Enucleation for prepubertal leydig cell tumor

PURPOSE: Leydig cell tumors in children are rare, comprising only 4% to 9% of all primary testis tumors in prepubertal males. Almost all of these boys present with isosexual precocious pseudopuberty associated with increased testosterone, low gonadotropin levels and a testis mass. We present our experience with testis sparing enucleation of Leydig cell tumor in prepubertal boys. MATERIALS AND METHODS: Two patients presented with isosexual precocious puberty at ages 6 and 9 years. Each patient had a well circumscribed, painless testicular mass, increased serum testosterone (101 and 444 ng/dl [normal 0 to 25]), normal gonadotropins and negative alpha-fetoprotein levels. Both patients underwent successful enucleation of the testis mass following proper testis oncological surgical principles. RESULTS: Both patients had normalization of the serum testosterone following enucleation of the Leydig cell tumor. At 9 and 44 months of followup they have maintained normal ipsilateral testicular volume compared to the contralateral gonad, and 1 patient entered puberty spontaneously at 1 year postoperatively. Neither patient suffered any morbidity, and both have presumably benefited from preservation of the involved gonad with preserved testicular volume. CONCLUSIONS: Prepubertal boys with isosexual precocious pseudopuberty, an isolated testis mass, increased testosterone and low or normal gonadotropin levels can reliably be diagnosed with Leydig cell tumors. Based on the ability to establish the diagnosis preoperatively and the universal benign behavior of unilateral, prepubertal Leydig cell tumor, we believe these patients are best treated with testis sparing enucleation of the tumor. In view of the high likelihood that this tumor in prepubertal boys is benign, a transscrotal surgical approach should be considered.     

Testicular tumors: wide spectrum in our short casuistics

Testicular tumors occur in 0.5 to 2 per 100,000 children. They are 1-2% of all solid tumors before puberty. The clinical history, testicular and abdominal ultrasonography, alpha-fetoprotein and human chorionic gonadotropin, estrogens and androgen levels, FSH and LH determine the diagnosis. The pathology determines the specific cell. We report seven cases, three germ cell tumors: a Yolk sac tumor in a child of 18 months and two mature teratomas in children between 2 and 11 years presenting as a painless testicular mass without other symptoms. Three tumors estrumales: one derived from Leydig cells and two of the granulosa cells, a palpable testicular mass was added precocious puberty in stage II-III of Tanner in the first, second gynecomastia in Tanner stage III and the third only with testicular mass. The seventh case, Lipoma para-testicular mass palpable. The treatment was radical orchiectomy in five cases. Testis-sparing surgery in Leydig cell tumor and resection of the paratesticular mass was performed through scrotal. The Yolk sac tumor requiring chemotherapy with good outcome. Retroperitoneal lymph node dissection is not recommended in prepubertal. Historically prepubertal testicular tumors have been treated in adults. Recent testicular preservation algorithms optimize and minimize the morbidity of adjuvant therapies. Many are benign and can be treated with preservation of the testis. Localized malignant tumors can be treated by orchiectomy.     

Bilateral Leydig cell tumor of the test: a case report

Testicular Leydig cell tumours are uncommon. Bilateral synchronous lesions are exceptional. They cause isosexual pseudo precocious puberty in childhood. The histological diagnosis of malignancy is sometimes difficult to establish and it can be made retrospectively when lymph nodes involvement or visceral metastasis appear in the follow-up. We report a case of a 9 year-old boy presenting bilateral Leydig cell tumour of the testis treated by bilateral radical orchiectomy who developed 2 years after the intervention a pulmonary metastasis.     

