Search

A 71-year-old woman was referred to the endocrinology clinic to investigate postmenopausal hirsutism with 10 years of evolution. She had history of regular menses and menopause with 50 years old. Physical examination showed a male pattern facies, deepening of the voice, androgenic alopecia and hirsutism with a score of 23 according to the modified Ferriman-Gallwey scale. Testosterone and androstenedione were increased. Transvaginal ultrasound, abdominal and pelvic CT showed uterine fibroids with no pathological findings in the adrenals or ovaries. Since she had postmenopausal vaginal bleeding, uterine fibroids and suspicion of an ovarian source for her hyperandrogenism, total hysterectomy and bilateral oophorectomy were performed. Histopathological diagnosis was a Leydig cell tumour located in left ovary and endometrial carcinoma. Improvement of hirsutism was started to notice 1 month after the surgery and she was referred to the oncology clinic for adjuvant treatment.

Leydig cell tumours (LCTs) of the ovary are rare ovarian tumours that usually present with hyperandrogenism. Conventional radiological imagings are helpful in localising these tumours. However, some tumours may be too small to be localised before curative surgical removal. It is important to identify these androgen-secreting neoplasms which originate mostly from adrenals or ovaries because they are potentially malignant and require specific treatment. When conventional imagings are unrevealing, selective ovarian and adrenal venous sampling (SOAVS) is the next option. We report a case of LCT that was localised by SOAVS after results from other imaging modalities remained inconclusive.

Aims: To investigate the morphological and molecular characteristics of Leydig cell tumours (LCTs) of the testis for the identification of cases that may metastasise. Methods and results: Six parameters for a predictive model of the metastatic risk were evaluated in 37 benign and 14 malignant LCTs of the testis [LCT Scaled Score (LeSS)]. The tumour size (benign LCTs, mean 13.3mm; malignant LCTs, mean 44mm) (P&nbsp

Leydig cell tumours are the most common sex cord-stromal tumours. In the last years, apparent increased incidence is noted while aetiology of the tumour is still unknown. Therefore, here, we focused on the genetics of Leydig cell tumours using the next-generation sequencing. Leydig cell micronodules were revealed in patients with azoospermia who were qualified for testicular biopsy. Complete gene set of Leydig cell tumours was compared with transcriptome of healthy Leydig cells obtained from donors. Bioinformatic analysis of the obtained sequencing data revealed alterations in expression of 219 transcripts. We showed, for the first time, that a significant proportion of differentially expressed genes is directly involved in regulation of apoptotic process, which downregulation might be important to Leydig cell tumour development. Additionally, we found a significant upregulation of heat shock protein genes that might be a unique feature of Leydig cell tumours when compared to other tumour types. Our study offers fundamental transcriptomic data for future studies on human Leydig cell tumour that are crucial to determine its causes. Moreover, presented here the in-depth analysis and discussion of alterations observed in tumour transcriptome may be important for the diagnosis and therapy of this pathology.

Background Testicular tumours are uncommon in children, accounting for only 1% of all childhood tumours. Prepubertal Leydig cell tumours actively secrete testosterone and as a result, patients typically present with isosexual precocious pseudopuberty, this being the first cause of consultation. We present three cases of Leydig cell tumours in prepubertal patients with an atypical presentation. Methods We studied three cases of Leydig cell tumours in prepubertal boys, who either consulted for testicular asymmetry or were incidentally found to have the tumour in the absence of systemic signs of systemic hyperandrogenism or precocious puberty. In all cases, a well-circumscribed testicular mass was found by testicular ultrasound. The diagnosis was confirmed by histology. In all three cases, testicular enucleation was performed with satisfactory follow-up. Results Following the surgical procedure, during the follow-up, all patients showed a normal testicular volume in comparison with the contralateral testis. No complications were seen during follow-up. Conclusions A testicular ultrasound in children developing asymptomatic testicular asymmetry might be recommended due to its possible hormonal action locally. An early testicular ultrasound, testicular swelling discrepancies, tumour size and androgen production are key factors in the prognosis and management of this type of tumour.

Leydig cell tumours (LCTs) are rare testicular stromal neoplasms classically presenting with a painless testicular mass or swelling in adults. Symptoms secondary to hypogonadism may occur resulting from the hormonal activity of these tumours. Loss of libido is described in LCTs in conjunction with other symptoms; however, no case has reported this as the sole presenting feature. We describe the case of a 42-year-old man presenting to his General Practitioner with loss of libido and no other features suspicious of testicular cancer. Ultrasound performed due to an unrelated epididymal cyst detected an incidental mass confirmed as a benign LCT following radical orchidectomy. Biochemical markers remained normal throughout and following treatment his libido returned to normal. This case may serve as a reminder for clinicians to maintain a high index of suspicion for testicular neoplasms in patients with features of hypogonadism in the absence of classical features for testicular cancer.

Leydig cell tumours of the ovary are rare and represent a diagnostic challenge not only due to their sporadic incidence but also due to the seemingly normal imaging. We present three cases of pre- and postmenopausal women who were presented with severe clinical signs of hyperandogenism where modern imaging modalities (including computed tomography (CT), magnetic resonance imaging (MRI) and positron-emission tomography combined with computed tomography (PET-CT)) failed to identify the tumour. Two patients underwent non-expert ultrasound, CT and MRI examination with uniform conclusion that ovaries are of normal appearance. One of the two patients even had a PET-CT performed, which was inconclusive. Our case reports show the importance of examination by specialists with established skills in gynaecologic ultrasonography in the diagnosis of the Leydig cell tumours. The most useful diagnostic tool seems to be the combination of age (postmenopause), symptoms (onset of hirsutism and virilisation), high total testosterone plasma values and expert sonography. On ultrasound, these tumours are unilateral, usually small, solid intraovarian nodules of a slightly increased echogenicity in contrast to the surrounding ovarian tissue, delineated by abundant perfusion with an enhanced vascularity. The appropriate setting of the sensitive colour Doppler is crucial for the detection of intraovarian Leydig cell tumour. Impact statement What is already known on this subject? A diagnosis of Leydig cell tumours is based on ultrasound performed by a trained examiner or by MRI. CT or PET/CT are not among the primary methods of choice. According to the results of imaging investigations surgical treatment is planned. Because these tumours are usually benign and have a good prognosis the unilateral salpingo-oophorectomy is a standard procedure. What do the results of this study add? Our case series show how difficult it can be to establish the diagnosis of Leydig cell tumours by imaging, including transvaginal ultrasound, the most frequently recommended diagnostic tool. We demonstrate in three cases how easily a small hyperechogenic tumour can be overseen or interchanged for a different gynaecological pathology if transvaginal scan is not performed by an experienced examiner trained in sonographic features of gynaecologic neoplasms. What are the implications of these findings for clinical practice and/or further research? This case series demonstrate how important it is to see the patient in the whole complexity with their medical history, proper clinical symptoms evaluation, laboratory test and not to rely solely just on sophisticated high-end investigations, such as the PET-CT, a CT and an MRI. It also emphasises the importance of specialists with established skills in gynaecologic ultrasonography. Further effort should be made to define the resources for the appropriate training of such sonographers.

