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PubMed1992

Does follicle-stimulating hormone or pregnant mare serum gonadotrophin influence testicular blood flow in rats?

Treatment of adult rats with 25 iu follicle-stimulating hormone (FSH) did not influence testicular blood flow, serum testosterone, vasomotion or intravascular leucocyte concentration at 6, 12 and 24 h after treatment. Treatment of adult rats with 50 iu pregnant mare serum gonadotrophin (PMSG) resulted in a two-fold increase in testicular blood flow at 24 h, and an increase in interstitial fluid volume at 36 h after treatment. This PMSG-induced increase in blood flow did not occur in Leydig cell-depleted animals, suggesting that the effect on blood flow is mediated via the Leydig cells. PMSG injection stimulated testosterone secretion but it did not influence vasomotion, and it only marginally increased the secretion of leucotactic factors in the testis. The present study suggests that FSH has no apparent effects on testicular blood flow and that the effects of PMSG (a hormone with both FSH and LH-like activity) is mediated via stimulation of the Leydig cells.

Animals↗
PubMed1989

Suppression of male-specific cytochrome P450 2c and its mRNA by 3,4,5,3',4',5'-hexachlorobiphenyl in rat liver is not causally related to changes in serum testosterone.

Rat cytochrome P450 2c (P450 gene IIC11) is a constitutive, male-specific hepatic enzyme which is suppressed greater than 90% by treatment with 3,4,5,3',4',5'-hexachlorobiphenyl (HCB) [H. N. Yeowell et al. (1987) Mol. Pharmacol. 32, 340-347]. HCB also decreases serum testosterone levels in adult male rats (greater than 98% loss). The present study assesses whether the suppression of P450 2c by HCB is a direct result of its effects on serum testosterone levels. Further, the site along the hypothalamic-pituitary-testicular axis at which HCB acts to depress testosterone secretion was examined. Administration of the synthetic androgen methyltrienolone to HCB-treated rats failed to prevent the suppression of P450 2c mRNA and its associated microsomal steroid 16 alpha-hydroxylase activity under conditions where it effectively reversed the large decrease in P450 2c mRNA and steroid 16 alpha-hydroxylase activity produced by castration. Hepatic steroid 6 beta-hydroxylase activity, which is catalyzed primarily by P450 2a (P450 gene IIIA2), was also suppressed by HCB and was not protected by methyltrienolone. Administration of either human chorionic gonadotropin, an analog of pituitary-derived luteinizing hormone, or the hypothalamic luteinizing hormone releasing hormone elevated serum testosterone levels to a much smaller extent in HCB-treated rats than in control rats. These results indicate that the effects of HCB on serum testosterone levels reflect its effects on testicular function rather than the pituitary or hypothalamus. However, the present study demonstrates that the consequential reduction in serum testosterone levels in HCB-treated rats is not causally related to the reduction in hepatic P450 2c levels. Thus, HCB must also act on some other regulatory mechanism involved in the expression of this protein.

Animals↗
PubMed1992

Effect of serum and serum lipoproteins on testosterone production by adult rat Leydig cells in vitro.

The effect of serum factors other than luteinizing hormone on Leydig cell testosterone secretion was examined using an in vitro bioassay system based on the stimulation of purified adult rat Leydig cells during a 20 h incubation in the presence of a maximal dose of human chorionic gonadotrophin (hCG). Charcoal-extracted serum and testicular interstitial fluid (IF) from normal adult male rats were separated into lipoprotein and lipoprotein-deficient fractions by density ultracentrifugation. Stimulatory bioactivity was found in the lipoprotein fraction of both serum and IF, although the levels of lipoprotein and corresponding bioactivity recovered from IF were significantly lower (25%) than those of serum. There was no difference between the effects of serum lipoproteins on Leydig cell testosterone production stimulated by either hCG or dibutyryl cAMP. In time-course studies, the serum lipoprotein fraction had no effect on hCG-stimulated testosterone production in vitro at 3.0 or 6.0 h, but partially prevented the normal decline in hCG-stimulated testosterone production after 6.0 h. In contrast, unfractionated serum was stimulatory at all time-points. In the absence of hCG, the lipoprotein fraction was stimulatory at both 6.0 and 20 h, although not at 3.0 h. The lipoprotein-deficient protein fraction of serum had no effect on hCG-stimulated testosterone production alone, but significantly enhanced the bioactivity of the lipoprotein fraction, and caused a dose-dependent stimulation of testosterone production in the presence of a constant concentration of serum lipoproteins. Both a stimulatory peak of activity (apparent MW 40-80 kDa), and a large MW (> 100 kDa) inhibitor of testosterone production were identified in serum after fractionation by gel filtration (Sephadex G-100). The data indicate that (i) the stimulatory effect of serum on short-term hCG-stimulated Leydig cell testosterone production in vitro is predominantly due to the serum lipoprotein fraction, possibly by providing additional precursors for testosterone synthesis, (ii) the biological activity of the lipoproteins is influenced by both stimulatory and inhibitory serum proteins in addition to luteinizing hormone, and (iii) that serum lipoproteins may be involved in supporting Leydig cell steroidogenesis in vivo.

