Leydig cell tumor with gynecomastia: further studies--the recovery after unilateral orchidectomy

The recovery of exocrine and endocrine testicular function was studied in six patients orchidectomized for an estrogen-producing Leydig cell tumor. Gynecomastia disappeared in four patients. The contralateral testis, whose volume was reduced, returned to normal size after 30 days. Sperm density returned to normal in only one of the four patients in whom the preoperative sperm count was reduced. One day after unilateral orchidectomy, plasma estradiol decreased to normal and testosterone (T) fell about 50%. On the 10th postoperative day, plasma T [5.60 +/- 1.20 ng/ml (SD)] was normal. On day 120, T was higher than on day 10 (6.83 +/- 1.20 ng/ml). There was no significant increase of T after a single injection of hCG (5000 IU) on day 10, and the T response was similar to that of normal men on day 120. Plasma FSH and LH were increased on the 10th postoperative day; they then decreased between 60 and 120 days after the operation but were still above the normal values on day 120. The FSH/LH ratio, which was 0.43 +/- 0.17 preoperatively returned to normal (1.60 +/- 0.25) 10 days postoperatively. In conclusion, after hemicastration for an estrogen-secreting tumor, testicular hormonal secretion returns to normal within 120 days but spermatogenesis may still be impaired at this time.     

Feminizing Leydig cell tumor: endocrine and incubation studies

A 32-year-old patient with a history of surgery for left gynecomastia four years previously presented with right gynecomastia; a tumor in the left testis proved to be a Leydig cell tumor. Preoperative investigations showed elevated but variable levels of plasma estradiol (E2) and estrone (E1), and reduced serum LH and FSH and plasma testosterone (T). After hCG stimulation, E2 response was increased and abnormally prolonged; T reached normal values, which has predictive value for a return to normal of post-operative T level. After left orchiectomy, gynecomastia regressed within a few days, gonadotropins increased by day 2, estrogens dropped by day 2 and were normal at day 7, T and 5 alpha-dihydrotestosterone dropped at day 2 but reached normal levels at day 16. Pathophysiology of these hormonal data are discussed. An incubation procedure with 3H testosterone showed an aromatase activity 21 times greater in the tumor than in normal peritumoral tissue, while the percentage of the volume occupied by Leydig cells was 34 times higher. This suggests that the aromatase activity of a single tumor cell is very similar to that of a normal Leydig cell. Furthermore, evidence of juxtatumoral Leydig cell hyperplasia in areas where the tumor was well encapsulated suggests the existence of a factor stimulating Leydig cell multiplication.     

An assessment of Leydig cell function after bilateral or unilateral efferent duct ligation: further evidence for local control of Leydig cell function

Leydig cell function was examined in adult male rats at 2 and 4 weeks after bilateral or unilateral efferent duct ligation. Bilateral efferent duct ligation resulted in significantly elevated serum LH levels, an increased size of Leydig cells and an enhanced testosterone response to gonadotropin stimulation in vitro despite a marked loss of LH-hCG receptors. After unilateral ligation of the vasa efferentia, the parameters of Leydig cell function in the ligated testes showed identical changes to those seen after bilateral ligation, whereas such changes were minor or absent in the unligated contralateral testes of the same animals. These results demonstrate that the modifications of Leydig cell function after efferent duct ligation are mainly due to local changes within the testes providing further evidence for an intratesticular control of Leydig cell function.     

Pulmonary sarcoidosis associated with Leydig cell testicular neoplasm

The first case of association between Leydig cell testicular tumor and sarcoidosis is reported. From a review of the literature, this is the ninth case of association between a testicular tumor and Besnier's disease. Lung biopsy should always be performed in patients with testicular cancer when retroperitoneal lymph node involvement cannot be demonstrated in order to avoid unnecessary antineoplastic chemotherapy.     

