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.

Adenocarcinoma de endometrio de patrón sertoliforme / Sertoliform carcinoma of the endometrium

Se presenta el caso de una paciente que consultó por metrorragia posmenopaúsica. En la biopsia histeroscópica dirigida se informó de adenocarcinoma de endometrio endometrioide bien diferenciado. Se practicó histerectomía, doble anexectomía y lavados peritoneales. Durante el acto quirúrgico se valoró el grado de infiltración miometrial, que al revelar afectación del útero hasta la serosa, implicó la realización de linfadenectomía de espacios pélvicos y paraaórtico. El diagnóstico definitivo anatomopatológico fue de adenocarcinoma de endometrio tipo endometrioide de patrón sertoliforme moderadamente diferenciado. El estadío FIGO fue IIIA, por lo que se indicó quimioterapia y radioterapia como tratamiento adyuvante. A los 2 años la paciente presenta recidiva ganglionar y metástasis pulmonares con progresión a pesar del tratamiento quimioterápico, por lo que finalmente fallece.

We report a case of a patient with postmenopausal bleeding. In hysteroscopic directed biopsy was reported endometrioid endometrial adenocarcinoma well differentiated, so that she underwent total hysterectomy, both salpingo-oophorectomy and peritoneal washings. In the surgery, we evaluated the miometrial infiltration, with report invasion until serosa, so we practised pelvic and paraaortic lymphadenectomy. The pathologic diagnosis was sertoliform endometrioid carcinoma of the endometrium with moderate differentiation. The FIGO stage was IIIA, and we indicated chemotherapy and radiotherapy. Two year after, the patient presented nodal recurrence and lung metastases with no response to the chemotherapy drugs, so she dies.

Propylthiouracil-induced hypothyroidism delays apoptosis during the first wave of spermatogenesis

Mammalian germ cell apoptosis plays a key role in controlling the correct number of germ cells supported by Sertoli cells during the first wave of spermatogenesis in mammalian puberty. However, little is known about hormonal factors that could influence the rate of germ cell apoptosis during puberty or adulthood. In this work we evaluate germ cell apoptosis under hypothyroidism induced by goitrogen propylthiouracil (PTU) during the first wave of spermatogenesis. Neonatally administered PTU promoted a delay in the differentiation of Sertoli cells as evaluated by the expression of clusterin using immunohistochemistry and RT-PCR. Clusterin had different expression levels in control and PTU-treated animals, but under both conditions the highest levels were found in 35-day-old rats. In addition, clusterin displayed a cytoplasmic localization in control testes, but appeared located in the nucleus in PTU-treated animals. The wave of apoptosis (determined by caspase activity and quantification of apoptotic cells) characteristic of the first round of spermatogenesis was delayed by at least 10 days in these animals. The expression levels of proapoptotic genes like BAX or BAD were different between control and PTU-treated rats; although in both groups the highest level was found at the same age (days). Thus our results indicate that the characteristic pubertal apoptotic wave during rat spermatogenesis is delayed in neonatal hypothyroid rats.

Leydig cells, thyroid hormones and steroidogenesis.

Leydig cells are the primary source of androgens in the mammalian testis. It is established that the luteinizing hormone (LH) produced by the anterior pituitary is required to maintain the structure and function of the Leydig cells in the postnatal testis. Until recent years, a role by the thyroid hormones on Leydig cells was not documented. It is evident now that thyroid hormones perform many functions in Leydig cells. For the process of postnatal Leydig cell differentiation, thyroid hormones are crucial. Thyroid hormones acutely stimulate Leydig cell steroidogenesis. Thyroid hormones cause proliferation of the cytoplasmic organelle peroxisome and stimulate the production of steroidogenic acute regulatory protein (StAR) and StAR mRNA in Leydig cells; both peroxisomes and StAR are linked with the transport of cholesterol, the obligatory intermediate in steroid hormone biosynthesis, into mitochondria. The presence of thyroid hormone receptors in Leydig cells and other cell types of the Leydig lineage is an issue that needs to be fully addressed in future studies. As thyroid hormones regulate many functions of Sertoli cells and the Sertoli cells regulate certain functions of Leydig cells, effects of thyroid hormones on Leydig cells mediated via the Sertoli cells are also reviewed in this paper. Additionally, out of all cell types in the testis, the thyrotropin releasing hormone (TRH), TRH mRNA and TRH receptor are present exclusively in Leydig cells. However, whether Leydig cells have a regulatory role on the hypothalamo-pituitary-thyroid axis is currently unknown.