Animals↗
PubMed1992

Isolation of human Leydig cell mesenchymal precursors from patients with the androgen insensitivity syndrome: testosterone production and response to human chorionic gonadotropin stimulation in culture.

Mature Leydig cells, the main source of testicular testosterone in mammals, arise from immature mesenchymal precursors through an LH-dependent differentiation process. In order to study the steroidogenic potential of these precursors, undifferentiated mesenchymal cells were obtained from the testicular interstitium of two patients with androgen insensitivity syndrome. After double digestion with collagenase and separation of the suspensions in a Percoll density gradient, the cells were cultured in Ham's F12 medium: Dulbecco's Modified Eagle Medium (1:1) supplemented with antibiotics, transferrin, insulin, hydrocortisone, and vitamin E with or without 1 IU of hCG/ml. At 11 days in culture, samples were removed for morphological characterization and determination of 3 beta-hydroxysteroid dehydrogenase activity (3 beta-HSD). Testosterone concentration was determined by RIA in the culture medium at different intervals. Cultured cells were mesenchymal in appearance, elongated in shape, with numerous processes running in different directions. No mature Leydig cells were present. In basal conditions, the percentages of 3 beta-HSD-positive cells at 11 days on patients 1 and 2 were 33% and 28%, respectively, and the testosterone concentrations in the culture media were 4.8 and 8.4 ng.10(6) cells.24 h, respectively. In cultures stimulated with hCG, there was an increase of histochemical reactivity (47% and 42% in patients 1 and 2, respectively) and in the amount of testosterone secreted (10.2 and 12.0 ng.10(6) cells, respectively). Electron microscopic studies of cultures grown in the absence of hCG demonstrated a homogenous population of poorly differentiated, fibroblastic-type mesenchymal cells.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxysteroid Dehydrogenases↗
PubMed1997

Effects of nutrition on testicular growth in mature Merino rams actively immunized against GnRH.

Nutrition-induced changes in testicular size in Merino rams appear to involve both GnRH-dependent and -independent pathways. This hypothesis was tested by feeding mature Merino rams that had been actively immunized against BSA or GnRH conjugated to BSA a diet that maintained initial body weight or the same diet supplemented daily with 1.5 kg of lupin grain. Blood was sampled every 20 min for 24 h on days-1, 19 and 70 relative to the change in diet. The plasma was used to assess the effects of treatments on changes in LH, FSH and testosterone concentrations. In the group immunized against BSA, FSH increased in lupin-supplemented rams compared with maintenance-fed rams, while LH and testosterone were not affected by diet. In comparison, the concentrations of LH, FSH and testosterone were significantly lower in the group immunized against GnRH than in rams immunized against BSA, but none of these endocrine variables was affected by nutrition. With both immunization treatments, the testes were significantly larger in lupin-supplemented than in maintenance-fed rams. In the group immunized against BSA, this difference was caused by testicular growth in lupin-supplemented rams, whereas in the group immunized against GnRH, lupin supplementation effectively maintained testicular mass, rather than allowed the regression observed in maintenance-fed rams. In conclusion, differences in testicular growth that were induced by dietary treatments in rams immunized against GnRH were not associated with changes in gonadotrophin or testosterone secretion. This supports the hypothesis that part of the effect of nutrition on testicular growth is independent of changes in GnRH secretion. The differences in testicular size observed in control rams were of similar magnitude to those observed in treated rams, but associated with large differences in plasma FSH concentrations, suggesting that this hormone plays an important role in this effect.

Animal Nutritional Physiological Phenomena↗
PubMed2003

Modulation of gap junction mediated intercellular communication in TM3 Leydig cells.