Do testicular opiates regulate Leydig cell function?

beta-Endorphin is believed to be synthesized in testicular Leydig cells. To gain more information about the role of this and other endogenous opioid peptides in the testis, opiate antagonists (naloxone and nalmefene, 100 micrograms/testis) were administered intratesticularly to hemicastrated adult rats. Leydig cell function was evaluated by measurement of serum testosterone and testosterone production in vitro. Estimation of androgen binding protein (rABP) was used as an index of Sertoli cell function. Serum testosterone was reduced significantly by intratesticular administration of naloxone and nalmefene in treated animals. Systemic administration of these antagonists had no effect at the doses used. Testes from treated animals incubated in vitro with or without hCG produced significantly less testosterone than vehicle-treated control testes. Hemicastration reduced rABP synthesis and secretion; however, treatment with opiate antagonists did not alter the amount of this protein in the serum or epididymides of these rats. These observations suggest that endogenous testicular opiates modulate testosterone secretion by Leydig cells.     

Enkephalin-like immunoreactivity in Leydig cell tumor

So far, the presence of an enkephalin-like immunoreactivity has never been reported in Leydig cell tumors at our knowledge. A 39 years old man having a painful gynecomastia and an impotency changing in time has been studied. At clinical examination, he was normal, without palpable testis tumor. The sperm count analysis showed an oligoastheno-spermia. Plasma testosterone (T) was low and plasma estradiol (E2) was high, varying from day to day. T/E2 ratio was always low (20 to 72 - N:220-240) and fell after HCG administration. Plasma LH was normal and plasma FSH was low. 17 hydroxyprogesterone (17 OH-P)/T ratio was increased (0.7 - N:0.23). A small tumor was localized in the left testis by ultrasonography. The spermatic vein catheterization, which was only possible on the left side, showed a decreased T, a high E2 and a low T/E2 ratio (19 - N:304). After unilateral orchidectomy, the histological study confirmed the diagnosis of Leydig cell tumor. With antibodies raised against synthetic Met-en-kephalin, it has been possible to detect an enkephalin-like immunoreactivity in the tumoral cells as well as in the surrounding normal cells.     

Hormonal profile of Leydig cell tumors with gynecomastia

The hormonal profile of estrogen-secreting Leydig cell tumors was studied in four patients. Plasma testosterone (T) and estradiol (E2) levels varied from day-to-day whereas the T/E2 ratios were decreased (22:85, normal 170 to 440). hCG administration induced a higher estrogen response in the patients than in normal men. The finding in the spermatic venous blood of the tumor-bearing testis of a particular biochemical profile, including a low T/E2 ratio (12:27), associated with high progesterone/17-hydroxyprogesterone ratios (0.13:0.26) and high 17-hydroxyprogesterone-androstenedione ratios (26:44), allowed localization of a small testicular tumor when no testicular abnormality was found clinically. Also, the E2 level was moderately elevated in the spermatic vein of one patient compared with normal men. Spermatic venous blood also was obtained after hCG administration in two patients. Increased estrogen and reduced T responses were found in the tumoral testis in comparison with the contralateral testis. In conclusion, the hormone content of spermatic venous effluent from testes containing an interstitial cell tumor is abnormal in several respects and such abnormalities allow detection of the tumor when it is not recognizable clinically.     

Radioimmunoassay of inhibin: serum responses to unilateral and bilateral orchidectomy

