Macrophage activation enhances the human chorionic gonadotrophin-induced disruption of spermatogenesis in the rat

Abstract

The objective of this study was to examine the role of intertubular macrophages in modifying the response of the rat testis to stimulation by human chorionic gonadotrophin (hCG). The phagocytic activity of macrophages was stimulated by a unilateral intratesticular injection of polystyrene latex beads. Latex beads were engulfed by the resident macrophages and retained within their cytoplasm. Contralateral testes received injection of vehicle alone. A group of control rats was killed 3 days later; other groups received 100 IU hCG s.c. and the morphological and functional responses of the testes were examined 12, 24 and 48 h later. Spermatogenesis was unaffected in control rats, whereas in the testes of all hCG-treated rats leukocytes infiltrated into the intertubular tissue and the seminiferous tubules exhibited focal disruptions of spermatogenesis which were more severe in testes containing activated macrophages. Spermatogenic disruption was dependent upon the stage of the spermatogenic cycle, with the maximum tubule degeneration occurring at or near stages III and IX-XI. However these changes were not a consequence of androgen deprivation, since no consistent correlation was demonstrated between alterations in testosterone levels in testicular interstitial fluid and the accompanying damage to germ cells. It is concluded that hCG alone or in combination with activated macrophages induces an inflammatory-type response of the intertubular tissue and localized degeneration of the seminiferous epithelium. The antispermatogenic effects of hCG may have important implications for in-vivo investigations of Leydig cell function in laboratory animals and for the efficacy of hCG administration used in the clinical treatment of male hypogonadism.

A physiological increase in LH may influence vascular permeability in the rat testis

“…The magnitude of the vascular response in the testis after physiological LH release is apparently discrete and con¬ siderably smaller than after maximal hCG stimulation. Superficially, this could suggest that these changes are only of importance when trying to understand the pathophysiology of testis damage (van Vliet et ai, 1988;Kerr & Sharpe, 1989) induced by supramaximal hormone stimulation. This in itself is, however, an important topic since cryptorchid infants and infertile men are currently treated with comparable doses of hCG (see Bergh, 1989).…”

“…It is therefore possible that they are only a sign of testis malfunction induced by supramaximal stimulation. Indeed, focal tubule damage has been demonstrated within 24 h after a high dose of hCG (van Vliet et ai, 1988;Kerr & Sharpe, 1989). On the other hand, it cannot be excluded that the same type of vascular changes may be induced, although perhaps not of the same magnitude, after LH stimulation in the physiological range, and that such changes could be involved in the physiological control of the vascular permeability for macromolecules in the testis.…”

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

“…A total of 2,602 round tubules were examined and stages of the spermatogenic cycle were identified according to the original classification in paraffin sections given by Leblond and Clermont (1952). Pyknotic germ cells were recognized using criteria established previously in our own laboratory (Bartlett et al, 1986;Kerr and Sharpe, 1989;Sharpe et al, 1990) and others (Dym and Madhwa Raj, 1977;Russell and Clermont, 1977;Russell et al, 1981Russell et al, ,1987. A total of 14,666 pyknotic germ cells were counted.…”

“…The approach described in this study is intended to impair or "run down" Sertoli cell function (after testosterone withdrawal) followed by a n attempt to reverse this process by restimulation with exogenous testosterone. Measurements of the extent of germ cell degeneration and the cytology of the Sertoli cells are then used as sensitive and quantifiable biological endpoints of the effects of testosterone withdrawal and replacement (Russell and Clermont, 1977;Russell et al, 1981Russell et al, ,1987Bartlett et al, 1986;Kerr and Sharpe, 1989;Sharpe et al, 1990;Ghosh et al, 1991). The aim of the present study was to examine the acute morphological effects of testosterone withdrawal upon selected stages of the spermatogenic cycle since it is not yet fully understood just how spermatogenesis fails after testosterone depletion.…”

Single Subcutaneous Administration of Chorionic Gonadotropin to Rats Induces a Rapid and Transient Increase in Testicular Expression of Pro-Inflammatory Cytokines

“…Therefore, it is feasible that the inflammatory effects of hCG may be mediated by cytokines, (e.g., IL-1␤) released by activated resident macrophages or by cells which migrate into the testis from the bloodstream. An involvement of macrophages in the response to hCG has been implicated previously (24). This hypothesis implies that the constitutive production of IL-1␣ does not contribute to an inflammatory reaction, which is, indeed, supported both by our finding that IL-1␣ production in Sertoli cells is down-regulated following activation of testicular macrophages by endotoxin (9) and by the observation cited above that purified testicular IL-1␣ and recombinant IL-1␣ fail to induce any inflammatory response when injected directly into the testis (10).…”