Long-term modulation of intercellular communication via gap junctions was investigated in TM3 Leydig cells, under low and high confluence states, and upon treatment of the cells for different times with activators of protein kinase A (PKA) and protein kinase C (PKC). Cells in low confluence were readily coupled, as determined by transfer of the dye Lucifer Yellow; on reaching confluence, the cells uncoupled. Western blots and RT-PCR revealed that connexin 43 (Cx43) was abundantly expressed in TM3 Leydig cells and its expression was decreased after the cells achieved confluence. Stimulation of PKA or PKC induced a decrease in cell-cell communication. Staurosporin, an inhibitor of protein kinases, increased coupling and was able to prevent and reverse the uncoupling actions of dibutyryl cAMP and 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Under modulation by confluence, Cx43 was localized to the appositional membranes when cells were coupled and was mainly in the cytoplasm when they were uncoupled. In addition, cAMP and TPA reduced the surface membrane labeling for Cx43, whereas staurosporin increased it. These data show a strong correlation between functional coupling and the membrane distribution of Cx43, implying that this connexin has an important role in intercellular communication between TM3 cells. Furthermore, increased testosterone secretion in response to luteinizing hormone was accompanied by a decrease in intercellular communication, suggesting that gap junction mediated coupling may be a modulator of hormone secretion in TM3 cells.

Animals↗
PubMed1980

Chronic treatment with the gonadotropin-releasing hormone agonist D-Ser(TBU)6-EA10-LRH for contraception in women and men.

The stimulatory analogue of luteinizing hormone-releasing hormone (LRH) D-Ser(TBU)6-EA10-LRH was administered subcutaneously (sc) or intranasally to 10 women with amenorrhea and to 44 healthy female and male volunteers. The LRH agonist evoked a pronounced initial release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) but the gonadotropin response decreased during the course of the chronic treatment. Ovulation could not be induced in seven amenorrheic women who were given prolonged treatment with the analogue. In normally ovulating women, ovulation was inhibited during chronic treatment with a daily sc dose of 5 microgram or a daily intranasal dose of 400 microgram. In four healthy men treated with 5 microgram of the LRH agonist daily over 17 weeks basal FSH, LH, and testosterone levels decreased but spermatogenesis and potency were unaffected. The negative effects on testosterone secretion may limit the use of the LRH agonist for male contraception. Chronic intranasal administration of the stimulatory LRH analogue paradoxically inhibited ovulation and proved to be a safe and effective new approach to contraception in women.

Administration, Intranasal↗
PubMed2005

Exploring the role of ghrelin as novel regulator of gonadal function.

In mammals, proper gonadal function critically relies on a complex regulatory network of systemic (endocrine) and locally-produced (paracrine and autocrine) signals. Among others, a number of factors primarily involved in the control of energy balance and metabolism have been proven as putative modulators of the gonadal axis, thus providing the basis for the well-known link between energy homeostasis and fertility. Ghrelin, the endogenous ligand of the GH secretagogue receptor (GHS-R), has been recently demonstrated as a pleiotropic regulator involved in a large array of endocrine and non-endocrine functions, including food intake and energy balance. However, the potential reproductive role of this newly discovered molecule has remained largely neglected. Yet, we review herein several lines of evidence which strongly suggest the involvement of ghrelin in the control of some aspects of gonadal function. Thus, expression of ghrelin has been demonstrated in mature Leydig cells of rat and human testis, as well as in steroidogenically active luteal and interstitial hilus cells of the ovary. In addition, expression of the functional ghrelin receptor, the GHS-R type 1a, has been shown in Sertoli and Leydig cells of the testis, and in follicular, luteal, surface epithelial and interstitial hilus cells of the ovary. In terms of function, ghrelin has been proven to dose-dependently inhibit testicular testosterone secretion in vitro, and to modulate Leydig cell proliferation in vivo, as well as the expression of relevant testicular genes, such as that encoding stem cell factor. Moreover, extragonadal actions of ghrelin upon the reproductive axis have been also reported, as ghrelin was able to suppress LH secretion in vivo and to decrease LH responsiveness to GnRH in vitro. In summary, the data so far available strongly suggest that, through local and/or systemic actions, ghrelin operates as a novel regulator of gonadal function that may contribute to the integrated control of energy balance and reproduction.

Animals↗
PubMed1979

Testicular function in post pubertal male pseudohermaphroditism.

