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In mammals spermatogenesis is totally dependent upon testosterone. It is produced by the Leydig cells and acts upon the Sertoli and peritubular cells of the seminiferous tubule and, via processes which are virtually unknown, drives spermatogenesis (Sharpe, 1986). There has been a long-running debate about how much testosterone is needed to maintain spermatogenesis and recent developments suggest that current concepts may require modification.
There are many studies in the literature which show that spermatogenesis can be 'maintained' by exogenous testosterone in hypophysectomized rats or in stalk-sectioned monkeys when the intratesticular level of testosterone is only 10–20% of normal (e.g. Boccabella, 1963; Buhl, Cornette, Kirton & Yaun, 1982; Marshall, Wickings, Ludecke & Nieschlag, 1984). However, it is clear that maintenance is only qualitative and that subnormal numbers of sperm would be produced in these situations, and these may suffer from subtle defects while appearing morphologically normal (Huang & Nieschlag, 1984). To
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There is general agreement that follicle-stimulating hormone (FSH) is of critical importance in the initiation and expansion of spermatogenesis in mammals during puberty (e.g. Russell, Alger & Nequin, 1987), but its role in the normal adult male is still debated. Much of this debate has stemmed from the apparently different results obtained in rodents and primates following immunoneutralization of FSH. Thus, passive immunization of adult rats with FSH antibodies was found to have relatively little or no effect on spermatogenesis (Davies, Main, Laurie & Setchell, 1979; Dym, Raj, Lin et al. 1979), whereas there are numerous studies in a variety of non-human primates which show that active or passive immunization against FSH or its β subunit leads to major suppression of spermatogenesis and a considerable reduction in sperm output (e.g. Wickings, Usadel, Dathe & Nieschlag, 1980; Nieschlag & Wickings, 1982; Raj, Murty, Sairam & Talbert, 1982; Srinath, Wickings, Witting &
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There have been a number of studies over the past 15–20 years which have suggested that sperm counts in men are on the decline (reviewed in Carlsen et al. 1992). These have been largely ignored, or dismissed on the grounds that they have been subject to selection bias and/or the inclusion of data from men with fertility or testicular problems (e.g. see MacLeod & Wang, 1979). Now comes a new and comprehensive study (Carlsen et al. 1992) which has avoided these 'pitfalls'. These authors have screened every publication between 1938 and 1991 which has reported sperm counts in normal (i.e. unselected) or fertile men - a total of 61 publications with data on 14 947 men. Analysis revealed a highly significant (P<0·0001) drop of 42% in the mean sperm counts between 1940 (113 × 106/ml) and 1990 (66 × 106/ml). Moreover, as semen volume also declined
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SUMMARY
Male rats aged 30, 60 or 125 days were injected once every 5 days with 5 mg of a long-acting testosterone preparation, or its vehicle, for periods of 5–40 days. Pituitary and serum follicle-stimulating hormone (FSH) levels were determined by bioassay and radioimmunoassay respectively. Treatment with testosterone produced a consistent pattern of change in pituitary FSH levels (compared with control animals) over a period of 35 days: an initial increase in relative FSH levels was followed by a sharp drop after which there was a further increase in content. However, the magnitude and rate of these changes varied according to the age of the animals involved. These changes in pituitary FSH levels are considered to reflect mainly changes in synthesis, as secretion of FSH was apparently reduced at all ages in testosterone-treated animals. The age-dependent changes in FSH synthesis in testosterone-treated animals may reflect a decrease in sensitivity to testosterone feedback with increase in age. Moreover, in untreated male rats the decrease in FSH secretion after 35 days of age and the apparent reduction in FSH synthesis after 76 days of age could be accounted for by changes in serum testosterone levels.
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ABSTRACT
Four hormones have been identified by various authors as possible paracrine regulators of testicular Leydig cells. The aim of this study was to evaluate their effects on purified adult rat Leydig cells under various conditions in vitro, and then to assess whether comparable effects occurred in vivo.
In agreement with previous findings, an LHRH agonist (LHRH-A) exerted clear-cut effects on testosterone secretion by Leydig cells both in vitro and in vivo. On its own, LHRH-A stimulated testosterone production by Leydig cells for up to 24 h in culture but inhibited testosterone production stimulated by human chorionic gonadotrophin (hCG) between 24 and 72 h of culture. In-vivo, unilateral intratesticular injection of adult rats with 1 ng LHRH-A resulted 5 h later in a significant increase in testosterone concentrations in testicular interstitial fluid (IF). Vasopressin exerted effects in vitro which were similar to those of LHRH-A. On its own, vasopressin stimulated testosterone production for up to 5 h of culture, but not thereafter, while in the presence of hCG, vasopressin inhibited testosterone production beyond 24 h of culture. The initial stimulatory effect of vasopressin on testosterone production occurred with concentrations of 1 nmol/l and higher, but the magnitude of stimulation (threefold or less) was considerably less than that induced by LHRH-A (ninefold) over the same time period. In contrast to LHRH-A, unilateral intratesticular injection of vasopressin in high doses (20 and 2 ng) had no effect on IF testosterone levels 5 h later. When Leydig cells were cultured in the presence of testicular IF, to approximate in-vivo conditions, there was marked stimulation of testosterone production, but the effects of vasopressin and LHRH-A in the presence of IF were comparable to those observed in its absence. Neither morphine nor oxytocin at concentrations of 0·1 μmol/l had any effect on testosterone production under any of the conditions of culture, and unilateral intratesticular injection of oxytocin, morphine or naloxone was without effect on the IF levels of testosterone.
