Unexpected effect of testosterone in hypergonadotropic hypogonadism and nodular Leydig cell hiperplasia. Report of one case / Efecto inesperado de la testosterona en un hipogonadismo hipergonadotrófico e hiperplasia de las células de Leydig. Informe de un caso

ABSTRACT We report a 27 -year-old male referred because of hypergonadotropic hypogonadism with low testosterone and azoospermia. At 23 years of age, he underwent an excision of a hypoechoic 0.7 cm nodule of the left testicle. The pathological diagnosis was a Leydig cell tumor. In the right testicle, there were three nodules at ultrasound, the biggest measuring 0.6 cm. Four years later, the nodules in the right testicle were still present and the larger nodule was excised. The biopsy showed tubules with only Sertoli cells in the perinodular zone. Diffuse and nodular hyperplasia of the Leydig cells was found in the interstitium. The pathological diagnosis was Sertoli syndrome with severe hyperplasia of the Leydig cells. With testosterone therapy, LH decreased, and the nodules disappeared. Thereafter, upon interrupting therapy, LH increased, and the nodules reappeared in two occasions. Resuming testosterone treatment, the nodules disappeared again, suggesting a Leydig cell hyperplasia dependent on chronic LH stimulation.

Presentamos un varón de 27 años referido por hipogonadismo hipergonadotrófico con testosterona baja y azoospermia. El paciente tenía el antecedente de un nódulo sólido hipoecogénico de 0,7 cm en el testículo izquierdo, extirpado los 23 años de edad en el año 2002 y diagnosticado patológicamente como tumor de células de Leydig. En ese año se encontraron tres nódulos en el testículo derecho por ultrasonografía, el mayor de 0,6 cm. Cuatro años después, en 2007, los micronódulos del testículo derecho seguían presentes. El mayor de ellos fue extirpado. En la biopsia, había túbulos con solo células de Sertoli en la zona perinodular. En el intersticio había hiperplasia difusa y nodular de las células de Leydig. El diagnóstico patológico fue un síndrome de Sertoli con severa hiperplasia de células de Leydig. La terapia con testosterona disminuyó la LH y los nódulos inesperadamente desaparecieron. En dos ocasiones, al interrumpir esta terapia, la LH aumentó y los nódulos reaparecieron. Este proceso revirtió nuevamente con el uso de testosterona, sugiriendo una hiperplasia de células de Leydig dependiente del estímulo crónico de LH.

Tumor de células de Leydig puro de ovario en mujer premenopáusica / Pure Leydig cell tumor of the ovary in a premenopausal woman / Pure Leydig cell tumor of the ovary in a premenopausal woman

RESUMEN Los tumores de células de Leydig del ovario son un tipo raro de tumores del estroma del cordón sexual, con menos de 0,1% de todos los tumores de ovario. Representan un desafío diagnóstico, no solo por su incidencia esporádica sino también por presentar imágenes aparentemente normales. Aunque son más comunes en las mujeres menopaúsicas, también se ha descrito casos en mujeres premenopáusicas. La característica clínica más común es la aparición de virilización rápida y progresiva; más de 75% de las pacientes muestra signos de virilización debido a la sobreproducción de testosterona. La concentración sérica de testosterona representa el marcador más útil en el diagnóstico del tumor ovárico secretor de andrógenos. El tumor de células de Leydig ovárico siempre debe ser considerado en mujer en edad reproductiva con síntomas de virilización. Se presenta un caso de tumor de células de Leydig puro de ovario en mujer premenopáusica.

ABSTRACT Leydig cell tumors of the ovary are a rare type of sex cord-stromal tumors, corresponding to less than 0.1% of all ovarian neoplasms. With a low incidence and frequent false-negative imaging results, these tumors represent a diagnostic challenge. Although more common in menopause, cases have also been described in premenopausal women. The most common clinical feature is rapidly progressive virilization; over 75% of patients show signs of virilization due to testosterone overproduction. Serum testosterone concentration is the most useful marker for diagnosing androgen-secreting tumors of the ovary. Leydig cell tumors should always be considered in women of reproductive age with virilization symptoms. We present the case of a pure Leydig cell tumor of the ovary in a premenopausal woman.