Male infertility: Y-chromosome deletion and testicular aetiology in cases of azoo-/oligospermia.

The spermatogenesis locus azoospermia factor (AZF) in Yq11 has been delineated into three microdeletion intervals designated as AZFa, AZFb andAZFc. AZFc is the most frequently deleted region. We have studied 270 male infertile patients for various genetic disorders associated with infertile phenotype. In this study, we have presented results of our studies on Y-chromosome deletions, chromosomal abnormalities (Klinefelter syndrome) and histology of testis with the objective of seeing whether there were cases of gonosomic mosaicism and a causal correlation between the genetic disorder; and testicular aetiology could be drawn. In all the 13 cases of Y-chromosome microdeletion, AZFc region and DAZ gene were deleted, while no case of AZFa deletion was detected. This result was at variance with other reports from India, where a considerable fraction of cases showed deletion in AZFa region of the Y-chromosome. Both Y-deleted and non-Y-deleted cases revealed heterogeneous testicular phenotype with comparable severity. This disparity among testicular phenotype in cases with known genetic aetiology and even in cases of unknown aetiology can be attributed to different genetic backgrounds and effect of modifiers. Since male infertility is a multifactorial disorder, the contributions of environmental and occupational insults may not be underestimated.

Mouse model of male germ cell apoptosis in response to a lack of hormonal stimulation.

As a prerequisite for studies using mutant mice, we established a mouse model for induction of male germ cell apoptosis after deprivation of gonadotropins and intratesticular testosterone (T). We employed a potent long acting gonadotropin-releasing hormone antagonist (GnRH-A), acyline, alone or in combination with an antiandrogen, flutamide for effective induction of germ cell apoptosis in mice. Combined treatment with continuous release of acyline (3 mg/kg BW/day) with flutamide (in the form of sc pellets of 25 mg) resulted in almost the same level of suppression of spermatogenesis, as judged by testis weight and by germ cell apoptotic index, in 2 weeks as that reported for rats after treatment with 1.25 mg/kg BW Nal-Glu GnRH-A for the same time period. Within the study paradigm, the maximum suppression of spermatogenesis occurred after a single sc injection of high (20 mg/kg BW) dose of acyline with flutamide. The combined treatment resulted in complete absence of elongated spermatids. Germ cell counts at stages VII-VIII showed a significant (P < 0.05) reduction in the number of preleptotene (27.1%) and pachytene spermatocytes (81.9%), and round spermatids (96.6%) in acyline + flutamide group in comparison with controls. In fact, treatment with a single high (20 mg/kg BW) dose of acyline combined with flutamide in mice achieved same or greater level of suppression, measured by germ cell counts at stages VII-VIII, in two weeks when compared with those reported after daily treatment with Nal-Glu GnRH-A for 4 weeks in rats. Both plasma and testicular T levels were markedly suppressed after administration of acyline alone either by miniosmotic pump or by a single sc injection. Addition of flutamide to acyline had no discernible effect on plasma or intratesticular T levels when compared with acyline alone. These results demonstrate that optimum suppression of spermatogenesis through increased germ cell death is only possible in mice if total abolition of androgen action is achieved and further emphasize the usefulness of acyline + flutamide treated mice as a suitable model system to study hormonal regulation of testicular germ cell apoptosis.

Effect of aqueous leaf extract of Azadirachta indica on the reproductive organs in male mice.

Effect of oral administration (50, 100, and 200 mg/kg body weight/day, for 28 days) of aqucous leaf extract of neem (Azadirachta indica) on the male reproductive organs of the Parkes (P) strain mice was investigated. The treatment had no effect on body weight and the reproductive organs weight. In treated mice, testes showed both normal and affected seminiferous tubules in the same sections; the affected seminiferous tubules showed intraepithelial vacuolation, loosening of germinal epithelium, marginal condensation of chromatin in round spermatids, occurrence of giant cells, mixing of germ cell types in stages of spermatogenesis and degenerated appearance of germ cells. In severe cases, the tubules were lined with Sertoli cells only, Sertoli cells and rare germ cells, or with Sertoli cells and several germ cells but without cellular association patterns. Also, the frequency of affected seminiferous tubules in testes of the extract-treated mice was significantly higher than the controls, though this remained unaffected in mice treated at 50 mg/kg body weight of the extract. Doses at 50 or 100 mg/kg body weight of neem leaf extract did not cause appreciable alterations in histological appearance of the epididymis, while a dose of 200 mg/kg body weight caused marked alterations both in histological appearance and the level of sialic acid in the duct. The treatment also had adverse effects on motility, morphology, and number of spermatozoa in the cauda epididymidis, level of fructose in the seminal vesicle, and on litter size. After 42 days of withdrawal of the treatment, the alterations induced in the reproductive organs recovered to control levels. Our results suggested that treatment with neem leaf extract caused reversible alterations in the male reproductive organs of P mice.