Is testosterone involved in the initiation of spermatogenesis in humans? A clinicopathological presentation and physiological considerations in four patients with Leydig cell tumours of the testis or secondary Leydig cell hyperplasia

The purpose of this study was to evaluate the role of testosterone on the puberal development of spermatogenesis and to present additional clinicopathological data which bring about new information to this controversial subject. Four pre-pubertal patients are presented, 2 of them bearing Leydig cell tumours of the testis in the form of nodular masses. In both cases seminiferous tubules in the immediate vecinity to the tumours showed complete development of spermatogenesis, while those located away from the tumours were infantile in nature. Gonadotrophic levels were within the normal pre-pubertal range in these 2 cases. In one of the patients, testosterone concentration in the testis showed higher values than normal, and a concentration gradient was detected between the tumoral nodule and non-tumoral parenchyma. The 3rd patient had a pineal choriocarcinoma producing high amounts of hCG and consequently a diffuse hyperplasia of Leydig cells with high levels of plasma testosterone. Seminiferous tubules showed development up to pachytene spermatocytes. The last case was a precocious puberty in a boy with a tumour of the 3rd ventricle area. He had elevated levels of testosterone in the testis and plasma. In the testicular biopsy, stimulation of Leydig cells was detected. The seminiferous tubules showed mature Sertoli cells and pachytene spermatocytes. FSH levels were abnormally low. These 4 cases present in common different situations in which abnormally high amounts of testos-happens in the immature rat, the interaction between testosterone and gonadotrophins is essential for the normal initiation of spermatogenesis in normal puberty. Considerations are discussed on the possible synergistic role of gonadotrophins or other factors in relation with stimulation of seminiferous tubules by testosterone.     

Leydig cell tumor in a child with spermatocyte maturation and no pseudoprecocious puberty

Leydig cell tumor in a child is uniformly associated with isosexual pseudoprecocity. We report a unique case of an 8-year-old boy diagnosed with Leydig cell tumor who had histologic evidence of discrete spermatocyte maturation and Sertoli cell hyperplasia along the periphery of his tumor but no clinical evidence of pseudoprecocious puberty.     

Morphometric study on leydig cells in capsulotomized testis of rats

AIM: To further clarify the changes occurred in the testicular capsulotomized rats. METHODS: In testicular capsulotomized and sham-operated rats, the cross sectional area, the nucleus diameter and the number of Leydig cells were morphologically analyzed by the Vidas Image Processing System connected to a microscope. RESULTS: In the capsulotomized animals, the cross sectional area of Leydig cells was gradually increased from 30 days onwards. There was no obvious change in the nucleus diameter of Leydig cells. However, The Leydig cell number was significantly increased from day 30 onwards. CONCLUSION: In rats, testicular capsulotomy may induce hyperplasia/hypertrophy of Leydig cells in the testis.     

Testicular histology in Klinefelter's syndrome

In 36 patients the diagnosis of Klinefelter's syndrome could not be made from the somatic status. A germinative sex examination must usually be carried out. Some set rules which are not applicable to all cases are outlined. Bearing this in mind, 3 groups are set up (excessive Leydig cell hyperplasia without tubuli, excessive Leydig cell hyperplasia with tubuli, incomplete or complete spermiogenesis) which will enable a better study. The relevant findings are tabulated and discussed. It shows that in Klinefelter's syndrome a great variability of testicular histology is to be expected. Special attention is devoted to 2 cases of histologically confirmed testicular spermatogenesis and aspermia in the ejaculate. It is suggested that a chromosomal disorder goes hand in hand with testicular histological findings, whereby all variations are possible.     

Men with nonobstructive azoospermia have Leydig cell hypertrophy but not hyperplasia