An overnight double antibody RIA using a rabbit antiserum to porcine inhibin alpha-chain [Tyr30] (1-30) NH2 [pI alpha(1-30)], radioiodinated pI alpha(1-30), and a preprecipitated second antibody complex has been developed to measure inhibin concentrations in sera and other biological fluids. The assay is accurate, precise (intraassay coefficient of variation, 4.8%), sensitive (25 pM; 2.5 fmol/tube), and specific for inhibin. The synthetic reference standard pI alpha(1-30) produced a displacement curve that paralleled intact male ovine and bovine sera, crude bovine follicular fluid, and a partially purified porcine follicular fluid reference preparation (WHO/NIH 86/690). Bilateral castration of prepubertal and postpubertal ram lambs resulted in a rapid decrease in serum inhibin concentrations and a subsequent increase in serum FSH. Inhibin levels were high in prepubertal lambs (approximately 375 pM), but these levels were not sustained near the time of puberty (approximately 180 pM). Intensive sampling by jugular venipuncture after castration indicated a 50% drop in circulating inhibin levels within 2 h of testes removal with chronic castrate levels (approximately 75 pM) achieved by 6 h postcastration. A rapid fall in circulating levels of inhibin was also observed after unilateral castration, but these values stabilized within hours to levels intermediate (i.e. approximately 200 pM) to those of intact and bilateral castrate rams. Hemicastrates exhibited a more subtle rise in serum FSH after testis removal, with FSH and inhibin levels of prepubertal hemicastrates returning to mature intact ram values by 15 weeks of age. Serum inhibin levels remained low and FSH levels high at 14 days in unilateral castrate postpubertal rams. Inhibin immunoreactivity increased abruptly in castrate ewes and rams injected iv with 5 ml bovine follicular fluid. Serum inhibin reached 300 pM immediately after bovine follicular fluid injection, and castrate FSH levels decreased 30% to a nadir 8 h later. These physiological findings provide support for the validity and utility of this inhibin RIA and further suggest that the Sertoli cells (not the germ cells) are the likely source of the FSH release-inhibiting factor from the testis.     

Feminizing testicular syndrome with multiple hamartomas and bilateral paratesticular leiomyomas

INTRODUCTION: Complete androgen insensitivity syndrome or testicular feminization syndrome (TF) is the most common form of male pseudohermaphrodism, caused by a failure of androgen receptor binding. Patient with male genotype 46 XY, has a female morphotype with well developed external sexual organs. EXEGESIS: - We report the case of a 29 year-old girl with a TF syndrome discovered during the exploration of a primary amenorrhoea. Bilateral orchidectomy was performed. The testis were immature; they showed bilateral leiomyoma of the tunica albuginea and multiple hamartomas on the right side. CONCLUSION: Benign tumors are developped in 80% of cases of TF and they are generally hamartomatous nodules of testis. Association of paratesticular leiomyoma to synchronous hamartoma has never been described, its histogenesis is discussed.     

A Leydig cell stimulatory factor produced by human testicular tubules

It is demonstrated that tubular fragments derived from human testes and cultured in vitro produce a factor that stimulates the production of testosterone by human interstitial cells and by Percoll-purified Leydig cells from rat and mouse origin. The active principle in the conditioned media is a thermo-labile and trypsin-sensitive protein with an MW greater than 10,000. The factor is active in the presence as well as in the absence of maximally effective concentrations of LH and its activity is not accompanied by measurable changes in cAMP production. There are several points of analogy between this factor and a Leydig cell stimulatory protein produced by rat Sertoli cells. Molecular weight fractionation of spent media from human testicular tubules using an Amicon ultrafiltration system results in a 38- to 102-fold increase in Leydig cell stimulatory activity in a fraction corresponding to a molecular weight of 10,000 up to 30,000. These figures are comparable to those observed after molecular weight fractionation of spent media from rat Sertoli cells. Dose-response curves with partially purified preparations from human and rat origin yield parallel dose-response curves. In rat Sertoli cells as well as in human testicular tubules, the production of the active principle is stimulated by FSH and dibutyryl cAMP. Finally, maximally effective concentrations of the active principles of human and rat origin display no additive effects whereas additive effects are clearly evident with other Leydig cell stimulatory factors such as LHRHa and EGF. The hypothesis is advanced that the Leydig cell stimulatory factors from tubular origin may act as paracrine regulatory molecules responsible for the effects of FSH on Leydig cell function.     