Leydig cell tumour (LCT) of the testis is a rare histological subtype of stromal tumours, accounting for 1 to 3% of testicular neoplasms. The natural history of LCT is poorly understood. The aim of this study was to assess the incidence and natural history of Leydig cell tumours (LCT) of the testes. A search of the National Cancer Registry of Ireland database was performed regarding Leydig cell testicular tumours. Recurrence free survival (RFS) and disease-specific survival (DSS) were analysed. Between 1994 and 2013, 2755 new cases of testicular cancer were diagnosed in Ireland. Of these, 22 (0.79%) were Leydig cell tumours. Nineteen were invasive (stage T1) and three were in situ (stage Tis). One patient developed a local recurrence following an organ preserving procedure and underwent a completion orchidectomy 107 days after initial diagnosis. No further treatment was required. There have been no disease-specific deaths. The 1-, 3- and 5-year overall survival (OS) rates were 95.5, 88.2 and 73.3%, respectively. The 5-year disease-specific survival (DSS) was 100% and the 5-year recurrence free survival (RFS) was 93.3%. From the National Cancer Registry, LCT has been shown to be a rare subtype of testicular tumour. Due to the relatively favourable natural history, it may be possible to tailor less aggressive surveillance regimens in these patients.

Leydig cell tumours of the testis are uncommon. They typically present in a bimodal age distribution between either 5 and 10 years of age, or 20 to 60 years of age. Affected prepubertal boys usually present with a palpable lump or precocious puberty. With improvements in imaging technology, diagnosis can be incidental and precede clinical symptoms. This report describes the incidental finding of a Leydig cell tumour of the testis in an eight-year-old boy with a history of scrotal trauma and haematuria.

Leydig-cell tumours (LCT) of the testis are poorly understood clinically. The aim of this report is to analyse the clinical characteristics of LCT in a large patient sample and to compare these findings with corresponding data of germ-cell tumours (GCT). In a sample of 208 patients treated during 1995–2017 in 33 institutions, the following characteristics were registered: age, presenting symptoms, primary tumour size, testis-sparing surgery (TSS) or orchiectomy, malignancy, laterality, medical history, and outcome. Data analysis included descriptive statistical methods and logistic regression analysis. The ratio LCT:GCT is 1:23 (4.4%). The findings are as follows: median age 41 years, undescended testis 8%, bilateral LCTs 3%, malignant LCT 2.5%, contralateral GCT 2.5%, incidental detection 28%, scrotal symptoms 43%, infertility 18%, elevated estradiol levels 29%. TSS was performed in 56% with no local relapse. Of the patients with malignant LCT, one was cured through surgery. LCT is rare, with a relative frequency (relative to GCT) of 1:23. Malignancy is found in 2.5%. LCT and GCT share a number of clinical features, e.g. bilaterality, history of undescended testis, and presenting age. TSS is safe in benign LCT. Surgery is the treatment of choice in malignant LCT.

There are various causes of primary amenorrhea in phenotypically females such as, complete androgen insensitivity syndrome, pure gonadal dysgenesis, 17b-hydroxysteroid dehydrogenase deficiency, or mixed gonadal dysgenesis. Primary amenorrhea in a phenotypically female is commonly encountered in Androgen Insensitivity Syndrome. In patients with Androgen Insensitivity Syndrome, with intra-abdominal testis there is high chances of developing testicular tumour, among them Sertoli cell tumour and seminoma being the most common types. Leydig cell tumour in androgen insensitivity syndrome, is very rare and malignant leydig cell tumour is even further rarer. There are few cases reported in the literature of malignant leydig cell tumour with complete androgen insensitivity. Here we are reporting a case of 65 years married elderly patient with malignant leydig cell tumour with complete androgen insentivity syndrome. Keywords: complete androgen insensitivity syndrome; leydig cell tumour; testicular feminization.

Leydig-cell tumours (LCTs) are rare endocrine tumours of the testicular interstitium, with recent increased incidence. Symptoms include precocious puberty in children; and erectile dysfunction, infertility and/or gynaecomastia, in adults. So far, scientific evidence points to aromatase (CYP19) overexpression and excessive oestrogen and insulin-like growth factor (IGF) –1 production as responsible for Leydig-cell tumourigenesis. LCTs are usually benign; however, malignant LCTs respond poorly to chemo/radiotherapy, highlighting the need to identify novel targets for treatment. Herein, we investigated the potential role of the histamine receptor H4 (HRH4) as a therapeutic target for LCTs using R2C rat Leydig tumour cells, a well-documented in vitro model for Leydigioma. Also, we studied for the first time the expression of CYP19, IGF-1R, oestrogen receptor (ER) α, ERβ, androgen receptor (AR) and HRH4 in human prepubertal LCTs versus normal prepubertal testes (NPTs). HRH4 agonist treatment inhibited steroidogenesis and proliferation in R2C cells and also negatively affected their pro-angiogenic capacity in vitro and in vivo, as assessed by evaluating the proliferative activity of human umbilical vein endothelial cells and by means of the quail chorioallantoic membrane assay, respectively. Moreover, E2 and IGF-1 inhibited HRH4 mRNA and protein levels. In human prepubertal LCTs, CYP19, IGF-1R, ERα and ERβ were overexpressed compared with NPTs. In contrast, HRH4 staining was weak in LCTs, but moderate/strong and confined to the interstitium in NPTs. Importantly, HRH4 was absent or barely detectable in seminiferous tubules or germ cells. Overall, our results point to HRH4 as a novel therapeutic target in LCTs. Fil: Abiuso, Adriana María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Varela, María Luisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Haro Durand, Luis Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Besio Moreno, Marcos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Marcos, Alejandra Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Ponzio, Roberto. Universidad de Buenos Aires. Facultad de Medicina; Argentina Fil: Rivarola, Marco Aurelio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Belgorosky, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Pignataro, Omar Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Berensztein, Esperanza Beatriz. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Mondillo, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina

Markedly elevated androgen levels can lead to clinical virilization in females. Clinical features of virilization in a female patient, in association with biochemical hyperandrogenism, should prompt a search for an androgen-producing tumor, especially of ovarian or adrenal origin. We herein report the case of a 60-year-old woman of Pakistani origin who presented with the incidental finding of male pattern baldness and hirsutism. Her serum testosterone level was markedly elevated at 21 nmol/L (normal range: 0.4–1.7 nmol/L), while her DHEAS level was normal, indicating a likely ovarian source of her elevated testosterone. Subsequently, a CT abdomen-pelvis was performed, which revealed a bulky right ovary, confirmed on MRI of the pelvis as an enlarged right ovary, measuring 2.9 × 2.2 cm transaxially. A laparoscopic bilateral salpingo-oophorectomy was performed, and histopathological examination and immunohistochemistry confirmed the diagnosis of a Leydig cell tumor, a rare tumor accounting for 0.1% of ovarian tumors. Surgical resection led to normalization of testosterone levels. Learning points: Hirsutism in postmenopausal women should trigger suspicion of androgen-secreting tumor Extremely elevated testosterone level plus normal DHEAS level point toward ovarian source Leydig cell tumor is extremely rare cause of hyperandrogenicity

A testicular Leydig cell tumour associated with metastatic disease is reported in a dog. An enlarged testis and three cutaneous nodules resected from an 11-year-old golden retriever were submitted for histopathological examination. Both testicular and cutaneous lesions showed identical morphological and cytological changes. Immunohistochemical labelling for expression of inhibin-α and calretinin confirmed the Leydig origin of the cutaneous neoplastic population. Based on the morphological and immunohistochemical findings, a final diagnosis of multiple cutaneous metastasis of a malignant testicular Leydig cell tumour was made.

Background and objectives: Testicular Leydig cell tumours (LCTs) are rare, steroid-secreting tumours. Elevated levels of aromatase (CYP19 or CYP19A1) mRNA have been previously described in LCTs; however, little is known about the mechanism(s) causing CYP19 over-expression. We report an LCT in a 29-year-old male with elevated plasma oestradiol caused by enhanced CYP19 transcription. Design and methods: First, we measured the intra-tumour expression of CYP19 and determined the use of CYP19 promoters by qPCR. Secondly, we explored CYP19 and promoter II (PII) for gene amplifications and activating mutations in PII by sequencing. Thirdly, we analysed intra-tumour expression of steroidogenic factor 1 (SF-1 (NR5A1)), liver receptor homologue-1 (LRH-1 (NR5A2)) and cyclooxygenase-2 (COX2 (PTGS2)). Finally, we analysed SF-1 for promoter mutations and gene amplifications. Results: Similar to what has been recorded in normal Leydig cells, we first found the bulk of tumour CYP19 transcripts to be PII derived, excluding promoter shift as a cause of enhanced transcription. Secondly, we excluded CYP19 and PII gene amplifications, and activating mutations in PII, as causes of elevated CYP19 mRNA. We found SF-1 mRNA to be up-regulated in the tumour, while LRH-1 and COX2 were down-regulated. The finding of elevated SF-1 levels in the tumour was confirmed by immunohistochemistry. The elevated level of SF-1 was not due to promoter mutations or amplifications of the SF-1 gene. Conclusions: Our results strongly suggest that the elevated levels of SF-1 have induced PII-regulated CYP19 transcription in this tumour. These findings are of relevance to the understanding of CYP19 up-regulation in general, which may occur in several tissues, including breast cancer.

Seven patients (aged 25-38 years) were admitted because of mono- or bilateral gynaecomastia. Plasma levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, testosterone, 17-beta-estradiol, delta4-androstenedione, dehydropiandrosterone sulphate (DHEA-S) and 17-OH-progesterone were determined and semen analysis was carried out. FSH and LH levels were also measured after acute LH-RH administration (100 microg intravenously), and testosterone and 17-beta-estradiol were also evaluated after acute human chorionic gonadotrophin (hCG) administration (5000 IU intramuscularly). Testicular echography demonstrated the presence of a solid hypoechoic tumour. Therefore all patients were submitted to hemicastration by orchidofuniculotomy and a benign Leydig cell tumour was diagnosed in the removed testes. Hormonal and semen evaluations were repeated 3, 6, 9 and 12 months after surgery. The data before and after surgery were compared with a control group of 10 age-matched males. Before surgery, patients showed low FSH basal plasma levels; high levels of 17-beta-estradiol and low testosterone levels similar to those after hCG administration. A dyspermia was observed. Unilateral orchidectomy eliminated the autonomous secretion of oestrogen(s) so an increase of LH, FSH and testosterone levels, together with an improvement of spermatogenesis, were obtained.