PURPOSE: We determined whether testicular histology in men with spermatogenic failure due to nonobstructive azoospermia shows true Leydig cell hyperplasia. MATERIALS AND METHODS: Testicular biopsy specimens from 17 patients evaluated for infertility were retrospectively analyzed. Interstitial, tubular and Leydig cell volume were quantitatively evaluated. The total volume and number of Leydig cells per testicle were then calculated. RESULTS: In 10 patients with obstructive azoospermia testicular histology showed normal spermatogenic function, while 7 had nonobstructive azoospermia. Average testicular volume plus or minus standard deviation was significantly larger in those with obstructive versus nonobstructive azoospermia (18.0 +/- 7.0 versus 9.3 +/- 8.7 cc, p = 0.025). Interstitial versus tubular volume was 32% of the total testis in the obstructive and 63% in the nonobstructive groups (p = 0.003). Although Leydig cell volume was proportionally greater in men with nonobstructive versus obstructive azoospermia (13.3% versus 0.05%, p = 0.045), there was no significant difference in the average number of Leydig cells per testicle (3.96 x 10 and 6.17 x 10, respectively, p = 0.16). The average volume of individual Leydig cells was significantly greater in men with the nonobstructive condition (253.0 +/- 98.7 versus 174.0 +/- 57.7 microm., p = 0.045). CONCLUSIONS: These results suggest that men with nonobstructive azoospermia and those with normal spermatogenesis have an equivalent number of Leydig cells. However, the Leydig cells are hypertrophic and occupy a larger proportion of total testis volume in men with nonobstructive azoospermia. Therefore, patients with spermatogenic failure show Leydig cell hypertrophy but not hyperplasia.     

Bilateral tumors of the testis in 21-alpha hydroxylase deficiency without adrenal hyperplasia

Congenital 21-alpha hydroxylase deficiency is a syndrome characterized by a cortisol synthesis deficiency and, rarely, by testicular masses. We present a case of bilateral nodular hyperplasia of the testis without adrenal hyperplasia in a patient affected by 21-alpha hydroxylase deficiency. This mass mimicked a testicular tumor and made differential diagnosis with a Leydig cell tumor extremely difficult. Multiple hard nodules (1 cm in diameter) could be palpated in both testes but were more prominent on the right. After an unsuccessful 30-day trial of an adrenocorticotropic hormone suppression regimen with dexamethasone (0.5 mg/qid), a right total orchifunicolectomy was performed. The final histological diagnosis was that of multiple, well-circumscribed nodules consisting of cord-like and microalveolar-like gonadal stroma, typical of an adrenogenital syndrome, and fibrosis. Differential diagnosis between testicular nodules in patients with congenital adrenal hyperplasia and Leydig cell tumors is a major clinical challenge. In cases of cortisol suppression resistant testicular masses, a serum adrenal hormone profile obtained from the gonadal vein and histology of the testicular nodule (with parenchyma sparing surgery) are recommended to obtain a correct diagnosis.     

Leydig cell transplantation restores androgen production in surgically castrated prepubertal rats

Prepubertal testicular dysfunction and the subsequent development of hypogonadism affects an estimated one in 200 children worldwide. As the testosterone levels are dynamic during development and puberty, traditional hormone treatment regimens are often inadequate, thereby leaving associated physiological conditions unresolved. Therefore, we have investigated the potential therapeutic effect of mature Leydig cell transplantation for the treatment of prepubertal primary hypogonadism through the use of a surgically induced hypogonadistic rat model system. In the experiment, Leydig cells were surgically isolated from mature Sprague-Dawley rats and transplanted into prepubertal recipients. Serum testosterone levels and microscopic analysis of the stained testicular interstitium were compared with sham-treated controls, as well as with castrated and intact rats during sexual development. At 4 weeks post-implantation, serum testosterone was detectable in Leydig cell recipients, but not in surgical controls, and progressively increased as a function of time until reaching levels comparable with sexually mature males at 12 weeks post-implantation. Histological analysis revealed a high rate of Leydig cell survival as well as steroidogenic secretory activity. Therefore, we conclude that mature Leydig cell transplantation in prepubertal hypogonadism recipients has therapeutic potential in rats and merits further investigation for clinical application.     

Interstitial-cell tumor of testicle in children

Precocious puberty due to a Leydig-cell testicular tumor associated with an elevated serum testosterone developed in a male dizygotic twin, four years and eleven months old. Orchiectomy resulted in regression of precocious puberty signs and a return of the serum testosterone to prepubertal concentrations.     