Testicular histopathological diagnosis as a predictive factor for retrieving spermatozoa for ICSI in non-obstructive azoospermic patients

OBJECTIVE: Histological testicular pattern has a predictive role in the possibility of finding spermatozoa for ICSI in cases of non-obstructive azoospermia because some individuals could show residual spermatogenic sites in the testis. The aim of this study was to evaluate the sperm retrieval rate in each of the histopathological groups (hypospermatogenesis-Hypo, spermatogenic maturation arrest-MA, Sertoli cell only-SCO and testicular hyalinization) in patients assisted in our clinic. MATERIALS AND METHODS: Retrospective study from March 1997 to October 2002. We analyzed 14 patients with mean age of 34.3 n 0.7, with non-obstructive azoospermia. All patients were submitted to previous diagnostic biopsy (Bx) elsewhere and came to our institution for treatment. After an average of 12 months (8 - 20), they were submitted to a new Bx procedure to retrieve sperm. RESULTS: Previous diagnostic Bx showed the following histopathological results: 5 patients with MA, 4 with Hypo and 5 SCO. In the following Bx (for sperm retrieval) spermatozoa was found in 33 percent of the procedures in patients with MA, 50 percent in patients with Hypo and 40 percent of the procedures in patients with SCO. CONCLUSION: Previous diagnostic Bx can help in patient counseling concerning the result of sperm retrieval.

Sclerosing Sertoli cell tumor of the testis

Sclerosing Sertoli-cell tumor is a rare, sex-cord-stromal tumor of the testis with distinct clinical and pathological features with only 14 such cases reported in contemporary literature. We report such a tumor in a young diabetic and hypertensive male. Serum beta-HCG, alpha-protein and LDH levels were normal. Pathological examination of right radical orchidectomy specimen was consistent with sclerosing sub-type of Sertoli-cell testicular tumor with no invasion. He remains free of disease recurrence at 6 years following surgery

Ovarian serous cystadenoma associated with Sertoli-Leydig cell tumor: a case report

We Describe a case of ovarian serous cystadenoma having Sertoli-Leydig cell tumor, well differentiated, in the cystic septum. Well differentiated Sertoli-Leydig cell tumor coexisting with other tumor, including serous tumor, has not yet been described. In all cases of Sertoli-Leydig cell tumor with heterologous components or other tumors, the androblastomatous components are intermediately or poorly differentiated. The present case revealed a well differentiated Sertoli-Leydig cell tumor arising in a septum of serous cystadenoma, as a circumscribed nodule. With these findings, we discuss the possibility of this Sertoli-Leydig cell tumor, considered a mural nodule, which is well established in cystic common epithelial tumors of the ovary.

Sertoli cell only syndrome: a variant of testicular germinal cell abscence

Con el objeto de estudiar el valor diagnóstico de la biopsia testicular n el Síndrome de las Células de Sertoli (SCS), se analizaron 70 biopsias de testículo obtenidas de pacientes que acudieron a una clínica de infertilidad. Los hallazgos morfológicos se correlacionaron con los datos clínicos, análisis del semen y perfil hormonal. Aún cuando catorce casos reunieron los criterios histológicos de ausencia de células germinales, los estudios de correlación revelaron que únicamente 8 de ellos presentaban las características clínicas y hormonales descritas originalmente para el SCS, incluyendo desarrollo sexual masculino normal, infertilidad primaria, azoospermia, concentraciones elevadas de FSH y normales o discretamente elevadas de LH en suero y testosterona normal. Los seis casos restantes mostraban características clínicas y endocrinológicas compatibles con otras causas de daño ubular incluyendo hipogonadismo hipogonadotrópico de origen suprahipofisiario. Síndrome de Noonan, deficiencia testicular de 17-oxoesteroide reductasa y daño tubular por agentes alkilantes. Los resultados de este análisis demuestran que para integrar el diagnóstico preciso del SCS se requiere del análisis detallado de las anormalidades morfológicas y hormonales y de aquellas obtenidas del estudio clínico