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Barry R Zirkin - One of the best experts on this subject based on the ideXlab platform.
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Leydig Cell aging and hypogonadism
Experimental Gerontology, 2015Co-Authors: Matthew C Beattie, Haolin Chen, L Adekola, Vassilios Papadopoulos, Barry R ZirkinAbstract:Leydig Cell testosterone (T) production is reduced with age, resulting in reduced serum T levels (hypogonadism). A number of Cellular changes have been identified in the steroidogenic pathway of aged Leydig Cells that are associated with reduced T formation, including reductions in luteinizing hormone (LH)-stimulated cAMP production, the cholesterol transport proteins steroidogenic acute regulatory (STAR) protein and translocator protein (TSPO), and downstream steroidogenic enzymes of the mitochondria and smooth endoplasmic reticulum. Many of the changes in steroid formation that characterize aged Leydig Cells can be elicited by the experimental alteration of the redox environment of young Cells, suggesting that changes in the intraCellular redox balance may cause reduced T production. Hypogonadism is estimated to affect about 5 million American men, including both aged and young. This condition has been linked to mood changes, worsening cognition, fatigue, depression, decreased lean body mass, reduced bone mineral density, increased visceral fat, metabolic syndrome, decreased libido, and sexual dysfunction. Exogenous T administration is now used widely to elevate serum T levels in hypogonadal men and thus to treat symptoms of hypogonadism. However, recent evidence suggests that men who take exogenous T may face increased risk of stroke, heart attack, and prostate tumorigenesis. Moreover, it is well established that administered T can have suppressive effects on LH, resulting in lower Leydig Cell T production, reduced intratesticular T concentration, and reduced spermatogenesis. This makes exogenous T administration inappropriate for men who wish to father children. There are promising new approaches to increase serum T by directly stimulating Leydig Cell T production rather than by exogenous T therapy, thus potentially avoiding some of its negative consequences.
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Leydig Cell aging and the mechanisms of reduced testosterone synthesis
Molecular and cellular endocrinology, 2008Co-Authors: Andrew Midzak, Haolin Chen, Vassilios Papadopoulos, Barry R ZirkinAbstract:In males, serum testosterone levels decline with advancing age. Though part of a complex process, this age-related decline in testosterone appears to occur, in part, due to a significant decline in the ability of aged Leydig Cells to produce testosterone maximally in response to luteinizing hormone (LH). The structure of the molecular machinery responsible for the synthesis of testosterone is described, and placed in the context of Leydig Cell biology. Multiple parameters related to the synthesis of testosterone by the Leydig Cell have been observed to change with age. Relationships among these changes are reviewed. A discussion of potential causes of the age-related decline in Leydig Cell steroidogenic capacity presents a model in which the inability of aged Cells to adequately respond to hormonal stimulation results in Cellular regression with concomitant decline in maximal testosterone output.
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Vitamin E, aging and Leydig Cell steroidogenesis
Experimental Gerontology, 2005Co-Authors: Haolin Chen, Mirza U. Baig, Barry R ZirkinAbstract:Abstract Previous studies have suggested that oxidant-induced damage may play a role in the reduced ability of aged Brown Norway rat Leydig Cells to produce testosterone. We reasoned that if this was the case, antioxidants such as vitamin E (VE) would be expected to have protective effects on steroidogenesis. To test this hypothesis, the effects of VE on Leydig Cell steroidogenesis were examined both in vitro and in vivo. In vitro studies were conducted using Leydig Cells isolated from the testes of young adult Brown Norway rats. In one experiment, isolated Cells were incubated with luteinizing hormone (LH) alone or with LH plus VE (1.3–40 μg/ml). At each of 3, 5 and 7 days thereafter, the ability of the Cells to produce testosterone was greater in the presence of VE than in its absence, and depended upon VE dose. Culturing the Leydig Cells with the antioxidants melatonin or N-tert-butyl-α-phenylnitrone also protected Leydig Cell steroidogenic function. Additionally, VE was found to suppress Fe 2+ /sodium ascorbate-induced lipid peroxidation in Leydig Cells. These studies strongly supported the contention that VE has a protective effect on Leydig Cell steroidogenesis. These in vitro results prompted us to ask whether, in vivo, VE also would affect steroidogenesis as Leydig Cells age. To this end, rats were provided one of three diets, begun when the rats were 6 months of age and carried out through age 25 months: VE-deficient, VE-control, or VE-supplemented. The VE-deficient diet had no effect on the age-related reductions in Leydig Cell testosterone production observed in VE-control rats. The VE-supplemented diet did not prevent age-related reductions in steroidogenesis, but the reductions at ages 23 and 25 months were significantly less than those seen in Leydig Cells from VE-control or VE-deficient rats. Taken together, the results of the in vitro and in vivo studies reported herein are consistent with the conclusion that vitamin E exerts a protective effect on Leydig Cell steroidogenesis.
