores de referencia de la insulina y de los índices de insulinosensibilidad en pediatría. OBJETIVO: Describir la variación de insulina e índices subrogantes de insulinosensibilidad en la etapa pediátrica. MATERIALES Y MÉTODOS: Variación de la concentración de insulina en ayuno y de los índices subrogantes, como el modelo de evaluación homeostática de resistencia a la insulina (homeostasis model assessment of insulin resistance; HOMA-IR, por sus siglas en inglés), en niños sanos con la edad, el índice de masa corporal, estadio puberal (EP), la concentración de IGF-I, colesterol total y triglicéridos. RESULTADOS: Se incluyeron 226 niños sanos (1-18 años). La insulina aumentó con la edad, el índice de masa corporal, el EP, los niveles de IGF-I y triglicéridos (r2= 0,38; p 〈 0,0001). Los niños prepuberales 〉 7,5 años presentaron mayores valores de insulina [mediana (Pc3 y Pc97) pUI/ mL: 5,0 (1,7-9,6)] que los prepuberales 〈 7,5 años [2,9 pUI/mL (1,3-10,9); p 〈 0,01]. En la pubertad (del EP II al EP V), la insulina fue mayor en las niñas que en los varones [(7,4 (1,8-16,9) versus 5,8 (1,8-12,9); p 〈 0,01]. El índice HOMA-IR aumentó en el grupo prepuberal 〉 7,5 años: 1,1 (0,3-2,0) versus niños 〈 7,5 años: 0,6 (0,3-1,4; p 〈 0,01). Los grupos puberales presentaron niveles más elevados de insulina y de HOMA-IR respecto de los niños prepuberales (p 〈 0,001). CONCLUSIONES: La insulina y el índice HOMA-IR mostraron los cambios fisiológicos conocidos en niños y adolescentes. Valores de insulinemia en ayuno de 10 pUI/mL en prepúberes y 17 pUI/ mL y 13 pUI/mL en niñas y niños púberes respectivamente pueden ser considerados como valor límite aceptable en niños sanos. HOMA-IR 〉 2,0 y 〉 2,6 en prepúberes y púberes, respectivamente, podrían alertar a los pediatras sobre un posible estado de insulinorresistencia.

Heterozygous IGFALS gene variants in idiopathic short stature and normal children: impact on height and the IGF system.

BACKGROUND: In acid-labile subunit (ALS)-deficient families, heterozygous carriers of IGFALS gene mutations are frequently shorter than their wild-type relatives, suggesting that IGFALS haploinsufficiency could result in short stature. We have characterized IGFALS gene variants in idiopathic short stature (ISS) and in normal children, determining their impact on height and the IGF system. PATIENTS AND METHODS: In 188 normal and 79 ISS children levels of IGF-1, IGFBP-3, ALS, ternary complex formation (TCF) and IGFALS gene sequence were determined. RESULTS: In sum, 9 nonsynonymous or frameshift IGFALS variants (E35Gfs*17, G83S, L97F, R277H, P287L, A330D, R493H, A546V and R548W) were found in 10 ISS children and 6 variants (G170S, V239M, N276S, R277H, G506R and R548W) were found in 7 normal children. If ISS children were classified according to the ability for TCF enhanced by the addition of rhIGFBP-3 (TCF+), carriers of pathogenic IGFALS gene variants were shorter and presented lower levels of IGF-1, IGFBP-3 and ALS in comparison to carriers of benign variants. In ISS families, subjects carrying pathogenic variants were shorter and presented lower IGF-1, IGFBP-3 and ALS levels than noncarriers. CONCLUSIONS: These findings suggest that heterozygous IGFALS gene variants could be responsible for short stature in a subset of ISS children with diminished levels of IGF-1, IGFBP-3 and ALS.

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.

Evaluación de los niveles séricos de la proteína de unión de alta afinidad de la hormona de crecimiento humana (GHBP) y del polimorfismo del exón 3 del gen del receptor de GH en niños con talla baja idiopática / Evaluation of serum levels of the high affinity binding protein of human growth hormone (GHBP) and exon 3 polymorphism of the GH receptor gene in children with idiopathic short stature

La talla baja idiopática (TBI) incluye a un grupo heterogéneo de pacientes con fallas en su crecimiento. Una causa probable de TBI puede ser la insensibilidad a la GH (IGH). La proteína de unión de GH de alta afinidad (GHBP) se genera por el clivaje proteolítico de la porción extracelular del receptor de GH (GHR) y su determinación se propone como un marcador periférico del nivel de GHR en los tejidos. El objetivo de este trabajo fue evaluar los niveles de GHBP circulantes y su asociación con factores de crecimiento y el polimorfismo del exón 3 del gen GHR en niños con TBI. Los niños con TBI presentaron talla, IMC, IGF-I, IGFBP-3, ALS y niveles de GHBP significativamente más bajos que un grupo de niños de edad comparable (p<0.001). El genotipo del exón 3 del GHR no fue un factor determinante de las diferencias observadas. La máxima respuesta de GH de los tests de estímulo de secreción correlacionó negativa y significativamente con los niveles de GHBP (r= -0.28, p= 0.012). Los perfiles de distribución de la concentración de GHBP, IGF-I, ALS y BP3 expresadas en score de desvío estándar (SDE) en la TBI, mostraron un sesgo hacia niveles bajos. En conclusión, los marcadores de acción de GH y los niveles de GHBP fueron bajos en la TBI, independientemente del genotipo del exón 3 del gen GHR. En un subgrupo de niños con TBI, niveles disminuidos de GHBP y de componentes del sistema de los IGFs, colaborarían en la evaluación de la IGH sugiriendo la búsqueda de defectos en el GHR.

Idiopathic Short Stature (ISS) includes a heterogeneous group of children with growth failure. One possible explanation for the growth failure is a reduced responsiveness to growth hormone (GH). Human circulating GH is partially bound to a highaffinity binding protein (GHBP) which is derived from proteolytical cleavage of the extracellular domain of the GH receptor. Many reports have demonstrated a close relationship between GHBP and liver GH receptor status in physiological conditions and diseases. Moreover, serum GHBP measurement has been proposed as an useful peripheral index of GH receptor abundance. Our objective was the evaluation of serum GHBP levels and its probable association with serum growth factors (IGF-I, IGFBP-3 and ALS) and the exon 3 polymorphism of the extracellular domain of the GHR gene in ISS children. Children with ISS presented significantly lower height SDS, BMI SDS, serum components of the IGFs system and GHBP concentration as compared to an age-matched control group of normal children (p<0.001). Interestingly, exon 3 genotype did not influence the differences observed in these parameters. The maximal GH response obtained after two GH provocative tests inversely and significantly correlated to GHBP serum levels (r= -0.28, p= 0.012). A frequency study showed a deviation to low SDS values of serum GHBP, IGF-I, IGFBP-3 and ALS. Conclusion: 1- in children with ISS the exon 3 genotype of the GHR gene is not a factor that could explain the lower levels observed in circulating GHBP concentration and components of the IGFs system; 2- low serum GHBP together with low IGF-I, IGFBP-3 or ALS levels would help pointing to GH insensitivity due to GH receptor gene abnormalities in ISS.

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.