Stage‐Dependent changes in spermatogenesis and sertoli cells in relation to the onset of spermatogenic failure following withdrawal of testosterone

Abstract

Rapid and complete withdrawal of intratesticular testosterone was achieved via the destruction of all Leydig cells with the specific Leydig cell cytotoxin ethane dimethanesulphonate (EDS). Restoration of testosterone levels was accomplished by administration of a single dose (25 mg) of testosterone esters (T) known to reverse the antispermatogenic effects of androgen withdrawal. Quantitation of the degenerating germ cells in cross sections of seminiferous tubules (ST) at stages IV-V, VII, IX, and X-XI of the spermatogenic cycle was used as a sensitive biological index of the effects of testosterone withdrawal and restoration upon the function of the Sertoli cells. Compared to control testicular tissues, the mean numbers of pyknotic germ cells per ST cross section at stages VII, IX and X-XI increased significantly (P < 0.01-0.001) between 4 to 8 days post-EDS treatment, but only in stage VII tubules was this trend reversed significantly (P < 0.005) within 2 days by T supplementation. In EDS-treated rats, stages VII, VIII, IX, and X-XI also exhibited significant (P < 0.05-0.001) increases (compared to controls) in the volumetric proportions by which intraepithelial vacuoles appeared within the seminiferous tubules. Again, in EDS+T supplemented rats, the appearance of vacuoles was significantly (P < 0.001) suppressed in stage VII and VIII. In contrast to tubules at stages VII-XI, those at stages IV-V were completely unaffected by testosterone withdrawal or replacement. The results show that at selected time intervals after EDS treatment, testosterone supplementation is capable of preventing/reversing these morphological changes within 2 days in stage VII tubules. It is suggested that the induction and subsequent prevention of seminiferous epithelial damage will serve as an important in vivo and in vitro approach for studies on the androgen-mediated changes in Sertoli cell biology during phases of impairment and recovery of their function. Manipulation of adult Sertoli cell function as provided by our model should permit identification of androgen-regulated gene products together with an understanding of their role(s) in normal and abnormal spermatogenesis.

Effects of Maternal Exposure to Low Doses of DES on Testicular Steroidogenesis and Spermatogenesis in Male Rat Offspring

“…Some rat-based studies have demonstrated that Sertoli cells require high levels of testicular testosterone to support spermatogenesis [43][44][45]. Testosterone is known to preferentially induce conversion of round spermatids between stages VII and VIII [46][47][48][49], and this coincides with the maximal immunoexpression of AR protein in Sertoli cells [50]. In the present study, the percentage of stage IV seminiferous tubules was increased in the DES 1.5 group at 6 weeks of age.…”

Androgen receptor function is required in Sertoli cells for the terminal differentiation of haploid spermatids

“…As with Gnrh-null mice, androgen or LH replacement leads to qualitative recovery of spermatogenesis in hypophysectomized rats while FSH has little direct stimulatory effect on spermatogenesis (El Shennawy et al, 1998;Elkington and Blackshaw, 1974;Russell and Clermont, 1977). Similar results are seen in response to suppression of Gnrh activity (Szende et al, 1990), and destruction of Leydig cells with the Leydig-specific cytotoxin EDS (Kerr et al, 1993;Sharpe et al, 1990).…”

Review Article: Evaluation of Testicular Toxicity in Safety Evaluation Studies: The Appropriate Use of Spermatogenic Staging

“…The complexity of these interactions, many of which are still poorly understood, makes investigation of toxicological mechanisms very difficult but the specificity of some of the chemically induced lesions have been used to examine the physiological interactions between one cell type and another. In particular, 2-methoxyethanol and ethane dimethane sulphonate have been widely used to elucidate paracrine regulation (5,38,42,55).…”