Idiopathic benign bilateral testicular enlargement in a pubertal boy: a case report and review of literature

We present a case of 12-year-old boy with idiopathic benign bilateral testicular enlargement. We eliminated precocious puberty, juvenile hypothyroidism, adrenal rest tumors, X-linked mental retardation, and bilateral testicular neoplasms. The clinical and laboratory features and differential diagnosis of benign bilateral testicular enlargement are discussed.     

Testicular Biopsy and Hormonal Study in a Male with Noonan''s Syndrome

The testicular biopsy study of a 17-year-old male with Noonan's syndrome revealed seminiferous tubules of reduced diameter with hypospermatogenesis. Many spermatocytes underwent degeneration and many spermatids developed abnormal. The Sertoli cells were similar to immature Sertoli cells. Fully differentiated Leydig cells were rare while precursor Leydig cells were numerous. Both gonadotropin and testosterone levels were low, and a lack of response to LH-RH as well as to clomiphene was found. The testicular biopsy performed at 20 years of age revealed a certain maturation of the seminiferous tubules which increased the germ cell number. The abnormalities in the spermatogenesis as well as the immature appearance of Sertoli cells continued. Leydig cells were more numerous and showed a certain development without reaching the normal pattern. Gonadotropin levels were normal while testosterone levels low. The response to LH-RH was increased and the absence of response to clomiphene persisted. These features suggest a delayed puberty.     

Testicular seminoma presenting withfeatures of androgen excess

A 32-year-old white man presented with worsening acne and noticeable increase in muscle bulk. On examination, a firmer area with a granular consistency was noted in the right testis. A right radical orchiectomy was performed and the histologic findings were those of a typical seminoma associated with marked Leydig cell hyperplasia. A solitary right iliac lymph node metastasis, but not the primary seminoma, contained human chorionic gonadotrophin- (HCG) producing syncytiotrophoblast, which was regarded as the hormonal stimulus for Leydig cell hyperplasia and elevated serum testosterone. This seems to be the first report of testicular seminoma presenting with symptoms of androgen excess.     

Hyperplasia of adrenal rests in the testicle: a rare cause of male infertility

We report the case of a 37-year-old man with infertility caused by bilateral testicular masses secondary to congenital adrenal hyperplasia (21-hydroxylase deficiency). Testicular biopsy was done and its was initially interpreted as Leydig cell tumor but after clinical information was histologically reclassified as tumor of the adrenogenital syndrome. The differential diagnosis with Leydig cell tumor is discussed and it must be established through the clinical, biochemical, radiological and pathological features.     

Infertility in a man with 21-hydroxylase deficient congenital adrenal hyperplasia

Congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency in men can cause profound oligospermia. The mechanism for this condition is overproduction of adrenal androgens, which in turn inhibit gonadotropin secretion. Men with a mild subclinical form of congenital adrenal hyperplasia may remain undiagnosed until adulthood. We report on a man who presented with infertility secondary to profound oligospermia. The treatment of this condition resulted in improved semen quality and subsequent conception. The importance of family history and determining whether precocious puberty was present, as well as obtaining appropriate laboratory tests is discussed.     

Brief maternal exposure of rats to the xenobiotics dibutyl phthalate or diethylstilbestrol alters adult-type Leydig cell development in male offspring

Maternal exposure to estrogenic xenobiotics or phthalates has been implicated in the distortion of early male reproductive development, referred to in humans as the testicular dysgenesis syndrome. It is not known, however, whether such early gestational and/or lactational exposure can influence the later adult-type Leydig cell phenotype. In this study, Sprague–Dawley rats were exposed to dibutyl phthalate (DBP; from gestational day (GD) 14.5 to postnatal day (PND) 6) or diethylstilbestrol (DES; from GD14.5 to GD16.5) during a short gestational/lactational window, and male offspring subsequently analysed for various postnatal testicular parameters. All offspring remained in good health throughout the study. Maternal xenobiotic treatment appeared to modify specific Leydig cell gene expression in male offspring, particularly during the dynamic phase of mid-puberty, with serum INSL3 concentrations showing that these compounds led to a faster attainment of peak values, and a modest acceleration of the pubertal trajectory. Part of this effect appeared to be due to a treatment-specific impact on Leydig cell proliferation during puberty for both xenobiotics. Taken together, these results support the notion that maternal exposure to certain xenobiotics can also influence the development of the adult-type Leydig cell population, possibly through an effect on the Leydig stem cell population.     