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modulation of rat Leydig Cell steroidogenic function by di 2 ethylhexyl phthalate
Biology of Reproduction, 2001Co-Authors: Benson T Akingbemi, Barry R Zirkin, Robert T Youker, Chantal M Sottas, Emily Katz, Gary R Klinefelter, Matthew P HardyAbstract:Exposure of rodents to phthalates is associated with developmental and reproductive anomalies, and there is concern that these compounds may be causing adverse effects on human reproductive health. Testosterone (T), secreted almost exclusively by Leydig Cells in the testis, is the primary steroid hormone that maintains male fertility. Leydig Cell T biosynthesis is regulated by the pituitary gonadotropin LH. Herein, experiments were conducted to investigate the ability of di(2-ethylhexyl)phthalate (DEHP) to affect Leydig Cell androgen biosynthesis. Pregnant dams were gavaged with 100 mg21 kg21 day21 DEHP from Gestation Days 12 to 21. Serum T and LH levels were significantly reduced in male offspring, compared to control, at 21 and 35 days of age. However, these inhibitory effects were no longer apparent at 90 days. In a second set of experiments, prepubertal rats, from 21 or 35 days of age, were gavaged with 0, 1, 10, 100, or 200 mg 21 kg 21 day 21 DEHP for 14 days. This exposure paradigm affected Leydig Cell steroidogenesis. For example, exposure of rats to 200 mg 21 kg 21 day 21 DEHP caused a 77% decrease in the activity of the steroidogenic enzyme 17b-hydroxysteroid dehydrogenase, and reduced Leydig Cell T production to 50% of control. Paradoxically, extending the period of DEHP exposure to 28 days (Postnatal Days 21‐48) resulted in significant increases in Leydig Cell T production capacity and in serum LH levels. The no-observed-effect-level and lowest-observed-effect-level were determined to be 1 mg21 kg21 day21 and 10 mg21 kg 21
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age related decreased Leydig Cell testosterone production in the brown norway rat
Journal of Andrology, 1994Co-Authors: Haolin Chen, Ilpo Huhtaniemi, Matthew P Hardy, Barry R ZirkinAbstract:Previous studies have demonstrated that Leydig Cell testosterone production diminishes with age in Brown Norway rats. The objective of the studies presented herein was to test the following possible explanations for age-related decline in steroidogenesis: (1) decline in Leydig Cell number; (2) understimulation by luteinizing hormone (LH); (3) reduced ability of individual Leydig Cells to produce testosterone; and (4) influence of loss of germ Cells. Leydig Cells isolated from the testes of young and aged rats by centrifugal elutriation and Percoll density gradient centrifugation were examined for their ability to produce testosterone when stimulated maximally with LH or with dibutyryl cyclic AMP (dbcAMP). Leydig Cell number and volume were examined in situ using stereological methods. Serum LH levels were measured using a highly sensitive immunofluorometric assay. Average Leydig Cell volume decreased with age, and consistent with this observation, individual Leydig Cells isolated from aging rats produced significantly less testosterone than those from young rats whether the Cells were cultured in vitro with maximally stimulating LH or with dbcAMP. The age-associated diminished testosterone production could not be explained by changes in Leydig Cell number, serum LH levels, Leydig Cell responsiveness to LH, or testicular germ Cell content. These results, taken together, suggest that the reduced testosterone production seen in aged rats is related to defects in the steroidogenic pathway beyond the LH receptor-cAMP cascade. The nature of the initial age-related changes that cause reduced steroidogenesis is not known, and therefore it is not known whether such changes are intrinsic or extrinsic to the Leydig Cells.
