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Biomedical subjects

I D Morris

Publications and source records attributed to I D Morris.

At least 73 records · Page 4Linked to original sources
PubMed1990

Protection of spermatogenesis in rats from the cytotoxic procarbazine by the depot formulation of Zoladex, a gonadotropin-releasing hormone agonist.

The hypothesis that adjuvant treatment designed to produce testicular atrophy would preserve fertility in males receiving cancer chemotherapy was examined in the rat. Testicular atrophy was induced by a depot formulation of Zoladex [D-Ser(Bu(t))6-Aza-Gly10-GnRH], a gonadotropin-releasing hormone (GnRH) analogue. The experiments were conducted in albino Wistar as well as in the piebald variegated rat. Rats received the depot Zoladex formulation 2 weeks before and immediately prior to being treated with four weekly doses of procarbazine (200 mg/kg). Testicular function was evaluated 50 and 90 days after the last procarbazine dose. Procarbazine induced testicular atrophy concomitant with marked germinal cell aplasia in both strains of rat. In the Wistar rat adjuvant treatment with Zoladex caused slight but not significant alleviation of the testicular toxicity of procarbazine. The testicular toxicity of procarbazine was more extensive in the piebald variegated rat, and 50 days after the last procarbazine treatment the testes were small, sperm were absent, and the stem cell index was close to zero. Serum luteinizing hormone (LH) concentrations were raised and testicular LH receptor binding was low in the presence of normal serum and testicular testosterone concentrations, indicating compensated Leydig cell failure. Testicular weight and sperm content, as well as LH receptor binding, were still decreased in rats which received both Zoladex and procarbazine, suggesting that the analogue offered no protection. However, the stem cell index of the seminiferous tubules in the procarbazine-Zoladex-treated rats was not significantly different from vehicle-treated rats, which suggested that recovery from the effects of procarbazine was in progress. Ninety days after the end of procarbazine treatment alone the testes of rats were still atrophied and there was little evidence of active spermatogenesis. Leydig cell failure appeared to have progressed as, in addition to the low testicular LH receptor content and raised serum LH concentration, the prostate and seminal vehicle weights were decreased. The combination of Zoladex treatment with procarbazine was successful in preserving testicular function in the piebald variegated rats as virtually all the functional and morphological parameters of both the seminiferous tubule and the Leydig cell were not significantly different from those of vehicle-treated rats. This study demonstrates for the first time that effective gonadal protection from the toxic effects of procarbazine chemotherapy can be achieved by administration of the depot formulation of the gonadotropin-releasing hormone analogue Zoladex. The results show clearly that complete suppression of spermatogenesis is not a prerequisite for the successful outcome of treatments designed to protect the gonad from cytotoxic chemotherapy.

Animals↗
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↗
PubMed1990

Growth and development of male and female rats treated with the Leydig cell cytotoxin ethane dimethane sulphonate during the suckling period.

The growth inhibiting effects of the Leydig cell cytotoxin ethane dimethane sulphonate (EDS) were investigated after treatment of both male and female neonatal rats. Pups were injected daily from day 4 to day 15 of age with EDS (50 mg/kg body weight sc), vehicle or water, or were not injected, according to a within-litter control experimental design. The rats were killed for necropsy at 40 and 80 days. The timing of attainment of the developmental milestones that appear during the suckling period was unaffected by treatment, but vaginal opening was 2 days later in EDS-treated females. After a delay of 9-10 days after the start of treatment the growth in body weight of both male and female EDS-treated rats was substantially and progressively depressed, such that by 80 days male and female EDS-treated rats showed body-weight deficits of 18 and 25%, respectively. The food intake of EDS-treated rats at 10 wk of age was less than that of controls, but was appropriate or more than appropriate for metabolic body size. As expected, testes were vestigial in EDS-treated males and the accessory male sexual organs were very small. Ovary and uterus weights were appropriate for body weight in EDS-treated females. At 80 days, liver weight was high for body weight in EDS-treated rats of both sexes. Possible mechanisms for the effect on body growth are discussed. Depressed food intake is discounted. Endocrine involvement, perhaps some anomaly of growth hormone release, or a more generalized toxic effect seem more likely.

Analysis of Variance↗
PubMed1990

Prolonged suppression of spermatogenesis by oestrogen does not preserve the seminiferous epithelium in procarbazine-treated rats.