Testicular endocrine function was studied in twelve post pubertal patients with male pseudohermaphroditism and 46 XY chromosomal constitution. Patients were divided into three groups, four subjects who became feminized during puberty, five who became masculinized during puberty and three who were castrated before puberty. Serum dehydroepiandrosterone, progesterone, 17-hydroxyprogesterone, androstendione, testosterone, dihydrotestosterone, LH and FSH were determined by radioimmunoassay. Patients of the first group had the clinical characteristics of testicular feminization secondary to absence of the androgen receptor. One of the five patients of the second group had deficient testosterone secretion but no enzymatic defect could be demonstrated. One of the subjects castrated before puberty had a deficiency in 17,20-desmolase. Therefore, evidence of a failure of the fetal testes could be found in only two of the twelve patients studied.

Adolescent↗
PubMed1987

Somatomedin C/insulin-like growth factor 1: an intratesticular differentiative factor of Leydig cells?

By using immature porcine Sertoli cells cultured in serum-free defined medium, we report that medium conditioned by Sertoli cells contained immunoreactive somatomedin C/insulin-like growth factor 1 (SmC/IGF1) measured following acidic gel filtration. The release of this immunoreactive SmC/IGF1 was slightly increased following Sertoli cell treatment with fibroblast growth factor but not with follicle-stimulating hormone or growth hormone. On the other hand, human biosynthetic SmC/IGF1 exerts a potent stimulatory effect on Leydig cell differentiated functions such as LH/hCG-binding (greater than 4-fold) and hCG-stimulated testosterone secretion (greater than 15-fold). This effect was dose and time dependent and the maximal increase of Leydig cell function was observed following 48 h treatment with 50 ng/ml SmC/IGF1. The steroidogenic action of the peptide was not related to Leydig cell growth since both cell number and 3H-thymidine incorporation into DNA were not or slightly (approximately equal to 1.5-fold) increased in the optimal conditions with SmC/IGF1 treatment (100 ng/ml for 48 h). Moreover, the concomitant treatment of Leydig cells by both arabinoside C (10(-5) M), a DNA synthesis inhibitor, and SmC/IGF1 did not modify the stimulating effect of the peptide on LH/hCG-binding and hCG-stimulated testosterone production. Taken together, the present findings support the concept that Sertoli cell derived SmC/IGF1 could be a potent regulator of Leydig cell differentiated functions.

Animals↗
PubMed1975

Investigations on Leydig cell function and regulation after renal transplantation.

The hypothalamic-hypophyseal-Leydig cell axis was investigated in 17 male patients following renal transplantation. Plasma levels of testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) were determined by radioimmunoassay under basal conditions and after stimulation with chorionic gonadotrophin (HCG) and hypothalamic releasing hormone (LH/FSH-RH) respectively. The investigations were carried out one to five years after renal transplantation. It was demonstrated, that primary dysfunction of Leydig cells may occur after renal transplantation. In some cases however normal Leydig cell function with adequate testosterone secretion may return. It remains uncertain, whether the Leydig cell dysfunction is a result of preexisting toxic uremic damage or whether it is due to immunosuppressive therapy with prednisone and azathioprine.

Adult↗
PubMedDate not supplied

[Aarskog's syndrome. Description of a case and endocrinological study].

A 7-year-old male with the Aarskog Syndrome is described. This observation is the seventh of the italian literature. The child had the typical findings of the syndrome: short stature, abnormal facies, short fingers with interdigital webbing, unusual scrotal folds encircling the penis ventrally, cryptorchidism and mild mental retardation. Endocrinological study showed only a reduction of Testosterone secretion attributable to malposition of the testis. The presence of minor abnormalities in the mother is compatible with a "X-linked" recessive transmission or with inheritance of an autosomal gene, dominant in males and recessive in females (sex controlled).

Abnormalities, Multiple↗
PubMed1992

Blockade of the LH response induced by the agonist D-Trp-6-LHRH in rats by a highly potent LH-RH antagonist SB-75.