OBJECTIVE To review all non-germ-cell testicular lesions presenting at our institution and to determine the feasibility of testis-sparing surgery for these patients. PATIENTS AND METHODS All surgery for testicular masses between June 1995 and June 2005 were reviewed retrospectively. Patients with atrophy, germ cell tumours, infection or torsion were excluded. The study comprised men who had radical orchidectomy for suspected germ-cell tumour but had other final pathology, and those where testis-sparing surgery was attempted for a presumed benign lesion. RESULTS Thirteen patients with lesions appropriate for the study were identified; all but one had a palpable lesion. The lesions could be categorized as inflammatory (three hyalinized fibrosis, two sarcoidosis, one chronic inflammation), cystic (one epidermoid cyst, one unilocular cyst), benign neoplasms (two adenomatoid tumours, one Leydig cell tumour, one capillary haemangioma) or malignant neoplasms (one lymphoma). Based on the preoperative impression, testis-sparing surgery was attempted in eight of the lesions and was successful in six where it was attempted. In the other five, testis-sparing surgery was not attempted because the preoperative impression was that of a germ cell tumour. Testis-sparing surgery was successful in only six of the 13 patients with these lesions. CONCLUSION Testis-sparing surgery might be possible if there is significant suspicion of a benign lesion. If frozen-section analysis is equivocal, a radical orchidectomy is required. Testis-sparing surgery was feasible in highly selected cases.

Context Male patients with congenital adrenal hyperplasia (CAH) may develop bilateral testicular adrenal rest tumours (TARTs). These tumours, in most cases, regress with glucocorticoid therapy and their histological differentiation from Leydig-cell tumors is quite difficult. Objective The aim of this study was to differentiate the histological and clinical features of the TARTs from those of the Leydig-cell tumours. Methods The authors report a case of bilateral Leydig-cell tumour associated with giant bilateral adrenal myelolipoma in a male with adrenogenital syndrome who was submitted to a bilateral orchiectomy. Results Testicular neoplasia continue to grow despite adequate hormonal treatment and a bilateral orchiectomy was performed. The histopathological examination of the specimen ultimately confirmed the diagnosis of bilateral Leydig-cell tumour. Conclusions This case shows the importance of all the relevant examinations, blood chemistry analysis, and instrumental tests in the differential diagnosis of TARTs and other testicular tumours.

Leydig cell testicular tumours are a rare cause of precocious pseudopuberty in boys. Surgery is the main therapy and shows good overall prognosis. The physical signs of precocious puberty are expected to disappear shortly after surgical removal of the mass. We report two children, 7.5 and 7.7 year-old boys, who underwent testis-sparing surgery for a Leydig cell testicular tumour causing precocious pseudopuberty. During follow-up, after an immediate clinical and laboratory regression, both boys presented signs of precocious puberty and ultimately developed central precocious puberty. They were successfully treated with gonadotropin releasing hormone analogues. Only 6 other cases have been described regarding the development of central precocious puberty after successful treatment of a Leydig cell tumour causing precocious pseudo puberty. Gonadotropin-dependent precocious puberty should be considered in children treated for a Leydig cell tumour presenting persistent or recurrent physical signs of puberty activation. In such cases, therapy with gonadotropin releasing hormone analogues appears to be the most effective medical treatment.

Among the various causes of gynaecomastia, testicular malignancies are an uncommon, life-threatening condition, which require prompt treatment. The case of a 26-year-old healthy man is described, who reported a 6-month painful bilateral gynaecomastia associated with secondary hypogonadism. Normal circulating 17beta-oestradiol (E2) levels showed an enhanced response to human chorionic gonadotrophin (hCG) testing, which led to a reduced testosterone (T)/E2 ratio. Both clinical and hormonal findings normalized following surgical exeresis of a left testicular mass, which proved to be a Leydig cell tumour (LCT) at histology. This report underlines the importance of ultrasonographic evaluation of the testes, whenever breast enlargement occurs in a healthy man, despite unremarkable findings on testicular examination. In addition, our case demonstrates that normal unstimulated circulating E2 levels do not allow the presence of a stromal testicular tumour to be ruled out and that the response of restored T levels to hCG testing can remain blunted up to 1 year after surgery. Finally, we claim that T/E2 ratio may be a useful tool in evaluating derangement of the endocrine milieu secondary to LCT.

Cell cycle dysregulation is one of the defining features of cancer. Cyclin-dependent kinase 4 (CDK4), together with its regulatory subunit cyclin D, governs cell cycle progression through the G1 phase. Cyclin-dependent kinase inhibitors, including p16(INK4A) (encoded by CDKN2A), in turn regulate CDK4. In particular, dysregulation of the p16/CDK4/cyclin D complex has been established in a variety of types of human tumours. Dominant activating mutations affecting codon 24 of the CDK4 gene (replacement of Arg24 by Cys or His) render CDK4 insensitive to p16(INK4) inhibition and are responsible for melanoma susceptibility in some kindreds. However, 'knock-in' mice homozygous for the CDK4(R24C) mutation were noted to develop multiple neoplasia, most commonly including endocrine tumours: pituitary adenomas, insulinomas and Leydig cell testicular tumours. We therefore speculated that sporadic human endocrine tumours might also harbour such mutations. The aim of the current study was to analyze the CDK4 gene for the two characterized activating mutations, R24C and R24H, in sporadic human pituitary adenomas, insulinomas and Leydig cell tumours. We used DNA extracted from 61 pituitary adenomas, and paired tumorous and neighboring normal genomic DNA extracted from 14 insulinoma and 6 Leydig cell tumour samples. Genomic DNA from patients with familial melanoma harbouring the R24C or the R24H mutations served as positive controls. All samples were subjected to PCR, mutation-specific restriction digests and/or sequencing. Both methodologies failed to detect mutations at these two sites in any of the sporadic endocrine tumours including pituitary adenomas, benign or malignant insulinomas or Leydig cell tumours, while the positive controls showed the expected heterozygote patterns. Protein expression of CDK4 was demonstrated by immunohistochemistry and Western blotting in pituitary and pancreatic samples. These data suggest that the changes in the regulatory 'hot-spot' on the CDK4 gene, causing various endocrine tumours in CDK4(R24C/R24C )mice, are not a major factor in sporadic pituitary, insulin beta-cell or Leydig cell tumorigenesis.

Leydig-cell tumours of the testis are rare and usually benign in children. The possibility of metachronous bilateral tumours should be considered not only for testicular teratomas but also in the follow up of a Leydig-cell tumour. Testis-sparing surgery is feasible and safe in prepubertal boys after exclusion of a malignant tumour.