Estudio de la expresión del receptor de vitamina D en la ontogenia del testículo y en tumores de células de leydig: posible interacción con el sistema histaminérgico

RESUMEN La vitamina D (VD), un esteroide pleiotrópico, ha sido relacionada con la función reproductiva masculina, pero aún no se ha estudiado la expresión de su receptor (RVD) en el desarrollo testicular. RVD regula la expresión de componentes del sistema histaminérgico, y la histamina (HA) modula la esteroidogénesis en células de Leydig (CL). Se ha relacionado a la deficiencia de VD con múltiples patologías, entre ellas cáncer. Los tumores de células de Leydig (TCL) son los más frecuentes del intersticio testicular, y al malignizar no responden a radio/quimioterapia. VD fue descripta como tratamiento para varios tumores, pero se desconoce su aplicación en TCL. Por lo expuesto, hemos estudiado la expresión de RVD en la ontogenia de testículo de rata, evaluando su correlación con los niveles de testosterona séricos (T) y el contenido de HA; y además evaluamos la expresión de RVD en testículo humano fetal, neonatal, prepuberal, TCL e hiperplasia de CL. En testículo de rata, se observó un aumento en la expresión de RVD en CL con la edad, en línea con el incremento de T, y en contraposición con la disminución del contenido de HA, lo cual fue consistente con la reducción en los niveles de la enzima que cataliza su síntesis, HDC. Esto sugiere que la VD podría ejercer una función en el desarrollo testicular normal, ya sea en forma directa sobre las CL o mediante la regulación de la expresión de componentes del sistema histaminérgico (HDC y/o receptores de HA). Por su parte, el TCL humano presentó sobreexpresión de RVD y HDC. Considerando que las hormonas esteroideas se encuentran aumentadas en esta patología y funcionan como factores de crecimiento, si el calcitriol pudiera modular la esteroidogénesis podría tener una aplicación terapéutica.

ABSTRACT Vitamin D (VD) is a steroid hormone traditionally related to bone health. However, several authors have associated VD with reproduction and steroidogenesis in males. The presence ofVD receptor (VDR) and the enzymes involved in its activation had been reported in several cell types of the testes. Until now, nobody has studied RVD expression during testicular development. In addition, VDR in association with its co-activators or co-repressors, regulates the expression of several genes, including those related to the histaminergic system. Previously, we demonstrated that histamine (HA) can modulate steroidogenesis in Leydig cells (LC) in a concentration-dependent manner. Also, we observed a decrease in the endogenous HA content, consistent with the previously described decrease of HDC (histidine decarboxylase, the enzyme responsible of HA synthesis) levels, during LC ontogeny. Epidemiologic studies strongly suggest that a relationship exists between VD deficiency and multiple pathologies, particularly cancer. Leydig cell tumors (LCT) are rare endocrine tumors ofunknown etiology, which originate in the testicular interstitium. The incidence worldwide is 1-3% in adults and 4% in prepubertal boys, but recent publications indicate that these figures have been increasing. While usually benign, approximately 10% of LCT in adults become malignant and do not respond to chemo or radiotherapy. It is imperative to deeply investigate the biology of LCT, to identify new therapeutic targets. The potential role of calcitriol (1a,25(OH)2-vitamin-D3) in cancer treatment has been described for several types of tumors, but it remains unexplored in LCT. Thus, as a first step, it is worth evaluating VDR expression in LCT.In view of the aforecited evidence, herein we studied VDR expression during the rat testicular ontogeny, evaluating a possible correlation withserum testosterone (T) levels in blood, endogenous levels of HA and the previously described HDC expression levels. We also analized VDR expression in human testes corresponding to three different stages of development (fetal, neonatal andjuvenile), in LCT and in LC hyperplasia. Methods: Rat testes of different ages (7, 21, 35, 90 y 240 days), human fetal, neonatal and pre pubertal testes, a human LCT and a human LC hyperplasia; were used for detection of VDR by immunohistochemistry. Results: In the rat testes, VDR expression increased with age in LC, in line with the increase in serum testosterone; and in contrast with the decrease in the endogenous content of HA and HDC levels. Likewise, we detected an increase in VDR expression with age in the human testes samples. LCT presentedVDR and HDC overexpression. We also detected VDR in LC hyperplasia. Conclusions: Given that VDR testicular expression increases with age in LC, as well as testosterone serum levels, it is reasonable to speculate thatVD may play a role in normal testicular development, either acting directly on LC or by regulating one of more components of the histaminergic system (HDC or HA receptors). Considering that VDR is overexpressed in LCT, and that steroids are increased in this pathology (and act like growth factors); if calcitriol could modulate steroidogenesis, it could have a therapeutic role.