We examined the hypothesis that induction of reversible testicular atrophy, subsequent to withdrawal of gonadotrophin support, would alleviate the testicular toxicity of the anti-cancer drug procarbazine. In rats, severe but reversible testicular atrophy and suppression of spermatogenesis were induced 56 days after the subcutaneous insertion of a silastic implant containing oestradiol-17 beta. The effect of this treatment upon the testicular toxicity of four weekly doses of procarbazine (200 mg kg-1) was examined 56 days after the termination of procarbazine/oestrogen treatment. At this time the testicular endocrine and spermatogenic functions were close to normal in rats which has received only oestradiol-17 beta. Procarbazine produced severe testicular atrophy which was associated with azoospermia and destruction of the germinal epithelium. Serum LH and FSH concentrations were raised and were associated with low serum concentrations of both testosterone and androgen-binding protein. The combination of procarbazine with the oestrogen treatment did not change any of the testicular toxicity and in some cases it appeared to be exacerbated. In contrast to these experiments other studies have indicated that the testis can be protected if spermatogenesis is reversibly suppressed by other agents which are also active via the pituitary endocrine system. The data would therefore suggest that protection is achieved either by some testicular change other than withdrawal of pituitary gonadotrophin support or that oestradiol-17 beta has additional activity which is permissive for the development of the testicular toxicity of procarbazine.

Analysis of Variance↗
PubMed1990

Changes in plasma inhibin levels following pulsatile gonadotrophin-releasing hormone therapy in a man with idiopathic hypogonadotrophic hypogonadism.

Changes in circulating inhibin levels were related to changes in testosterone (T) and the gonadotrophins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in a hypogonadotrophic hypogonadal man before and during pulsatile gonadotrophin-releasing hormone therapy which resulted in normal spermatogenesis. Before treatment, the plasma inhibin levels in the patient (210 +/- 50 U/l; mean +/- SD of four samples) were lower than in normal controls (552 +/- 150 U/l; p less than 0.01), as were T (1.1 nmol/l) and gonadotrophin (less than 1.0 IU/l) levels. Within 1 week of gonadotrophin-releasing hormone treatment, plasma LH (14.1 +/- 0.7 IU/l) and FSH (14.4 +/- 0.6 IU/l) reached supraphysiological levels. In response, T and inhibin concentrations increased progressively to reach high normal levels (27.7 +/- 1.6 nmol/l and 609 +/- 140 U/l) at 4 weeks, by which time the gonadotrophin levels stared to decline and gradually returned to the normal range between 12 and 24 weeks of treatment. There was a concomitant decrease in T and inhibin levels which remained within the normal range. The decline in the FSH level following the rise in testicular hormones was earlier and steeper than that of LH (37.5% decrease at 4 weeks vs. 30.4% at 12 weeks), suggesting that T and inhibin may act together to inhibit pituitary FSH secretion as opposed to LH secretion which is primarily controlled by T. It is concluded that, in man, during maturation of the pituitary-testicular axis, changes in circulating inhibin parallel those of T, and quantitatively normal inhibin secretion is dependent on gonadotrophin stimulation. FSH secretion may be regulated through negative feedback control, by both T and inhibin.

Adult↗
PubMed1990

Immunoactive inhibin as a marker of Sertoli cell function following cytotoxic damage to the human testis.

Sertoli and Leydig cell functions were evaluated in men with testicular damage due either to cytotoxic chemotherapy (CCT) or radiotherapy (XRT). Serum immunoactive inhibin, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone concentrations were measured in 15 men (19-50 years) who had received 6-10 courses of combination CCT (mustine, vinblastine, procarbazine and prednisolone) for Hodgkin's disease 1-8 years earlier and 18 men (21-49 years) who had undergone unilateral orchidectomy for testicular seminoma followed by XRT (30 Gy) to the remaining testis, 1-4 years earlier. Normal men (n = 16, 19-36 years) acted as controls. Median inhibin (422 U/l) and testosterone (16.0 nmol/l) levels in the CCT-treated group were not significantly different from controls, whereas median FSH (14.5 IU/l) and LH (10.0 IU/l) levels were higher (p less than 0.0001 and p less than 0.001) than normal (2.9 and 5.5 IU/l). The median inhibin/FSH (I/FSH) ratio in the patients was lower (p less than 0.0001) than in the controls (33.8 vs. 187.0) as was the testosterone/LH (T/LH) ratio (1.7 vs. 3.8, p less than 0.001). In the XRT-treated group, both median inhibin (194.5 U/l) and testosterone (12.7 nmol/l) levels were lower (p less than 0.0001 and p less than 0.01) than normal (532.8 U/l and 20.0 nmol/l) in the presence of greatly elevated FSH (26.0 IU/l) and LH (14.5 IU/l) levels. In conclusion, CCT-induced testicular damage is associated with subtle Sertoli and Leydig cell dysfunction demonstrated by the reduced I/FSH and T/LH ratios; however, compensatory mechanisms maintain normal testosterone and inhibin levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Strain-dependency of procarbazine-induced testicular toxicity.