Qingquan Lian - One of the best experts on this subject based on the ideXlab platform.
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stem Leydig Cell regeneration in the adult rat testis is inhibited after a short term triphenyltin exposure
Toxicology Letters, 2019Co-Authors: Yinghui Fang, Xiuxiu Chen, Yiyan Wang, Lin Zhenkun, Qingquan LianAbstract:Abstract Triphenyltin (TPT) is an organotin compound and may be an endocrine disruptor, impairing the male reproductive system. However, the effect of short-term TPT exposure on stem Leydig Cell regeneration later on remains unknown. Here, we show that TPT affects stem Leydig Cell regeneration in the adult rat testis. Adult male Sprague Dawley rats were gavaged with TPT (0, 0.5, 1.0, 2.0 mg/kg body weight/day) for 10 days, followed by a single intraperitoneal injection of ethane dimethane sulfonate (EDS, 75 mg/kg body weight) to eliminate Leydig Cells. Testis parameters and hormone levels were investigated on post-EDS days 21, 35, and 56. TPT significantly reduced serum testosterone levels, decreased Leydig Cell number and Cell size, and down-regulated its specific gene and protein expression at 1.0 and 2.0 mg/kg even 56 days after cession of treatment. TPT lowered PCNA-labeling index of progenitor Leydig Cells on post-EDS day 21. TPT also lowered AKT1 and AKT2, and ERK1/2 phosphorylation on post-EDS day 56. This study reveals that a short-term exposure to TPT blocks stem Leydig Cell regeneration in the long term thus delaying spermatogenesis.
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in utero methoxychlor exposure increases rat fetal Leydig Cell number but inhibits its function
Toxicology, 2016Co-Authors: Shiwen Liu, Yiyan Wang, Tiantian Song, Tingting Hong, Qingquan LianAbstract:The objective of the present study is to determine whether in utero exposure to methoxychlor (MXC) affects rat fetal Leydig Cell number, Cell size, or functions. Pregnant Sprague Dawley dams were gavaged with corn oil (control, 0mg/kg/day MXC) or MXC at doses of 10, 50, or 100mg/kg/day from gestational day (GD) 12 to 21. The results show that MXC increased fetal Leydig Cell numbers dose-dependently from 95±8×103 Cells/testis (control, mean±SEM) to 101±6, 148±22, and 168±21×103 Cells/testis, at the doses of 10, 50, and 100mg/kg, respectively. The increase of Leydig Cell number by MXC was contributed by the increase of single Cell population of Leydig Cells, which increased from 21±2% of the control to 31±4%, 39±3%, or 40±4% at the doses of 10, 50 or 100mg/kg, respectively. Quantitative PCR results show that MXC increased Lhcgr expression at dose of 10mg/kg and Scarb1 and Cyp11a1 mRNA levels at doses of 50 and 100mg/kg. Immunohistochemical staining demonstrated the increase of CYP11A1 protein level from the dose of 10mg/kg. However, at the highest dose (100mg/kg) MXC reduced the testicular testosterone level and MXC (1μM) in vitro treatment also inhibited androgen production from isolated fetal Leydig Cells. In conclusion, our findings indicate that at low dose MXC may increase fetal Leydig Cell numbers and the expressions of some steroidogenic enzymes, but at high dose it reduces the testicular testosterone level leading to reproductive tract malformations in the male offspring.
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adverse effects of di 2 ethylhexyl phthalate on Leydig Cell regeneration in the adult rat testis
Chemical Hazards in Industry, 2012Co-Authors: Yong Liang, Haiyun Deng, Jingjing Guo, Qingquan LianAbstract:The objective of the present study is to determine whether di-(2-ethylhexyl) phthalate (DEHP) exposure at adulthood affects regeneration of rat Leydig Cells. 90-day-old Long-Evans rats received intraperitoneal injection of 75 mg/kg ethane dimethanesulfonate (EDS) to eliminate mature Leydig Cells, and then were randomly divided into 3 groups, in which rats were gavaged with the corn oil (control) or 10 or 750 mg/kg DEHP daily for 35 days. Serum testosterone and luteinizing hormone levels were assessed by RIA, Leydig Cell numbers and proliferation rate were evaluated, and the mRNA levels of Leydig Cell specific genes were measured by qPCR. Both 10 and 750 mg/kg DEHP treatments increased Leydig Cell numbers on day 14, 21 and 35 post-EDS, due to significant increase of the number of Leydig Cell precursors from day 14 to 21 post-EDS. However, serum testosterone levels were halved in 10 and 750 mg/kg DEHP groups compared to control on day 35 post-EDS despite the increased Leydig Cell numbers. Quantitative PCR showed that Leydig Cell specific genes including Lhcgr, Cyp11a1, Hsd3b1, and Insl3 were significantly down-regulated in 750 mg/kg DEHP-treated testes on post-EDS day 21 and beyond. The present study suggests that DEHP increases Leydig Cell proliferation but inhibits differentiation during the regeneration of Leydig Cells.