Androgen-producing ovarian tumours can lead to assessment difficulties because of their small size. We present a case of virilising steroid cell ovarian tumour in a 41-year-old woman localised with Fluorine-18-Deoxyglucose Positron Emission Tomography/Computed Tomography ((18)FDG-PET/CT). Although the biochemical evaluation pointed to an ovarian source of androgen, diagnostic attempts to localise the source of hyperandrogenism with transvaginal ultrasound (US), and magnetic resonance imaging (MRI) of pelvis failed. Additional evaluation with (18)FDG-PET/CT showed an increased uptake in the right ovary. A laparoscopic right oophorectomy was performed and histopathology examination revealed a 1.2-cm Leydig cell tumour. The patient showed regression of clinical signs.

Gynaecomastia (enlargement of the male breast tissue) is a common finding in the general population. Most cases of gynaecomastia are benign and of cosmetic, rather than clinical, importance. However, the condition might cause local pain and tenderness, could occasionally be the result of a serious underlying illness or a medication, or be inherited. Breast cancer in men is much less common than benign gynaecomastia, and the two conditions can usually be distinguished by a careful physical examination. Estrogens are known to stimulate the growth of breast tissue, whereas androgens inhibit it; most cases of gynaecomastia result from deficient androgen action or excessive estrogen action in the breast tissue. In some cases, such as pubertal gynaecomastia, the breast enlargement resolves spontaneously. In other situations, more active treatment might be required to correct an underlying condition (such as hyperthyroidism or a benign Leydig cell tumour of the testis) or medications that could cause breast enlargement (such as spironolactone) might need to be discontinued. For men with hypogonadism, administration of androgens might be helpful, as might antiestrogen therapy in men with endogenous overproduction of estrogens. Surgery to remove the enlarged breast tissue might be necessary when gynaecomastia does not resolve spontaneously or with medical therapy.

We present the first reported case of a concomitant Leydig cell tumour (LCT) and paratesticular leiomyoma in an adult man with a history of bilateral cryptorchidism. An 80-year-old man presented with a 2-month history of a left testicular lump associated with mild discomfort and a gradual increase in size on a background of bilateral cryptorchidism requiring multiple orchidopexy procedures as a child. Ultrasound confirmed a lesion suspicious for malignancy and he proceeded to a left radical orchidectomy. Histopathological assessment of the left testis revealed a concomitant testicular LCT with rare malignant features and paratesticular leiomyoma.

International audience; ContextMultiple Endocrine Neoplasia Type 1 (MEN1) is an autosomal dominant inherited syndrome, related to mutations in the MEN1 gene. Controversial data suggest that the nonsynonymous p.Ala541Thr variant, usually considered as a non-pathogenic polymorphism, may be associated with an increased risk of MEN1-related lesions in carriers.ObjectiveThe aim of this study was to evaluate the pathogenic influence of the p.Ala541Thr variant on clinical and functional outcomes.Patients and methodsWe analysed a series of 55 index patients carrying the p.Ala541Thr variant. Their clinical profile was compared to that of 117 MEN1 patients. The biological impact of the p.Ala541Thr variant on cell growth was additionally investigated on menin-deficient Leydig cell tumour (LCT)10 cells generated from Men1+/Men1− heterozygous knock-out mice, and compared with wild type (WT).ResultsThe mean age at first appearance of endocrine lesions was similar in both p.Ala541Thr carriers and MEN1 patients, but no p.Ala541Thr patient had more than one cardinal MEN1 lesion at initial diagnosis. A second MEN1 lesion was diagnosed in 13% of MEN1 patients and in 7% of p.Ala541Thr carriers in the year following preliminary diagnosis. Functional studies on LCT10 cells showed that overexpression of the p.Ala541Thr variant did not inhibit cell growth, which is in direct contrast to results obtained from investigation of WT menin protein.ConclusionTaken together, these data raise the question of a potential pathogenicity of the p.Ala541Thr missense variant of menin that commonly occurs within the general population. Additional studies are required to investigate whether it may be involved in a low-penetrance MEN1 phenotype.; ContexteLa néoplasie endocrinienne multiple de type 1, NEM1, est une affection à transmission autosomique dominante qui associe chez un même patient ou ses apparentés des tumeurs des parathyroïdes, du pancréas endocrine et de l’hypophyse. Des données controversées suggèrent que le variant Ala541Thre pourrait avoir un rôle pathogénique, et pourrait être associé à un risque accru de développer des lésions de MEN1.ObjectifsLe but de cette étude était d’évaluer les atteintes cliniques et fonctionnelles du variant p.Ala541Thr.Patients et méthodesNous avons analysé une série de 55patients porteurs du variant p.Ala541Thr. Leur présentation clinique a été comparée à celle de 117patients MEN1. L’effet biologique de ce variant sur la croissance cellulaire a été également étudié dans un modèle cellulaire issus de tumeurs de cellules de Leydig déficientes en MEN1 (LCT10).RésultatsL’âge moyen à la première lésion est similaire dans les 2groupes p.Ala541Thr et MEN1, mais aucun des patients p.Ala541Thr n’avait plus d’une lésion au diagnostic. Une deuxième lésion a été diagnostiquée chez 13% des MEN1et 7% des p.Ala541Thr l’année qui a suivi le diagnostic initial. Les études fonctionnelles montrent que la réexpression du variant p.Ala541Thr ne permet pas d’inhiber la croissance cellulaire, contrairement à ce qui a été observé avec la protéine sauvage.ConclusionsCe travail vient perturber le concept de polymorphisme et de leur potentielle non-pathogénicité. Des études complémentaires sont cependant nécessaires afin de déterminer si ce variant peut-être impliqué dans la survenue d’un phénotype MEN1de faible pénétrance.