Tumor de células de Leydig do ovário associado a virilização em paciente na pós-menopausa / Ovarian Leydig cell tumor associated with virilization in postmenopausal patient

Tumores de células de Leydig são neoplasias de células esteroides e correspondem a menos de 0,5% dos tumores ovarianos. Ocorrem mais comumente na pós-menopausa e se apresentam com virilização em metade dos casos. Relatamos o caso de uma mulher de 53 anos com história de virilização. A investigação com ressonância magnética demonstrou altos níveis séricos de testosterona e um nódulo de 2 cm no ovário direito. A paciente foi submetida a ooforectomia bilateral, e a análise patológica confirmou o diagnóstico de tumor de células de Leydig do ovário direito. Um dia após a cirurgia, o nível sérico de testosterona se normalizou. Em quatro meses, a paciente apresentou nível sérico normal de testosterona e regressão parcial da alopecia. Em mulheres pós-menopáusicas com quadro de virilização progressiva, deve-se suspeitar de neoplasias ovarianas produtoras de andrógenos (AU)

Leydig cell tumors are tumors of the steroids cells and represent less than 0.5% of ovarian tumors. They occur most often in postmenopausal women and present with virilization in half of the cases. We report the case of a 53-year-old woman with virilization history. Magnetic resonance imaging showed high serum testosterone levels and a 2-cm nodule in the right ovary. The patient underwent bilateral oophorectomy, and the pathological analysis confirmed the diagnosis of Leydig cell tumor in the right ovary. The day after surgery, serum testosterone level was normalized. In four months, the patient had normal serum testosterone level and partial regression of alopecia. In postmenopausal women with progressive virilization, ovarian neoplasms producing androgens should be investigated (AU)

Hiperplasia nodular de células de Leydig / Nodular Leydig cell hyperplasia

A hiperplasia de células de Leydig (HCL) é uma condiçãobenigna que pode trazer dificuldade no diagnósticodiferencial com neoplasias testiculares, levando aorquiectomia desnecessária. Não existem diretrizes notratamento, riscos e acompanhamento destes pacientes.Discute-se a possibilidade de diagnóstico desta condiçãobenigna pré-tratamento. Relatamos o caso de umnódulo sólido testicular em um paciente de 33 anos percebidopela palpação e confirmado pela ecografia commarcadores tumorais negativos. Submetido à orquiectomiaradical direita, o exame histológico revelou hiperplasianodular de células de Leydig e ectopia adrenalem cordão espermático. A conduta seguinte constituiuacompanhamento clínico trimestral. Conclusão: pareceser consenso que um nódulo sólido testicular palpávelou demonstrado por USG em homem jovem, independentementedos marcadores tumorais, deverá ser levadoa orquiectomia radical. Mas o achado de múltiplos nódulosmenores que 6mm bilaterais sugerem, inicialmente,HCL e podem ser seguidos, desde que apresentem marcadoresnegativos. De modo semelhante, quando houveressecção prévia de uma HCL, a exerese parcial pode seruma alternativa.

The Leydig cell hyperplasia (LCH) is a benign conditionthat can cause difficulty in differential diagnosiswith testicular neoplasms, leading to unnecessary orchiectomy.There are no guidelines for the treatment,risks and monitoring these patients. It discusses the possibilityof pretreatment diagnosing this benign conditio.The case of a solid testicular nodule in a patient of 33years detected by palpation and confirmed by sonographywith negative tumor markers. Underwent right radicalorchiectomy, the histologic examination revealednodular hyperplasia of Leydig cells and adrenal ectopicin the spermatic cord. The following constitutes conductclinical monitoring quarterly. It seems to be consensusthat a solid nodule or a palpable testicular demonstratedby ultrasonography in a young man, regardless of tumormarkers should be taken to radical orchiectomy. Butthe finding of multiple bilateral nodules smaller than6mm suggests, initially, LCH and may be followed, providedthat they have negative markers. Similarly, whenthere was a previous resection of the LCH partial resectionmay be an alternative.