Three strains of rat were used to examine strain-dependency of procarbazine-induced testicular toxicity. CCFHB and CCFY1 outbred albino rats and inbred PVG piebald variegated rats were treated weekly with procarbazine (200 mg/kg/dose x 4). Fifty-six days later, the rats were killed and reproductive parameters evaluated. Strain-related differences in body, testis, prostate, seminal vesicle weights, testis sperm, intratesticular testosterone, and [125I]hCG binding to testicular LH receptors were observed. Although treatment with procarbazine affected testis function in all strains, significant interactions occurred between treatment and strain. LH receptor binding and stem-cell survival were more severely affected in the inbred strain than in outbred strains. Serum testosterone increased in the outbred strain but decreased in the inbred strain, generating an interaction that obscured possible main effects. Significant strain-related differences in within-group variances demonstrated that measurements were more variable in the outbred strains than in the inbred strain. Testes of the inbred strain appeared to be more sensitive to the effects of procarbazine than those of the outbred strains. These data illustrate two important toxicologic phenomena: differences in response variability and differences in target-organ sensitivity, both of which were explained by genetic variability.

Animals↗
PubMed1989

Inhibitory effects of alkane sulphonates on the function of immature rat Leydig, Sertoli and peritubular cells cultured in vitro.

Ethane 1,2-dimethane sulphonate (EDS) selectively destroys Leydig cells in the interstitium of the testis of adult rats. The toxic activity of this compound is much less obvious in the immature rat testis. We examined the effects of EDS, its monomethyl derivative and busulphan on cultured interstitial cells, percoll-purified Leydig cells, Sertoli cells and peritubular cells derived from immature rats. The studies with interstitial cells and Leydig cells showed that EDS (40-160 micrograms/ml) blocked the conversion of C21 and androgen precursors into testosterone and androstenedione. Higher concentrations of this compound also inhibited the production of C21 steroids and the LH-induced production of cyclic AMP (cAMP). The observed effects required a latent period of at least 8 h and were slowly reversible. Isolated cells were more sensitive to EDS than monolayer cultures. Reaggregation cultures were even less sensitive. EDS was markedly more effective on immature Leydig cells than its monomethyl derivative and busulphan. In cultured Sertoli cells FSH-inducible aromatase activity, cAMP production, androgen-binding protein (ABP) production and the secretion of a paracrine factor with Leydig cell-stimulatory activity were markedly reduced by busulphan. In these cells, busulphan was clearly more active than EDS and its monomethyl derivative. The production of paracrine factors which increase ABP production and decrease FSH-inducible aromatase activity in Sertoli cells was studied as a parameter of the effects of alkane sulphonates on peritubular cells. Only busulphan markedly decreased the production of these paracrine factors. It is concluded that EDS displays a selective toxicity to Leydig cells derived from immature animals and that, apart from its effects on germ cells, busulphan may also directly impair the function of Sertoli cells and peritubular cells.

Alkanesulfonates↗
PubMed1989

Leydig cell recovery following a second challenge with ethane-1,2-dimethanesulphonate is enhanced by short intervals between cytotoxin administration to rats.