690 patients were treated for testicular tumour in the course of 18 years. The histology of 7 cases showed Leydig cell tumour. In 4 of the 7 cases, a metastatic process leading to death was observed. At the time of diagnosis, 5 patients were found to have low stage, whereas 2 of the patients had advanced lymphatic involvement. The hematogenous and lymphatic metastases proved to be resistant to chemotherapy. Contrary to the major part of the literature, retroperitoneal lymphadenectomy should be performed with this histological type for the exact pathological staging immediately following orchiectomy.

Inhibin is a peptide hormone produced by ovarian granulosa cells and testicular Sertoli cells. Ovarian granulosa cell and other sex cord-stromal tumors usually exhibit positive immunohistochemical staining with antiinhibin antibodies, and this may be valuable in differentiating these neoplasms from histologic mimics. In the present study, we investigated the immunohistochemical staining of testicular sex cord-stromal tumors using antiinhibin. Immunostaining with CAM5.2, vimentin, S-100 protein, desmin, epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), and placental alkaline phosphatase (PLAP) also was performed because few studies have investigated in detail the immunophenotype of testicular sex cord-stromal tumors. Fifteen of 16 Leydig cell tumors exhibited strong positive staining with antiinhibin. A proportion of Leydig cell tumors also stained positively with CAM5.2 (7 of 16), vimentin (14 of 16), S-100 protein (10 of 16), desmin (2 of 16) and epithelial membrane antigen (4 of 16). Four of six testicular sex cord-stromal tumors with varying degrees of Sertoli or granulosa cell differentiation were positive with antiinhibin, as were two of three sex cord-stromal tumors that were unclassified. Some of these tumors were positive with CAM 5.2, vimentin, S-100 protein, desmin, and epithelial membrane antigen. All tumors were negative with carcinoembryonic antigen and placental alkaline phosphatase. The immunohistochemical findings show that, analogous to their ovarian counterparts, most testicular sex cord-stromal tumors are immunoreactive with antiinhibin. Immunohistochemistry using this antibody as part of a panel may be valuable in confirming a diagnosis of testicular sex cord-stromal tumor and in differentiating these neoplasms from others that may mimic them.

Synchronous bilateral testicular germ cell tumours (TGCT) of different origin are very rare; the simultaneous appearance of a TGCT with a contralateral benign non-germ cell tumour represents an even more seldom event. We report on three patients with nonseminomatous TGCT and a contralateral benign testis tumour being Leydig cell tumour, leiomyoma and epidermopid cyst, respectively. Patients were treated by radical orchiectomy in one case and by enucleation resection of the tumour in two cases. After follow-up of more than 5 years all patients are NED; no local recurrence occurred in the patients treated by tumour enucleation with their endogenous testosterone production being maintained. Although very rare the simultaneous appearance of a malignant TGCT and a contralateral benign intratesticular mass should be considered with bilateral tumours. Frozen section examination of the tumours might enable an organ sparing approach in benign testis tumours thereby maintaining endogenous testosterone production and fertility.

Leydig cell hyperplasia and Leydig cell tumours of the ovary are rare. We present two cases in which patients had increased blood levels of testosterone and frank hirsutism. Imaging showed minimal abnormalities. After adrenal disease had been ruled out, they underwent a bilateral oophorectomy. One case showed a Leydig cell hyperplasia, the other a Leydig cell tumour. An androgen producing tumour should be excluded in every woman with evidence of hirsutism or frank virilization and markedly elevated testosterone levels. Adrenal disease with androgen hypersecretion can be suspected by detailed clinical, laboratory and radiologic imaging. Although DHEAS has a good sensitivity in the detection of adrenal origin of hyperandrogenism (and hence a good negative predictive value) it is not specific (specificity ranging from 85 to 98%). Imaging of the ovaries can be helpful but does not rule out ovarian disease if normal. Indeed, diffuse stromal Leydig cell hyperplasia and Leydig cell tumours (usually small) may escape imaging and in some cases diagnosis can only be made on pathology. As these clinical entities represent a diagnostic and therapeutic challenge, oophorectomy should be considered in postmenopausal women with hirsutism and elevated testosterone levels, after the exclusion of adrenal causes. The procedure is relatively safe and effective. Follow-up remains indicated.

Androgen-secreting ovarian tumours are extremely rare accounting for

A 65-year-old woman presented to the endocrine clinic with increasing facial hirsutism over the past 6 months. She was noted to have excess hair on forearms, back and abdomen, along with some frontal balding. There were no abnormalities of the external genitalia, blood pressure was satisfactory and weight was stable. Biochemistry confirmed elevated testosterone (4.1 nmol/l). No abnormalities were seen on CT of abdomen and pelvis, nor by transvaginal ultrasound of the ovaries. Six months after her initial clinic visit, testosterone had increased to 6.0 nmol/l, rising to 7.3 nmol/l a few months later. Testosterone failed to suppress to low-dose dexamethasone suggesting excessive adrenal production was unlikely. Urine steroid profiling revealed no abnormality of adrenal steroid metabolites. Testosterone suppression was achieved with a rapidly-acting luteinizing-hormone-releasing hormone antagonist (cetrorelix), suggesting an ovarian source of excess production. Histology following bilateral salpingo-oophorectomy revealed a benign 6 mm diameter Leydig cell tumour in the right ovary.

Case Report: A 10-year-old male was referred to our institution due to short stature and bilateral cryptorchidism and reported pubic hair development and acne since the age of 4 years. Laboratory and molecular genetic tests indicated congenital adrenal hyperplasia due to 21-hydroxylase deficiency. After treatment with prednisone, adrenal hormones normalised but testosterone remained elevated. Magnetic resonance imaging of the abdomen due to cryptorchidism revealed uterus and adnexal attachments, a prostate and poorly defined nodules on the iliac chains. Upon exploratory laparotomy, a hysterectomy, bilateral oophorectomy and resection of a peri-adnexal nodular lesion on the patient's right side were performed. Histopathology of the nodule mass was compatible with a Leydig cell tumour with a low proliferation rate according to Ki67.