Tumor de células de Leydig, presentación con pubertad precoz

Objetivos: Presentar un caso de pubertad precoz secundaria a tumor de células de Leydig. Caso Clínico: Paciente preescolar masculino de 5 años, quien fue referido por presentar aparición de vello púbico, aumento de tamaño del pene, piel oleosa y crecimiento acelerado para la edad, sin antecedentes de traumatismo craneal o procesos infecciosos cerebrales. Al examen físico: peso 22,7kg y talla 117,2 cm, ambos en el percentil 97, masas musculares evidentes en tórax y miembros superiores, vello púbico tanner II, pene de 6cm de longitud, con volumen testicular de 4 mL el derecho y de 3 mL el izquierdo, observándose mucho adelanto de caracteres sexuales secundarios para el volumen testicular. Los estudios de laboratorio revelaron valores elevados de andrógenos: testosterona libre: 237 ng/dL, 17OHP: 3.7 ng/mL, prueba de GnRH con respuesta prepuberal, no plana (pico de LH: 3,4 y de FSH: 1,8 ng/mL), prueba de estimulación con ACTH reporta 17OHP basal 5.3 y postestímulo 6 ng/mL, TSH: 2,1 mUI/mL, T4L: 1,10 ng/dL. Edad ósea de 10 años, relación EO/EC de 1.9, predicción de talla final de 157 cm, con potencial genético de talla de 169,7. Se planteó Pubertad Precoz Periférica (HAC hiperplasia adonal congénita vs. Gonadal) que desencadenó una pubertad verdadera. Se indicó tratamiento con Triptorelina e Hidrocortisona a dosis habituales por kg de peso. En su evolución clínica, a pesar del tratamiento y mostrando normalización de niveles de 17OHP (1.4 ng/mL) y adecuada supresión del eje Hipotálamo-Hipófisis-Gónada, continuó progresión de caracteres sexuales secundarios, aumentando la asimetría testicular VD: 8mL y VI: 6mL, pene de 9 cm y la velocidad de crecimiento de 12 cm/año. Nuevos niveles de testosterona muy elevados (770 ng/dL). TAC de abdomen normal y ultrasonido testicular reportó LOE sólido en testículo derecho. Marcadores tumorales normales, excepto ligera elevación de Gonadotropina Coriónica. Se realiza orquidectomía derecha y ligadura alta de cordón. El estudio anatomopatológico reportó tumor de células de Leydig sin signos de malignidad. Conclusiones: Los tumores testiculares son muy raros en niños (1 a 2%) y aproximadamente el 1 a 3% de éstos, corresponden a los de células de Leydig, que se presentan con desarrollo somático precoz y virilización progresiva, siendo una causa de precocidad puberal.

Objectives: To report a case of precocious puberty due to a Leydig cell tumor. Clinical Case: A 5 years old male patient, with pubic hair, penis enlargement, oiliness of skin and accelerated growth was referred. There was no previous cranial traumatism or cerebral disease. Physical examination: weight 22,7 kg, height 117,2 cm, both over 97th percentile for age, muscular development in thorax and upper extremities, pubic hair (Tanner II), penis of 6 cm of longitude, volume of right testicle 4 mL and left 3 mL. More signs of pubertal development than would be expected for the size of the testis were evident. The laboratory analysis showed elevated levels of androgens: free testosterone: 237 ng/dL, 17OHP: 3,7 and 5,3 ng/mL basally and 6 ng/mL post stimulation with ACTH, slight response to the GnRH stimulation test (LH peak: 3,4 and FSH peak: 1,8 ng/mL), normal levels of TSH and FT4. Bone age of 10 years, BA/CA of 1,9, predicted adult height of 157 and target height of 169,7 cm. The diagnostic of peripheral precocious puberty (congenital adrenal hyperplasia vs gonadal tumor) that triggered a central precocity was suggested. Treatment with Triptorelin and Hydrocortisone was initiated in usual doses. With this therapy, the 17OHP levels were normal and a suppression of LH and FSH were obtained. Nevertheless, the boy showed progression of the pubertal development, right testicle of 8 mL, left of 6 mL, penis of 9 cm and growth velocity of 12 cm/ year. Testosterone levels were higher (770 ng/dL). Abdominal computerized axial tomography was normal and the testicular ultrasonography disclosed a solid tumor in the right testicle. Tumor markers were normal. Surgical removal of the right testicle was done. The histopathology study revealed a Leydig cell tumor without malignancy signs. Conclusions: Testicular tumors are rare in children (1 a 2%) and 1-3% of them are Leydig cell tumors. They may cause incomplete precocious puberty with somatic development and progressive virilization.

Tumor de células de leydig em crianças - relato de caso / Leydig cell tumor in child - case report

Objetivo: relatar um caso em criança de sete anos, apresentando puberdade precoce e submetida à orquiectomia total esquerda por via inguinal, devido dificuldade no diagnóstico preciso do tumor de células de Leydig, durante o ato cirúrgico. Considerações finais: as manifestações endócrinas devem ser levadas em consideração para o diagnóstico diferencial, fazendo com que crianças possam, efetivamente, se beneficiar de cirurgias menos radicais. Após um ano de seguimento não houve recidiva clínica ou hormonal do tumor.

Case Report: the authors report a case of a seven-year-old child, with isosexual precocity, in who had performed a left radical inguinal orchiectomy, due to difficulties in precise diagnosis during surgery. Final Considerations: manifestations of endocrine imbalance could help in diagnosis, permitting further children benefit least radical procedures. No clinical or endocrine relapse after 1 year follow-up.