It is concluded that opiates and oxytocin are probably not involved in the paracrine regulation of Leydig cells, whereas vasopressin may play such a role. However, as the stimulatory effects of vasopressin were small in relation to those of LHRH-A and were not evident in vivo, the physiological significance of the effects of vasopressin are uncertain.
J. Endocr. (1987) 113, 89–96
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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.
Journal of Endocrinology (1989) 121, 285–292
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ABSTRACT
Testosterone concentrations have been measured in testicular interstitial fluid (IF), and in blood plasma sampled from various parts of the rat testis and spermatic cord, to assess (1) the most accurate method for determination of the intratesticular levels of testosterone, and (2) the route of secretion of testosterone from the testis. In untreated adult rats, testosterone concentrations were highest in blood collected from veins on the surface of the testis (269·50 ± 30·63 (s.e.m.) nmol/l), but were reduced by 56% on average in blood collected from veins at the proximal end of the spermatic cord (123·06±24·75 nmol/l), and were reduced considerably in peripheral venous blood (4·55 ± 0·55 nmol/l). Similar changes occurred in adult rats in which steroidogenesis was either stimulated (by treatment with human chorionic gonadotrophin; hCG) or inhibited (by treatment with aminoglutethimide; AMG), and in rats of various ages during sexual maturation. The reduction in testosterone levels during passage of blood from the testis up the spermatic cord is probably due mainly to dilution by incoming arterial blood which transfers to venous blood via anastomoses in the spermatic cord. Venous-arterial transfer of testosterone in the cord contributed to this in only a minor way. Concentrations of testosterone in testicular IF were always greater than testicular venous concentrations in control, developing and hCG-stimulated rats, but were comparable in rats treated with AMG to suppress Leydig cell steroidogenesis. These and other results demonstrate that the method of drip-collection of IF results in over-estimation of the actual intratesticular levels of testosterone. However, the present study also suggests that testicular venous blood probably provides the most accurate indication of the concentrations of testosterone in IF (and therefore in the testis) at any given time.
Journal of Endocrinology (1989) 122, 323–329
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ABSTRACT
Levels of immunoactive and bioactive inhibin were measured in venous blood collected at a point just before (testicular venous) and after (spermatic venous) its passage through the mediastinal venous plexus over the anterior pole of the rete testis, and compared with levels in peripheral venous blood and testicular interstitial fluid (IF). In 15 control rats, levels of inhibin were highest in IF (8900 ± 432 ng/l; mean ± SEM) and lowest in peripheral (290 ± 32 ng/l) and testicular (288 ± 34 ng/l) venous blood, whilst levels in spermatic venous blood (633 ± 99 ng/l) were always higher (P<0.002) than the levels in testicular venous blood. The latter difference was either reduced or abolished after disruption of spermatogenesis by local heating of the testes 8, 14, or 21 days previously, and by ligation of the efferent ducts for 6 h or more, but was not affected by acute removal of the epididymis. It is concluded that inhibin secreted into seminiferous tubule fluid may be reabsorbed from the rete testis and this may be the major route by which it reaches the peripheral bloodstream in rats with normal spermatogenesis.
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ABSTRACT
Regulation of testicular interstitial fluid (IF) volume has been investigated in adult male rats in which the Leydig cells were selectively destroyed with a single i.p. injection of ethane dimethane sulphonate (EDS). Following this treatment, some animals also received testosterone supplementation by s.c. injection every 3 days, beginning either from the time of EDS injection, or 3–12 days afterwards. The volume of IF obtained by drip collection was determined, and testosterone and gonadotrophin concentrations measured in blood and in IF. Testosterone levels in IF and serum became undetectable by 3 days after EDS treatment. IF volume was reduced by 50% (P < 0·01) to reach a minimum level between 6 and 9 days after treatment. However, this decline was prevented in the absence of Leydig cells by supplementation with testosterone from the time of EDS injection, a treatment which also kept gonadotrophins at minimum or undetectable levels. Furthermore, the reduced IF volume seen up to 9 days after treatment with EDS alone could be restored to control levels within 3 days by a single injection of testosterone. The results obtained demonstrate that androgens, but not Leydig cells or gonadotrophins, are required for the maintenance of interstitial fluid volume in the adult rat testis. It is suggested that the seminiferous tubules may mediate this response, through an androgen-dependent mechanism.
Journal of Endocrinology (1989) 120, 215–222
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The subcutaneous injection of human chorionic gonadotrophin (HCG) into adult male rats caused appreciable rises in capillary permeability and lymph flow in the testis, accompanied by smaller rises in the volume of extratubular, extracellular fluid. Most of these changes were already apparent 8 h after injection, but became progressively greater during the next 12 h. Testicular blood flow was unchanged at 12 h but increased slightly between 12 and 16 h after injection. The primary effect is probably the increase in capillary permeability. The timing of these changes suggests that HCG does not affect the capillaries directly, but it would seem that the changes are due to some substances secreted by the testis in response to the HCG. It is clear that these changes will have important influences both on the access to the testicular cells of peptide hormones in the blood and also on the passage into the venous blood of hormones secreted by the testis.