Involvement of testicular growth factors in fetal Leydig cell aggregation after exposure to phthalate in utero

Exposures to di-(2-ethylhexyl) phthalate (DEHP) have been shown to be associated with decreased adult testosterone (T) levels and increased Leydig cell numbers. As yet, little is known about DEHP effects in utero on fetal Leydig cells (FLC). The present study investigated effects of DEHP on FLC function. Pregnant Long-Evans female rats received vehicle (corn oil) or DEHP at 10, 100, or 750 mg/kg by oral gavage from gestational day (GD)2-20. At GD21, T production, FLC numbers and distribution, and testicular gene expression were examined. The percentage of FLC clusters containing 6-30 cells increased in all treatment groups, with 29 +/- 2% in control vs. 37 +/- 3, 35 +/- 3, and 56 +/- 4% in rats receiving 10, 100, and 750 mg/kg DEHP, respectively. In contrast, FLC numbers were 33% and 39% lower than control after exposures to 100 and 750 mg/kg DEHP, respectively. At these doses, mRNA levels of leukemia inhibitory factor (LIF) increased. LIF was found to induce cell aggregation in FLCs in vitro, consistent with the hypothesis that DEHP induced FLC aggregation. Testicular T levels were doubled by the 10 mg/kg dose and halved at 750 mg/kg. The mRNA levels of IGF-1 and c-Kit ligand (KITL) were induced by 10 mg/kg DEHP. These results, taken together, indicate that fetal exposures to DEHP have effects on FLC number, distribution, and most importantly, steroidogenic capacity and suggest that abnormal expressions of IGF1, KITL, and LIF genes may contribute to the reproductive toxicity of phthalates.     

Decreased Leydig cell responsiveness in the testicular feminized male rat.

The Stanley-Gumbreck pseudohermaphrodite or testicular feminized male (tfm) rat exhibits a decreased Leydig cell sensitivity to human CG (hCG) measured by androgen and cyclic-3',5',-adenosine monophosphate production in vitro. These changes were associated with an 80% reduction in the number of LH receptors in the tfm testis, when compared on the basis of equivalent amounts of testis particle protein or per 10(6) isolated Leydig cells. Androstenedione and not testosterone is the major androgen secreted by the tfm Leydig cell and androstenedione secretion is, therefore, a more appropriate end point than testosterone secretion for Leydig cell function in tfm animals. A dose of hCG (3 ng/2 ml) which elicited a near maximal response in androgen production from the decapsulated testes and Leydig cell suspensions of normals rats, did not significantly stimulate androgen production from Leydig cells of the tfm animals. A much higher dose of hCG (200 ng/2 ml) gave a response from the tfm Leydig cells which was comparable to that obtained with 3 ng from Leydig cells of normal littermates. This indicates that the small number of LH receptors on the tfm Leydig cell membrane are functional and that the reduction in receptor number results in a decrease in the sensitivity of response to LH rather than a reduction in the maximum steroid response.     

Feminizing adrenocortical tumor: steroid hormone response to ketoconazole

A 58-yr-old man presented with gynecomastia and elevated serum estrogens. The diagnosis of an estrogen-secreting adrenal tumor was made based upon the finding of a 4-cm left adrenal mass, elevated levels of estradiol in peripheral and left adrenal venous blood, and increased urinary 17-ketosteroids. In addition to marked elevations in estradiol and 17-ketosteroids there was an increased baseline level of 11-deoxycorticosterone and a slightly decreased level of 18-hydroxycorticosterone, suggesting the possibility of impaired P450c11 activity. The effect of ketoconazole administration (600 mg/day) for 4 weeks was studied. Urinary free cortisol and 17-ketosteroid excretion and serum testosterone levels fell acutely (1 week). Serum estradiol levels decreased gradually over the 4-week course. Plasma aldosterone levels were essentially unaltered and 18-hydroxcorticosterone levels fell gradually, but there were marked increases in 11-deoxycorticosterone and corticosterone. Coincident with the increase in 11-deoxycorticosterone there was an increase in blood pressure and a transient fall in serum potassium. We conclude that ketoconazole administration may result in a hypermineralocorticoid state. Therefore, the usefulness of ketoconazole therapy for steroid hormone-producing neoplasms will depend upon the individual tumor's steroidogenic profile.