During treatment of prostate cancer patients with luteinizing hormone-releasing hormone agonist, a transient LH and sex steroid release, which precedes the secretion blockade, may result in a flare-up of the disease, whereas the antagonists induce an immediate suppression. The administration of the modern, superactive LHRH antagonist SB-75 before or together with the agonist D-Trp-6-LHRH should prevent the "flare-up" phenomena. In order to demonstrate that the LHRH antagonist can prevent the initial stimulation of gonadotropins in response to LHRH agonists, groups of 5-7 male rats were injected s.c. with the antagonist SB-75 in doses in 100, 500, and 1,000 micrograms/rat 1 hour prior to or 1, 2, and 3 days before administration of D-Trp-6-LHRH agonist (50 micrograms/rat). Supraphysiological doses of the agonist were used in order to obtain prolonged stimulation of LH release, which was necessary to study the duration and the extent of LH release inhibition. Blood samples were taken before and 2, 6, 24, 48, and 72 hours after D-Trp-6-LHRH stimulation for measurement of LH levels. The administration of SB-75 in doses of 500 and 1,000 micrograms/rat 3 days prior to administration of the agonist significantly lowered LH response (P less than 0.01), as compared to animals injected with D-Trp-6-LHRH alone. The D-Trp-6-LHRH-stimulated LH secretion was markedly more suppressed by all 3 doses of the antagonist in rats pretreated with SB-75 2 days prior to the stimulation with the agonist. An even greater reduction in LH response could be observed in rats injected with SB-75 1 day prior to the agonist, the magnitude of LH response being decreased by 75% with 500 micrograms/rat SB-75 and by 90% with 1 mg/rat SB-75. The LH response was virtually abolished when the antagonist, SB-75 was given in doses of 500 or 1,000 micrograms/rat 1 hour prior to the D-Trp-6-LHRH injection. Under these conditions, the agonist-induced LH and testosterone secretion was completely suppressed during the whole period of the experiment. The antagonist to agonist dose ratio of 2 to 1 produced a 90% decrease in the LH response to D-Trp-6-LHRH at 2 hours and 75% at 5 hours after agonist administration. The effects of LHRH decapeptide itself (500 micrograms/rat) on LH secretion could be totally suppressed by an injection of 50 micrograms/rat of SB-75 1 hour beforehand.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1981

[Kurloff's thymic inclusion : action on rat gonads in culture].

Thymic and splenic extracts rich in FOA-KURLOFF (F.K.) body cells, obtained from guinea-pigs treated with oestrogen, were added to rat testis or ovaries in culture. Controls were prepared with extracts from thymus and spleen of non treated animals and from kidneys of treated or non treated animals. After five hours the level of sexual hormones and the germinal cells were studied. The F.K. substance has no effect on germinal cells and on progesterone and testosterone secretion. The F.K. substance induces a significative decrease of oestrogen secretion. In an other paper we established that F.K. bodies induced a hyperactivity of internal theca folliculi and of ovarian interstitial cells. It is a false image of activity in connection with a hypersecretion of FSH. The F.K. substance inhibits oestrogen synthesis.

Animals↗
PubMed2005

Stress hormone and male reproductive function.

The Leydig cell is the primary source of testosterone in males. Levels of testosterone in circulation are determined by the steroidogenic capacities of individual Leydig cells and the total numbers of Leydig cells per testis. Stress-induced increases in serum glucocorticoid concentrations inhibit testosterone-biosynthetic enzyme activity, leading to decreased rates of testosterone secretion. It is unclear, however, whether the excessive glucocorticoid stimulation also affects total Leydig cell numbers through induction of apoptosis and thereby contributes to the stress-induced suppression of androgen levels. Exposure of Leydig cells to high concentrations of corticosterone (CORT, the endogenously secreted glucocorticoid in rodents) increases their frequency of apoptosis. Studies of immobilization stress indicate that stress-induced increases in CORT are directly responsible for Leydig cell apoptosis. Access to glucocorticoid receptors in Leydig cells is modulated by oxidative inactivation of glucocorticoid by 11 beta-hydroxysteroid dehydrogenase (11 betaHSD). Under basal levels of glucocorticoid, sufficient levels of glucocorticoid metabolism occur and there is likely to be minimal binding of the glucocorticoid receptor. We have established that Leydig cells express type 1 11 betaHSD, an oxidoreductase, and type 2, a unidirectional oxidase. Generation of redox potential through synthesis of the enzyme cofactor NADPH, a byproduct of glucocorticoid metabolism by 11 betaHSD-1, may potentiate testosterone biosynthesis, as NADPH is the cofactor used by steroidogenic enzymes such as type 3 17beta-hydroxysteroid dehydrogenase. In this scenario, inhibition of steroidogenesis will only occur under stressful conditions when high input amounts of CORT exceed the capacity of oxidative inaction by 11 betaHSD. Changes in autonomic catecholaminergic activity may contribute to suppressed Leydig cell function during stress, and may explain the rapid onset of inhibition. However, recent analysis of glucocorticoid action in Leydig cells indicates the presence of a fast, non-genomic pathway that will merit further investigation.

Animals↗
PubMed2006

Progesterone treatment of adult male rats suppresses arginine vasopressin expression in the bed nucleus of the stria terminalis and the centromedial amygdala.