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phthalate induced testicular dysgenesis syndrome Leydig Cell influence
Trends in Endocrinology and Metabolism, 2009Co-Authors: Qingquan Lian, Dianne O HardyAbstract:Phthalates, the most abundantly produced plasticizers, leach out from polyvinyl chloride plastics and disrupt androgen action. Male rats that are exposed to phthalates in utero develop symptoms characteristic of the human condition referred to as testicular dysgenesis syndrome (TDS). Environmental influences have been suspected to contribute to the increasing incidence of TDS in humans (i.e. cryptorchidism and hypospadias in newborn boys and testicular cancer and reduced sperm quality in adult males). In this review, we discuss the recent findings that prenatal exposure to phthalates affects Leydig Cell function in the postnatal testis. This review also focuses on the recent progress in our understanding of how Leydig Cell factors contribute to phthalate-mediated TDS.
Richard Ivell - One of the best experts on this subject based on the ideXlab platform.
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Prepubertal nutrition alters Leydig Cell functional capacity and timing of puberty
'Public Library of Science (PLoS)', 2019Co-Authors: Anand-ivell Ravinder, Byrne, Colin J., Arnecke Jonas, Fair Sean, Lonergan Pat, Kenny, David A., Richard IvellAbstract:Leydig Cell functional capacity reflects the numbers and differentiation status of the steroidogenic Leydig Cells in the testes and becomes more or less fixed in early adulthood with the final establishment of the hypothalamo-pituitary-gonadal (HPG) axis after puberty. Factors influencing Leydig Cell functional capacity and its role in puberty are poorly understood. Using a bovine model of dairy bulls fed four different nutritional regimes from 1 month to 12 months, and applying circulating Insulin-like peptide 3 (INSL3) as an accurate biomarker of Leydig Cell functional capacity, showed that a high plane of nutrition in the first 6 months of life, but not later, significantly increased INSL3 in young adulthood. Moreover, INSL3 concentration at 4 months indicated a marked differential in early feeding regime and correlated well (negatively) with the timing of puberty, as reflected by the age in days for the first production of an ejaculate with >50 million sperm and >10% forward motility, as well as with testis size at 18 months. Reversing the diet at 6 months was unable to rectify the trend in either parameter, unlike for other parameters such as testosterone, body weight, and scrotal circumference. This study has shown that early prepubertal nutrition is a key factor in the development of Leydig Cell functional capacity in early adulthood and appears to be a key driver in the dynamic progression of puberty
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Molecular Human Reproduction vol.5 no.2 pp. 104–108, 1999 Expression of relaxin-like factor is down-regulated in human testicular Leydig Cell neoplasia
2013Co-Authors: Thomas Klonisch, Martin Bergmann, Bernd Fischer, Richard Ivell, Marga Balvers, Sabine Kliesch, Klaus StegerAbstract:4To whom correspondence should be addressed In addition to their role in steroidogenesis in the male, testicular Leydig Cells constitutively express large amounts of the peptide relaxin-like factor (RLF), also known as Ley-IL. The Leydig Cell-derived RLF belongs to the insulin-like superfamily, which also includes relaxin, insulin and the insulin-like growth factors, and within the testis is a specific marker of Leydig Cells. Little information is available either on the regulation of gene expression or on the function of this Leydig Cell-derived peptide. In the present study we have investigated the expression pattern of human RLF in patients with rare Leydig Cell hyperplasia and adenoma. The expression of both mRNA and protein appear to be decreased in hyperplastic Leydig Cells, whereas in the Leydig Cell adenomas studied, large central areas of the adenoma were devoid of RLF mRNA and protein. Only Leydig Cells located at the periphery of the adenoma displayed expression of RLF, with full agreement between in-situ hybridization and immunohistochemistry. It thus appears that the expression of the RLF gene and its products are down-regulated in Leydig Cell hyperplasia and adenoma, consistent with a concomitant dedifferentiation of these Cells. Key words: adenoma/human testis/hyperplasia/Leydig Cell/relaxin-like facto