Testicular biopsies in 101 cases of varicocele

Testicular biopsies were done on 101 patients who underwent ligation of the internal spermatic vein as primary treatment for infertility. Retrospective analysis included evaluation of tubular thickening, Leydig cell hyperplasia, premature sloughing, maturation arrest and decreased spermatogenesis. A comparison was made of biopsy profiles, sperm counts and pregnancies in an attempt to determine further the value of testicular biopsy in the subfertile man. The pregnancy rate was 40 per cent over-all, with 32 per cent of the patients with tubular thickening reporting pregnancies. There was only 1 pregnancy in patients with Leydig cell hyperplasia. The controversial finding of premature sloughing had no consistent relationship to results.     

Reducing estrogen synthesis in developing boars increases testis size and total sperm production

The abundant production of testicular estrogens and the presence of both ESR1 and ESR2 within boar testes are consistent with a role for estrogen in testicular development and/or function in this species. This study was aimed at determining the role of endogenous estrogen in the regulation of testicular development and function, including the effects on testis weight, histology, sperm production (detergent-resistant spermatid numbers), Sertoli cell numbers, and Leydig cell volume in the boar. Twenty-eight littermate pairs of boars were assigned to groups as follows: 1 boar from each pair was assigned to the control group (vehicle) and the other was assigned to treatment and received 0.1 mg/kg body weight of an aromatase enzyme inhibitor (letrozole) orally each week beginning at 1 week of age until castration at 2, 3, 4, 5, 6, 7, or 8 months of age. Testes were weighed and testicular parenchyma was recovered for determination of histology and detergent-resistant spermatid numbers, and for determination of Sertoli cell number and Leydig cell volume by staining for GATA-4 and 17-alpha hydroxylase/17-20 lyase respectively. Testes of aromatase-inhibited boars initially exhibited delayed lumen formation, lower testicular weight, fewer detergent-resistant spermatids, and fewer Sertoli cells, but by 7 to 8 months, these boars had recovered and had larger testes, more detergent-resistant spermatids per testis, and more Sertoli cells. Total Leydig cell volume increased in proportion to testis size. Reducing endogenous estrogen is consistent with a delay in testicular maturation/puberty that allows for a longer window for the proliferation of Sertoli cells and maturation of Leydig cells, resulting in larger testes and higher spermatid production.     

Developmental pattern of the testicular androgen response to gonadotrophin stimulation in vitro and its modification by chronic hypoprolactinaemia

Developing male rats were treated chronically with bromocriptine (BR, 3 mg/kg b.w. daily) to maintain severe hypoprolactinaemia throughout postnatal development. This treatment induced a precocious increase in Leydig cell numbers per testis and caused substantial, but age-dependent, modifications of the androgenic responsiveness of incubated hemi-testis preparations to stimulation with hCG. Most conspicuous were: (i) a decrease in sensitivity of the testis to hCG at the approach of adult age (due presumably to reduced responsiveness of the Leydig cells), and (ii) a precocious increase in the steroidogenic maximum of the testis at peripubertal age. This probably resulted from the precocious increase in Leydig cell numbers, which was able to mask the negative consequences of reduced androgenic capacity per Leydig cell. The precocious increase in number of Leydig cells induced by hypoprolactinaemia could have resulted from facilitation of the proliferative action of the high prepubertal LH levels on Leydig cell numbers. There were no clear-cut indications for an important effect of BR-induced changes in LH levels, or of a direct effect of BR on the testis.