Ethane-1,2-dimethanesulphonate (EDS) destroys Leydig cells in the testis of the adult rat and subsequently a new population of Leydig cells develops. It has been reported that EDS is not cytocidal to the new immature Leydig cell population. In the present study, the effect of increasing the time-interval between injections of EDS on cytotoxicity to Leydig cells was examined. At time-intervals of 4-10 weeks between injections the response was similar to that seen after a single injection of EDS to the adult rat. Four days after the second injection, EDS was found to reduce substantially serum testosterone concentrations and in-vitro binding of 125I-labelled human chorionic gonadotrophin (hCG) to testicular LH receptors which can be correlated with Leydig cell destruction. However, when the interval was only 2 or 3 weeks there was no reduction in serum testosterone, and 125I-labelled hCG binding was not so markedly reduced. During days 1-6 after a second injection of EDS, administered 3 weeks after the first, there were marked reductions in serum testosterone concentrations and in 125I-labelled hCG binding to testis homogenates within 24 h. Recovery from the effects of EDS was rapid, and increased Leydig cell activity was seen from 2 to 6 days after injection. In contrast to the established changes in the adult rat, there was only a 50% reduction in the number of Leydig cells positive for 3 beta-hydroxysteroid dehydrogenase 2 days after the second injection of EDS, and after 6 days the number of cells had increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Lack of protection by oestrogen from radiation-induced testicular damage in the rat.

The influence of pretreatment with oestradiol dipropionate (E) on the response of the rat testis to radiation has been studied. Treatment of rats for 3 weeks with E (100 mg/kg per week) induced severe atrophy of the testis. At this time, the testes were locally irradiated to doses of 0, 4 or 15 Gy, E treatment was continued for a further week and the rats were killed 24 or 36 weeks later. Radiation alone had a marked effect on spermatogenesis as assessed by testicular weight and counts of regenerating tubule cross-sections. At 24 weeks, 8% of cross-sections were found to possess spermatogenic cells after 4 Gy and this had increased to 15% at 36 weeks. No significant regeneration was observed after 15 Gy. Similar results were obtained in those rats pretreated with E. Following irradiation alone, decreases in interstitial cell numbers and testicular luteinizing hormone (LH) receptors reflected Leydig cell damage. Again, pretreatment with oestrogen did not appear to reduce Leydig cell damage. The results of the present study suggest that pretreatment with oestrogen is not able to reduce the testicular damage induced by moderate to high single doses of radiation.

Animals↗
PubMed1988

Delayed effects of doxorubicin on spermatogenesis and endocrine function in rats.

Doxorubicin was administered to adult male Wistar rats (1 mg/kg body weight, three times per week, for one, two, three, or four weeks) in order to examine testicular and reproductive endocrine toxicity 56 days after treatment. Doxorubicin treatment produced persistent dose-related reductions in testis, epididymis, and seminal vesicle weights, but did not alter ventral prostate weight. Testis and serum testosterone levels were not significantly affected by treatment, but serum LH was increased after treatment, and binding of iodinated hCG to testicular LH receptors was reduced. Serum FSH was elevated by the two lower total administered doses, but was not different from controls after treatment with the two higher total doses. There was clear histologic evidence of dose-dependent damage to the seminiferous tubules, which was reflected by decreased testicular and epididymal sperm content and by reductions in the stem-cell survival index. These results indicate that doxorubicin produces significant and persistent damage to the endocrine and spermatogenic compartments of the testis.

Animals↗
PubMed1988

Plasma inhibin levels in men with chemotherapy-induced severe damage to the seminiferous epithelium.

Immunoreactive plasma inhibin levels and free testosterone index (FTI) were estimated in 17 patients who had previously received combination chemotherapy for Hodgkin's disease and in 16 age-matched controls. In the same patients we had previously found significantly raised FSH and LH levels in the presence of normal basal and HCG-stimulated total testosterone levels. Mean plasma inhibin levels were not different between the patients (601 +/- 321 U/l) and controls (530 +/- 174 U/l) nor were FTI values (81.5 +/- 35 vs 91 +/- 47 respectively). There was a positive correlation (r = 0.53, P less than 0.05) between FSH and inhibin levels and a negative correlation between FSH and FTI (r = -0.51, P less than 0.05) in the patients but not in the controls. No such correlations with inhibin or FTI existed for LH but there was a positive correlation between LH and FSH levels in the patients. In four patients inhibin levels were pathologically raised and in this group mean FSH values (21.7 +/- 4.7 IU/l) were higher (P less than 0.001) and mean FTI (59.1 +/- 22.6) lower (P less than 0.001) than respective values (13.6 +/- 5.3 IU/l and 88.4 +/- 35) for the remainder of the patients. These data are not compatible with the hypothesis that inhibin is the major negative feedback signal for the control of FSH secretion.

Adolescent↗
PubMed1988

Androgen binding protein in serum, testis and epididymis following treatment with the Leydig cell cytotoxic agent, ethylene dimethanesulphonate.