The steroid sensitive vasopressin cells of the bed nucleus of the stria terminalis (BST) and centromedial amygdala (CMA) are involved in numerous behavioural and physiological functions. These cells are known to be greatly influenced by gonadal steroids. Castration reduces and testosterone replacement restores arginine vasopressin (AVP)-immunoreactive (-ir) labelling and AVP mRNA expression in the BST and CMA. Gonadal steroids appear to act directly in AVP-expressing cells within the BST and CMA, because the majority of AVP-ir cells in these areas contain oestrogen and androgen receptor immunoreactivity. Recently, we have localised progestin receptor immunoreactivity in virtually all of the AVP-ir cells in the BST and CMA. To understand the role played by progestin receptors in AVP cells within the BST and CMA, we treated male rats with 1 mg of progesterone or oil for 5 days, and then examined AVP immunoreactivity within the brain. We found that progesterone decreased AVP-ir labelling within the BST and CMA, as well as in two of the projection sites of these cells, the lateral septum and lateral habenula. Progesterone treatment did not alter testosterone secretion from the testes, nor did it alter adult male sexual behaviour. These data illustrate an additional mechanism by which the AVP cells in the BST and CMA can be regulated. These data also suggest that progesterone may act in the male brain to influence behaviours that are AVP-dependent.

Amygdala↗
PubMed2000

Accumulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in porcine preovulatory follicles after in vitro exposure to TCDD: effects on steroid secretion and cell proliferation.

The present experiments were conducted to test 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) accumulation in the tissues, and its influence on cell proliferation and steroid secretion. A dose of 3.2 ng of TCDD/g tissue was added at the beginning of the culture, and the media were changed every 24 h or not changed till the end (96 h) of the culture. TCDD in the tissue was analysed by mass spectrometry, and the percentage of proliferating cells was measured using the MIB-1 labelling index. TCDD added to the culture medium accumulated in the tissues after 24 h (59.3%) and 96 h (81.2%) of exposure. The accumulative effect of TCDD was manifested by a reduction in the percentage of proliferating cells (53.5 and 33.8%, after 24 and 96 h exposure, respectively). A single exposure to TCDD had no effect on progesterone, reduced testosterone secretion and caused a significant increase in oestradiol secretion. Prolonged exposure to TCDD caused an increase in the concentration of the three steroids investigated in the culture medium. The results suggest that TCDD action is complex in the follicles.

Androgens↗
PubMed1990

Testicular endocrine effects of alkane methanesulphonates related to the Leydig cell cytotoxic compound, EDS.

A series of compounds structurally similar to the specific Leydig-cell-cytotoxic substance ethane-1,2-dimethanesulphonate (EDS) were examined for Leydig cell toxicity in the rat. Within 48 h of a single injection of butane-2,3-dimethanesulphonate (BDS), propan-1,3-dimethanesulphonate (P-1,3-DS) or propan-1-chloro-2,3-DS (PCDS) there was a reduction in serum and testicular testosterone levels. The serum luteinizing hormone (LH) concentration was reduced following BDS or P-1,3-DS, and Leydig-cell LH receptors (measured by 125I-labelled hCG binding) were reduced by less than 15%, from which it is concluded that these compounds are not selectively toxic to Leydig cells. However, PCDS reduced human chorionic gonadotropin (hCG) binding by greater than 70% and could be considered to be a potential toxin. The effects of hydroxy-ethanemethane-sulphonate (HEMS), 1,5,2,4-dioxadithiepane-2,2,4,4-tetraoxide (cyclic SOSO), PCDS, propan-2,3-DS, alpha-chlorohydrin and cyclohexane-1,2-dimethane-sulphonate were compared with the effects of EDS 7 days after injection. Systemic toxicity, indicated by a loss of body weight, was associated with cyclic SOSO, PCDS and EDS, although only EDS and PCDS reduced both testicular hCG binding and serum and testis testosterone levels consistent with Leydig-cell toxicity. Further studies indicated that the potency of PCDS in reducing testicular hCG binding and serum and intratesticular testosterone levels was similar to that of EDS. However, unlike EDS, PCDS was systemically toxic and also reduced LH, which could at least in part account for changes in testosterone secretion. The experiments confirm the unique cytotoxicity of EDS. Loss of specific Leydig-cell cytotoxicity and an increase in systemic toxicity occurred when the EDS molecule was altered, even if the distance between the alkylating centres was maintained. The mechanism of action of EDS remains elusive.

Animals↗