The amount of testosterone required for quantitative maintenance of spermatogenesis has been re-evaluated using techniques aimed at minimizing the synthesis of testosterone after removal of the testis. Adult male rats were treated with ethane dimethane-sulphonate (EDS) to destroy the Leydig cells, and were supplemented with 25, 5 or 1 mg testosterone esters by injection every 3 days for 21 days. Serum hormone levels, testicular morphology and spermatogenesis were assessed and the intratesticular levels of testosterone compared in testes either removed under ether anaesthesia and placed in liquid nitrogen (right testis) or removed after collection of blood and placed in ice (left testis). Data for testosterone-supplemented rats were compared with those for control rats and rats treated with EDS alone. All doses of testosterone suppressed LH and FSH levels in serum to within the hypophysectomized range, and Leydig cell regeneration in EDS-treated rats was prevented completely. Treatment of EDS-injected rats with 25 or 5 mg testosterone maintained testicular weight, the number of germ cells and the diameter of seminiferous tubules at stage VII within or above the control range, although there was a significant increase in the number of degenerating pachytene spermatocytes at stage VII with 5 but not 25 mg testosterone; none of these parameters was maintained at control levels by a dose of 1 mg testosterone. Levels of testosterone in testosterone-supplemented rats differed little between testes collected in ice and liquid nitrogen, but in controls and rats treated with EDS alone, testosterone levels were overestimated by 75 and 27% respectively when comparing testes collected in ice with those collected in liquid nitrogen.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of a single i.p. administration of ethane dimethanesulphonate (EDS) upon rat testicular histology was studied by light microscopy and morphometry up to 4 weeks after treatment. One day after injection the interstitial tissue exhibited degenerating Leydig cells, abundant pyknotic interstitial cells, deposition of cellular debris and extensive networks of fibrillar material. Macrophages contained greatly increased numbers of cytoplasmic inclusion bodies. From 3 to 7 days morphometric analysis showed that Leydig cells and cellular debris had disappeared from the interstitial tissue, leaving only macrophages, fibroblasts and lymphatic endothelial tissue. A very small number of new Leydig cells were seen on day 14, often located in peritubular or perivascular positions. Regeneration of foetal-like Leydig cells occurred by 4 weeks, their cytoplasm containing large lipid inclusions and, numerous Leydig cells were often observed closely applied to the walls of the seminiferous tubules. The observations suggest that, after experimental destruction and depletion of Leydig cells, an interstitial precursor cell, as yet unidentified, gives rise to a new Leydig cell population. EDS thus offers a valuable opportunity to study further the interactions between the seminiferous tubules and the interstitial tissue following the destruction and subsequent regeneration of the Leydig cells.
Leydig cells in testes of adult rats were selectively destroyed by a single intraperitoneal injection of ethane dimethane sulphonate. Four days later rats were made unilaterally cryptorchid and 1, 2 and 4 weeks later the histology of the testes were examined by light microscopy and morphometry. After induction of unilateral cryptorchidism, the volume of abdominal compared to scrotal testes was reduced by 45-60% due to rapid impairment of spermatogenesis in abdominal testes. Leydig cells were not present in either scrotal or abdominal testes in the 1-week unilateral cryptorchid group. A new generation of foetal-type Leydig cells were observed in scrotal testes of the 2-week unilateral cryptorchid group although their total volume per testis estimated by morphometry, was small, being approximately 1 microliter. In contrast, the abdominal testis exhibited a remarkable proliferation of foetal-type Leydig cells (total volume per testis, 16 microliter) which predominantly surrounded the peritubular tissues of the seminiferous tubules. A similar morphology and pattern of Leydig cell development was observed in scrotal and abdominal testes of the 4-week unilateral cryptorchid group where total Leydig cell volume was 7 microliter vs 21 microliter, respectively. The results show that regeneration of a new population of Leydig cells occurs more rapidly in the abdominal testis than in the scrotal testis of the same animal. These observations suggest the possibility that augmentation of Leydig cell growth is mediated by local intratesticular stimulatory factors within the abdominal testis. Development of new Leydig cells from the peritubular tissue provides circumstantial evidence that the seminiferous tubules and in particular the Sertoli cells, are a likely source of agents that stimulate the growth of Leydig cells.
The cytotoxic effects of ethane dimethanesulphonate upon rat Leydig cells were examined ultrastructurally up to 3 days after treatment and related to changes in serum levels of gonadotrophins and testosterone. Six hours after administration of ethane dimethanesulphonate the usual tubulo-vesicular morphology of Leydig-cell smooth endoplasmic reticulum was converted to small vesicles and the Golgi apparatus showed focal hypertrophy into anastomosing tubules. These changes became more marked by 12 h with many Leydig cells exhibiting karyopyknosis and hyperchromatism. Necrotic Leydig cells were often engulfed by macrophages, the latter containing pyknotic fragments of Leydig cells within their cytoplasm. One day after administration, advanced necrosis of Leydig cells occurred, many of which were phagocytosed by macrophages, and on day 3, destruction of Leydig cells was complete resulting in their elimination from the interstitial tissue, which contained only loose connective tissue and macrophages. Structural alterations to the Leydig cells from 6-24 h was reflected by a significant reduction in serum testosterone levels which further declined to the limits of detection accompanying the abolition of Leydig cells on day 3. These changes were paralleled by a significant elevation of serum LH and FSH levels suggesting diminished feedback regulation of pituitary gonadotrophin secretion. The results indicate that ethane dimethanesulphonate is a rapidly acting Leydig cell toxin which may be a useful experimental tool in further studies of spermatogenic function mediated via Sertoli cell-Leydig cell interaction.
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