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the endocrine disruptors dibutyl phthalate dbp and diethylstilbestrol des influence Leydig Cell regeneration following ethane dimethane sulphonate treatment of adult male rats
International Journal of Andrology, 2012Co-Authors: Kee Heng, Richard Ivell, Ravinder Anandivell, K J TeerdsAbstract:The manner by which endocrine-disrupting xenobiotics, such as phthalates, can induce changes in the development of the male reproductive system still remains largely unknown. Herein, we have explored the application of ethane dimethane sulphonate (EDS) to eliminate adult-type Leydig Cells in the mature rat testis, leading to their regeneration from resident stem Cells, as a novel system to investigate the effects of dibutyl phthalate (DBP) and diethylstilbestrol (DES) on adult-type Leydig Cell differentiation. The advantage of this model is that one can study adult-type Leydig Cell differentiation in vivo divorced from the concomitant endocrine development of puberty. In these preliminary studies, we show that both DBP and/or DES, given for 2 or 4 days following EDS application, indeed affect Leydig Cell differentiation in the adult testis, largely by increasing early Leydig Cell proliferation and possibly thereby delaying early differentiation. In particular, on day 27 post-EDS, a time-point when the differentiation trajectory appears to be most discriminating, we observe that both DBP and/or DES cause a fourfold increase in Leydig Cell density, and a significant increase in the expression of the Leydig Cell-specific marker transcripts INSL3, LH receptor, Cyp17a1 and Cyp 11a1. In conclusion, both DBP and DES are able to affect adult-type Leydig Cells during their differentiation to cause a significant perturbation in their ultimate functional capacity.
Humphrey H C Yao - One of the best experts on this subject based on the ideXlab platform.
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dynamic changes in fetal Leydig Cell populations influence adult Leydig Cell populations in mice
The FASEB Journal, 2013Co-Authors: Ivraym B Barsoum, Jaspreet Kaur, Paul S Cooke, Humphrey H C YaoAbstract:Testes contain two distinct Leydig Cell populations during development: fetal and adult Leydig Cells (FLCs and ALCs, respectively). ALCs are not derived from FLCs, and it is unknown whether these two populations share common progenitors. We discovered that hedgehog (Hh) signaling is responsible for transforming steroidogenic factor 1-positive (SF1(+)) progenitors into FLCs. However, not all SF1(+) progenitors become FLCs, and some remain undifferentiated through fetal development. We therefore hypothesized that if FLCs and ALCs share SF1(+) progenitors, increased Hh pathway activation in SF1(+) progenitor Cells could change the dynamics and distribution of SF1(+) progenitors, FLCs, and ALCs. Using a genetic model involving constitutive activation of Hh pathway in SF1(+) Cells, we observed reduced numbers of SF1(+) progenitor Cells and increased FLCs. Conversely, increased Hh activation led to decreased ALC populations prepubertally, while adult ALC numbers were comparable to control testes. Hence, reduction in SF1(+) progenitors temporarily affects ALC numbers, suggesting that SF1(+) progenitors in fetal testes are a potential source of both FLCs and ALCs. Besides transient ALC defects, adult animals with Hh activation in SF1(+) progenitors had reduced testicular weight, oligospermia, and decreased sperm mobility. These defects highlight the importance of properly regulated Hh signaling in Leydig Cell development and testicular functions.
Luca Carmignani - One of the best experts on this subject based on the ideXlab platform.