Kuhn JM, Duranteau L, Rieu MA, Lahlou N, Roger M, Luton JP. Evidence of oestradiol-induced changes in gonadotrophin secretion in men with feminizing Leydig cell tumours. Eur J Endocrinol 1994;131:160–6. ISSN 0804–4643 To study the sex steroid-gonadotrophin relationship, plasma oestradiol (E2), testosterone and gonadotrophin-releasing hormone (GnRH)-induced (100 μg iv) gonadotrophin response were measured in 42 male partners of infertile couples with normal sperm count (group I) and in 21 men with Leydig cell tumour (LCT, group II) in which a basal evaluation was repeated after tumour removal. Plasma free α-subunit (FAS), immunoreactive α-inhibin and luteinizing hormone (LH) pulse analysis were assessed in 10 LCT before and in six of them after surgery. Testosterone was significantly (p < 0.01) lower whereas E2 was significantly (p < 0.001) higher in group II than in group I. Gonadotrophin data were similar in both groups. The mean FAS was higher in group II than in group I and α-inhibin was higher than the normal range in 6/10 LCT. In group II, E2 levels were significantly (p < 0.01) and negatively correlated with testosterone, FSH, GnRH-induced gonadotrophin rise and LH pulse amplitude but not frequency. Significant (p < 0.001) changes were observed after surgery: E2 and α-inhibin fell; testosterone, LH and FSH rose; whereas FAS did not change significantly. The LH pulse amplitude but not frequency increased significantly (p < 0.05). In conclusion E2 oversecreted by LCT decreased LH and testosterone levels concomitantly. The GnRH-induced gonadotrophin level rose and the LH pulse amplitude decreased when the plasma E2 level rose, whereas the pulse frequency remained unaffected. A concomitant increase in α-inhibin and E2 is likely to be responsible for the drop in plasma FSH levels. These data support an action of excessive amounts of E2 at pituitary level, perhaps by decreasing the sensitivity of gonadotrophs to GnRH. JM Kuhn, Service d'Endocrinologie, Hôpital de Bois Guillaume, 147 avenue du Maréchal Juin, 76230 Bois Guillaume, France

Pubertal gynecomastia is common, and may affect up to 70% adolescents boys. Its course is spontaneously benign with resolution occurring by age 18 years. Although the exact physio-pathological mechanism remains unknown, it is thought to result from hormonal imbalance between estrogens and testosterone at puberty. Association with Leydig cell tumour is more common in adults, so that scrotal ultrasound is part of routine work up. A 15-years-old boy with Leydig cell tumour revealed by bilateral gynecomastia is reported. Diagnosing this condition requires high level of suspicion, we suggest that clinicians always do a testicular examination on adolescents especially if they have gynecomastia, scrotal ultrasound may be performed in boys aged > or =14 years with gynecomastia that measures > or =4 cm, should there be any doubt.

A 60-year-old woman, presented with hirsutism, male pattern baldness, deepening voice and plethora over the past 5 years. Hormonal evaluation showed markedly elevated serum testosterone level (> 1600 ng/dl) and oestradiol level (220 pg/ml) normal DHEA-SO4 level with suppressed LH and FSH levels. She had markedly erythrocytosis with normal hematological indices. The diagnosis of probable secondary erythrocytosis was made. Trans abdominal ultrasound and CT scan revealed a 14 cm × 11 cm × 9 cm solid pelvic mass. An ovarian androgen secreting tumour was suspected and surgery was performed. Histological examination showed a leydig cell tumour. After the operation testosterone and haematocrit levels returned to normal with regression of clinical symptoms. This is the first case of a leydig cell tumour with an erythropoietic effect of excess testosterone.

Objective The purposes of our study concerning two patients with oestrogen secreting Leydig cell tumour were to determine whether endogenous LH levels are involved in testicular tumour steroidogenesis and whether aromatase activity of oestrogen secreting Leydig cell tumours is directly or indirectly dependent on LH levels. Measurements E2 and T were evaluated after hCG injection (5000 IU) during 96 hours. Bio and immuno LH, T, E2, were determined at the basal state and after administration of D-Trp-6-GnRH agonist (3.75 mg) every 3 weeks. The abnormal testis was removed after the third injection and testicular venous blood was collected during the operation. Testicular tumour was incubated with 4-14C-T. Results Oestradiol (E2) response to hCG injection (5000 IU) was prolonged and exaggerated while that of testosterone (T) was similar to that of the controls. The aromatase index (E2/T) remained elevated even 96 hours after hCG. Intramuscular injection of the GnRH agonist, D-Trp-6-GnRH (3.75 mg) resulted in a reduction of immunoreactive and bioactive LH. T was decreased to about 10% of baseline levels and E2 fell from 240 to 36 pmol/l. In the blood of the spermatic veins collected in the course of surgery, E2 levels were found to be lower in comparison with the controls. E2 was found to be twofold higher in the spermatic vein draining the tumoral side than in that of the contralateral testis. Incubation of the testicular tumours with 4-14C-T, displayed a reduced aromatase activity (conversion of T to E2: 0.3 and 0.1% in patients 1 and 2 respectively). Conclusions The kinetics of E2 response to hCG administration would suggest a modification of the regulation of the aromatase activity in this type of oestrogen secreting tumour. A certain endogenous LH level may be necessary to supply a sufficient quantity of T substrate, and to maintain aromatase activity of such Leydig cell tumours secreting oestrogens. These tumours seem to be responsive to endogenous LH levels.

We have studied immunolocalization of all steroidogenic enzyme involved in sex steroids biosynthesis, P-450 side chain cleavage (P-450scc), 3 beta hydroxy steroid dehydrogenase (3 beta-HSD), P-450 17 alpha hydroxylase (P-450(17 alpha)) and P-450 aromatase (P-450arom) and that of vimentin and cytokeratin in 14 cases of testicular sex cord-stromal tumours (6 Leydig cell tumours, 5 Sertoli cell tumours, 2 fibromas and 1 granulosa cell tumour) as well as 4 cases of hyperplasia (2 Leydig and 2 Sertoli). Leydig cell tumour expressed all four steroidogenic enzymes examined, indicating that this tumour can synthesize oestrogen from cholesterol. In 2 cases of Sertoli cell tumour, the tumour cells with clear cytoplasm and without Reinke's crystals expressed P-450ssc, 3 beta-HSD and P-450(17 alpha), suggesting the capability of androgen production in these tumour cells. Fibromas and granulosa cell tumour were negative for the enzymes examined. In immunohistochemistry of intermediate filaments, Leydig cell tumours demonstrated only vimentin. Sertoli cells in hyperplasia and non-neoplastic testis expressed only vimentin but Sertoli cell tumours expressed both cytokeratin and vimentin. Cytokeratin immunoreactivity was correlated with morphological epithelial differentiation in Sertoli cell tumour. These findings in testicular Sertoli cell tumour are considered to represent the multiple differentiation capacity of this neoplasm. Immunohistochemical study of steroidogenic enzymes and intermediate filaments provided new insight into neoplastic steroidogenesis and the differentiation capacity of testicular sex cord-stromal neoplasms.