Androgen binding protein (ABP) was measured in the serum, testes and epididymides of adult male rats after treatment with ethylene dimethanesulphonate (EDS), which has direct cytotoxic effects on Leydig cells and secondarily affects sperm production. Serum ABP increased to a maximum 7 days after treatment and remained elevated for most of the 63 days of observation. The ABP content of both the epididymides and testes declined and were low between 14 days and 21 days following treatment. By contrast, the concentration of ABP in these tissues was maintained after EDS treatment and was sometimes elevated. This divergence between ABP content and concentration was due to atrophy of the testes and epididymides after the decline in androgen secretion. The changes in serum and tissue ABP levels after EDS occurred earlier than those observed in adult hypophysectomized animals, possibly due to local paracrine influences that are lost secondarily to destruction of the Leydig cells. Testicular testosterone did not parallel ABP content as it fell dramatically 2 days after EDS and remained low for about 21 days before returning to near control values after 63 days. Testicular and epididymal sperm heads decreased in number after EDS, but were not clearly associated with the changes in ABP. The results confirm that androgens are important for the production of ABP and for the partitioning of this protein between the blood and the lumen of the reproductive tract.

Androgen-Binding Protein↗
PubMed1988

Abnormal development of the testis after administration of the Leydig cell cytotoxic ethylene-1,2-dimethanesulphonate to the immature rat.

Male rats were injected with 50 mg ethylene-1,2-dimethanesulphonate/kg from Day 5 to Day 16 after birth and control rats received injections of the same volume of vehicle. Testes were studied at various times from Day 6 to Day 108 using histochemistry, light and electron microscopy. Fine structural degenerative changes were observed in the Leydig cells and seminiferous tubules of EDS-treated animals as early as Day 6. By Day 11 no Leydig cells could be detected and the interstitia of EDS-treated testes contained large numbers of fibroblast-like cells which formed peritubular collars 3-5 cells thick; the tubules contained Sertoli cells with heterogeneous inclusions and large numbers of lipid droplets. A small number of Leydig cells was found at Day 14 and their numbers increased so that, in animals of 28 days and older, large clusters of Leydig cells were present between severely atrophic tubules. These tubules contained Sertoli cells with few organelles; germinal cells were not observed after 28 days in EDS-treated animals. These results show that EDS destroys the fetal population of Leydig cells postnatally and this mimics the well documented effect of EDS on adult Leydig cells. The seminiferous tubules were permanently damaged by EDS in the present experiments. Tubular damage could have been due to a direct cytotoxic effect of multiple injections of EDS on the tubule before the blood-testis barrier develops or due to withdrawal of androgen support secondary to Leydig cell destruction.

Animals↗
PubMed1988

Characterization of the regenerated Leydig cell population of the rat after destruction by ethylene-1,2-dimethanesulphonate.

The Leydig cells repopulating the adult rat testis after destruction by a single injection of the cytotoxic ethylene-1,2-dimethanesulphonate (EDS) were investigated. After 14 days, serum concentrations of LH and FSH were significantly raised and concentrations of testosterone in the serum and testis reduced. At 21 days, hormone concentrations had returned to within the normal range. Binding of 125I-labelled human chorionic gonadotrophin (hCG) to testis homogenate, however, was still less than 10% of normal. After 21 or 28 days the 125I-labelled hCG binding profiles of isolated Leydig cells from EDS-treated rats, separated on a Percoll gradient, showed a single peak similar to that of immature (25 days old) rats. After 49 days, 125I-labelled hCG binding resolved into two peaks more like that of normal adult rats. Using a quantitative cytochemical method, 3 beta-hydroxysteroid dehydrogenase activity in individual Leydig cells of unfixed testis sections was determined. Activity was increased by 70% (P less than 0.05) in repopulating Leydig cells 21 days after EDS treatment compared with cells from vehicle-treated rats. In addition, Leydig cells were still capable of further 'in-vivo' stimulation by pharmacological doses of hCG. These data indicate that Leydig cells repopulating the testis are homogeneous. Fewer cells from the newly formed population are capable of maintaining normal serum concentrations of testosterone and must thus be individually more active in secreting testosterone. In these respects, the Leydig cells repopulating the adult rat testis after EDS treatment more closely resemble those of the fetal rat testis.

3-Hydroxysteroid Dehydrogenases↗