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long term follow up using testicle sparing surgery for Leydig Cell tumor
Clinical Genitourinary Cancer, 2013Co-Authors: Giorgio Bozzini, Renzo Colombo, Franco Gadda, Giovanni M. Colpi, Ottavio Decobelli, Stefano Picozzi, Jean Palou, Luca CarmignaniAbstract:Abstract Background Our objective was to perform a long-term evaluation of conservative surgical treatment of Leydig Cell tumors. Patients and Methods A multicenter retrospective clinical study was performed at 6 European centers. Case files of all patients diagnosed with Leydig Cell tumor and treated with conservative surgery were examined. Patients underwent physical examination, hormone and tumor marker assays, scrotal and abdominal ultrasonography, chest radiography, and endocrinologic examination. Results From 1987 to 2006, 22 patients with Leydig Cell tumor underwent conservative surgery. Mean patient age was 35 years (range, 5-61 years). Mean follow-up was 180 months (range, 77-290 months). No local recurrence or metastasis was observed. Patients presented with a palpable testicular nodule (3 patients [13.7%]), a nodule diagnosed by ultrasonography (15 patients [68.2%]), gynecomastia (2 patients [9.1%]), precocious pseudopuberty (1 patient [4.5%]), or scrotal pain (1 patient [4.5%]). Diagnosis after frozen section examination was Leydig Cell tumor in 20 of 22 patients (91%). Mean histologic size of the nodule was 1.11 cm. Follow-up was conducted for all patients every 3 to 6 months, with physical examination, tumor marker assays, scrotal and abdominal ultrasonography, chest radiography, and computed tomography (CT). No local recurrences or metastases were observed. One hundred percent of patients are still alive with a 100% disease-free survival. Conclusions When diagnosed and treated early, long-term favorable outcomes are seen at follow-up in Leydig Cell tumors, even with its potential metastatic behavior. In these patients, testicle-sparing surgery proved to be a feasible and safe choice and could be regarded as the first line of therapy.
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Conservative Surgical Therapy for Leydig Cell Tumor
The Journal of urology, 2007Co-Authors: Luca Carmignani, Renzo Colombo, Franco Gadda, G. Galasso, Andrea Lania, Juan Palou, Ferran Algaba, Humberto Villavicencio, Giovanni M. Colpi, Ottavio DecobelliAbstract:Purpose: We performed a long-term evaluation of conservative surgical treatment of benign Leydig Cell tumor.Materials and Methods: A multicenter retrospective clinical study was performed at 6 European centers. Case files of all patients diagnosed with Leydig Cell tumor and treated with conservative surgery were examined. Patients underwent physical examination, hormone and tumor marker assays, scrotal and abdominal ultrasound, chest x-ray, and an endocrinological examination.Results: From 1987 to 2006, 22 patients with Leydig Cell tumor underwent conservative surgery. Mean patient age was 35 years (range 5 to 61). Mean followup was 47 months (range 1 to 230). No local recurrence or metastasis was observed. Patients presented with a palpable testicular nodule (3 patients, 13.7%) or a nodule diagnosed by ultrasound (15 patients, 68.2%), gynecomastia (2 patients, 9.1%), precocious pseudopuberty (1 patient, 4.5%) or scrotal pain (1 patient, 4.5%). Three patients were monorchid after contralateral orchiectomy...
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long term followup and clinical characteristics of testicular Leydig Cell tumor experience with 24 cases
The Journal of Urology, 2006Co-Authors: Luca Carmignani, Franco Gadda, Giovanni M. Colpi, Roberto Salvioni, Maurizio Colecchia, Giacomo Gazzano, Tullio Torelli, F Rocco, Giorgio PizzocaroAbstract:Purpose: The natural history of Leydig Cell testicular tumors is not well known, and differentiation between malignant and benign forms is not easy. We performed a retrospective multicenter evaluation of clinical and histological characteristics as well as followup of Leydig Cell tumors.Materials and Methods: From 1990 to August 2004 surgery was performed on 24 Leydig Cell tumors. Before surgery all patients underwent clinical examination, tumor markers (α-fetoprotein, β-human chorionic gonadotropin, lactate dehydrogenase), scrotal ultrasound and chest x-ray. Surgery was performed under ultrasound or palpation guidance via inguinotomy with clamping of the spermatic cord. Lesions less than 3 cm in diameter were resected and sent for frozen section examination. Histological criteria were considered. Abdominal computerized tomography or ultrasound and chest x-ray were performed postoperatively every 3 months for the first 2 years and every 6 months thereafter.Results: Patient age range was 22 to 61 years (me...