To report our single-centre experience of patients with Leydig cell tumour (LCT) of the testis, which represents the most frequent interstitial neoplasm of the testis, and for which the natural history and therapy are debated. Between 1990 and 2006, 37 patients were treated for LCT of the testis. All patients had testicular markers assessed and 21 (57%) had their hormonal profile assessed (total testosterone, follicle-stimulating hormone, luteinizing hormone and oestradiol). We analysed the symptoms at presentation, laboratory findings, organ-sparing vs. radical surgery and oncological and symptomatic follow-up data. Medical referral was for a testicular mass in 32% of patients, gynaecomastia in 8%, testicular pain in 8%, infertility in 11%, and isosexual pseudo-puberty in 5%. The mean (range) diameter of the tumour was 16.5 (6-68) mm. Before surgery testosterone levels exceeded the upper limit in a third of patients, while levels were hypogonadal in 19%. Oestradiol levels were increased in 29% of patients. At surgery, 29 patients (78%) had organ-sparing surgery. The median (range) follow-up was 4.6 (0.6-16.2) years; no patient had disease relapse. Gynaecomastia was present in two of six patients at the follow-up, despite pharmacological treatment. Four patients had a low testosterone level. Patients diagnosed with LCT have a good prognosis; this study shows the safety of conservative surgery. Surgical removal of the tumour is not always associated with resolution of symptoms and abnormal laboratory values. To report our single-centre experience of patients with Leydig cell tumour (LCT) of the testis, which represents the most frequent interstitial neoplasm of the testis, and for which the natural history and therapy are debated. Between 1990 and 2006, 37 patients were treated for LCT of the testis. All patients had testicular markers assessed and 21 (57%) had their hormonal profile assessed (total testosterone, follicle-stimulating hormone, luteinizing hormone and oestradiol). We analysed the symptoms at presentation, laboratory findings, organ-sparing vs. radical surgery and oncological and symptomatic follow-up data. Medical referral was for a testicular mass in 32% of patients, gynaecomastia in 8%, testicular pain in 8%, infertility in 11%, and isosexual pseudo-puberty in 5%. The mean (range) diameter of the tumour was 16.5 (6-68) mm. Before surgery testosterone levels exceeded the upper limit in a third of patients, while levels were hypogonadal in 19%. Oestradiol levels were increased in 29% of patients. At surgery, 29 patients (78%) had organ-sparing surgery. The median (range) follow-up was 4.6 (0.6-16.2) years; no patient had disease relapse. Gynaecomastia was present in two of six patients at the follow-up, despite pharmacological treatment. Four patients had a low testosterone level. Patients diagnosed with LCT have a good prognosis; this study shows the safety of conservative surgery. Surgical removal of the tumour is not always associated with resolution of symptoms and abnormal laboratory values.

The stromal Leydig cell tumour of the ovary is a very rare benign neoplasm which usually occurs in postmenopausal women. Due to a significant production of androgens by the tumour, it is frequently associated with symptoms of virilization. To our knowledge only 7 cases have been reported in the literature, one of them with bilateral manifestation. We report an additional case affecting both ovaries in a 59-year-old nun with long-standing virilism, review the literature, and discuss the histomorphological features for differential diagnosis.

A rare case of Sertoli and Leydig cell tumour was investigated in a 6-month-old boar. The neoplasm was found in the right testis and had metastasized to the liver, spleen, kidneys and diaphragmatic peritoneum. Metastatic nodules were also present in the tissues near the right testis and some neoplastic cells were present in the superficial inguinal lymph node. The neoplastic cells exhibiting severe pleomorphism were divided into Sertoli and Leydig cell types, although in some sites, it was not possible to classify tumour cells clearly as Sertoli or Leydig in type. In the metastatic lesions there were anaplastic Sertoli cells with abundant collagen fibres. Some neoplastic Sertoli cells and a few neoplastic Leydig cells revealed cytoplasmic reactivity for testosterone. Ultrastructurally, the neoplastic cells were characterized by mitochondria with tubulovesicular cristae, smooth endoplasmic reticulum, membranous structures, lysosomes, lipofuscin granules or lipid droplets.

International audience; Multiple endocrine neoplasia. type 1 (MEN1) is a hereditary syndrome caused by the inactivation of the responsible gene, MEN1. To date, the lack of MEN1-deficient cell lines derived directly from MEN1 tumours has hampered the detailed study of the MEN1 gene. We have established several stable Men1-deficient Leydig cell tumour (LCT) lines derived from a Leydig cell tumour developed in a male heterozygous Men I mutant mouse. Our data show that these cell lines maintain the basic characteristics of Leydig cells in terms of both androgen synthesis and gene expression. interestingly, reconstituted menin expression in one of Men1-deficient LCT cell lines resulted in cell growth inhibition, suggesting that the function of cell growth suppression of the menin pathway, apart from menin itself, is essentially preserved in these cells. Furthermore, we show that menin re-expression in these Men1-deficient cells leads to a block in the transition from G0/G1 to S phase of the cell cycle and an increase in apoptosis, accompanied by a marked increase of p18(INK4C) and p27(Kip1) expression. The current study therefore highlights the importance of menin expression in cell cycle and cell survival control in endocrine cells, and may provide insights into the mechanisms of tumour suppression by menin in related endocrine tumours.