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Biomedical subjects

I D Morris

Publications and source records attributed to I D Morris.

At least 91 records · Page 5Linked to original sources
PubMed1988

Inhibition of testicular and somatic development after treatment of the postnatal rat with the Leydig cell cytotoxic ethylene dimethanesulphonate.

The Leydig cell cytotoxic ethylene dimethanesulphonate (EDS) was administered s.c. daily (50 mg/kg) to male rats aged 5-16 days. Apart from loss of weight and that the eyelids unfused earlier, no gross toxicity was observed during treatment. On day 17 testis weights, serum testosterone concentrations, testicular serum testosterone content and 125I-labelled human chorionic gonadotrophin (hCG) binding to testicular homogenates were reduced. Serum LH and FSH concentrations were elevated. The testes did not recover from EDS treatment and at 63 and 120 days were minute (less than 2% of control), and the prostate and seminal vesicles were small although not completely atrophied. In addition, body weights were substantially reduced. Serum and testicular testosterone and 125I-labelled hCG binding to testicular homogenates were reduced but not absent. Serum LH and FSH concentrations were increased. Light microscopy of the adult testes showed that EDS treatment inhibited the development of the seminiferous tubules. Most of the tubules were devoid of germ cells and Sertoli cells were rare. Occasionally tubules also contained spermatogonia and spermatocytes but no signs of spermiogenesis. The testes were composed mainly of closely packed interstitial tissue with no lymphatic space. The interstitial cells resembled Leydig cells and stained for 3 beta-hydroxysteroid dehydrogenase. Histochemically identified Leydig cells were absent during treatment but reappeared when treatment was withdrawn.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Accelerated recovery of Leydig cells of the immature rat testis after administration of the cytotoxic ethylene dimethanesulphonate.

A single injection of ethane-1,2-dimethanesulphonate (EDS; 100 mg/kg) selectively destroys Leydig cells in the testis of the adult rat; however, unconfirmed reports indicate that Leydig cells in the immature rat are not affected. In this study the effect of EDS was examined 2 days after treatment of rats aged 20, 25 or 35 days. There was a large reduction in the in-vitro binding of 125I-labelled human chorionic gonadotrophin (hCG) to the homogenates of testes from EDS-treated immature rats. EDS reduced the testosterone content of the testes at all ages studied, but 2 days after injection had only significantly lowered the serum testosterone concentration of 25- or 35-day-old animals. Light microscopic examination of the testis of the 22-day-old rat, 2 days after treatment with EDS, indicated that there were still many cells staining for 3 beta-hydroxysteroid dehydrogenase. The interstitium also contained numerous atypical cells which did not stain for 3 beta-hydroxysteroid dehydrogenase. Electron microscopy of testes from the 22-day-old EDS-treated rat showed that Leydig cells were still present in the interstitium together with macrophages and fibroblast-like cells. Six days after EDS treatment of 20-day-old rats, but not 35-day-old rats, there was an increase in the binding of 125I-labelled hCG to testis homogenate to 70% of control value. Testicular testosterone content 6 days after treatment of the 20-day-old rat had risen to 50% of the control testis value.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxysteroid Dehydrogenases↗
PubMed1987

Evidence suggesting that germ cells influence the bidirectional secretion of androgen binding protein by the seminiferous epithelium demonstrated by selective impairment of spermatogenesis with busulphan.

Androgen binding protein (ABP) was measured in the serum, testes and epididymides of adult rats up to 105 days after the induction of reversible impairment of spermatogenesis by a single injection of busulphan. This treatment decreased testicular and epididymal weights within 7-21 days after treatment, reaching a minimum at 63 days with partial recovery by 105 days. The testicular and epididymal content of sperm was unchanged up to 42 days after busulphan administration, was reduced considerably at 63 days and thereafter increased towards control values. The serum and testicular concentrations of testosterone were normal at all times after treatment, even though serum LH levels were increased at 42 and 63 days. Serum levels of FSH were also increased at 43 and 63 days after treatment. A biphasic pattern in the serum levels of ABP was observed. Concentrations were low up to 43 days post treatment when only the early germ cell types were depleted from the seminiferous epithelium and when the testicular and epididymal contents of ABP were normal. Serum levels of ABP increased as the more mature germ cells were depleted in numbers and the testicular and epididymal contents of ABP declined. It is concluded that bidirectional secretion of ABP into the interstitium (serum) and into the seminiferous tubular lumen by Sertoli cells is influenced considerably by the population of germ cells that are present in the seminiferous epithelium.

Androgen-Binding Protein↗
PubMed1986

Calcium antagonism by the antioestrogen tamoxifen.

Tamoxifen, an oestrogen receptor antagonist and an effective treatment for breast carcinoma, has recently been shown to possess spasmolytic activity in smooth muscle. Tamoxifen in vitro inhibited the contraction of smooth muscle from rat myometrium and aorta produced by exogenous calcium. At the same concentration tamoxifen did not affect the uptake of calcium into the muscle. The importance of calcium in cell proliferation suggests that some of the unexplained antitumor activity of the oestrogen antagonists may be accounted for by intracellular calcium antagonism.

Animals↗
PubMed1986

Leydig cell function in the pubertal rat following local testicular irradiation.

Dose- and time-response relationships were measured after irradiation of the pubertal rat testis with between 1 and 20 Gy of 300 kVp X-rays. The threshold dose for Leydig cell dysfunction was about 5 Gy. Dysfunction after higher doses was observed by 2 weeks post-irradiation as a dose-dependent decrease in serum testosterone (T) concentrations, and the levels were undetectable after 15 or 20 Gy. Despite the recovery of serum T by 24 and 36 weeks, dysfunction of the Leydig cell population was still observed as an increase in luteinizing hormone (LH) secretion (1.5 to 2-fold increase after 15 or 20 Gy at 24 weeks; 2 to 3-fold increase after 10 or 20 Gy at 36 weeks). The endocrine changes were probably due to the observed loss of Leydig cells following irradiation. These results indicate that the Leydig cells of pubertal rats are more radioresponsive than those of the adult.

Animals↗
PubMed1986

Seminiferous epithelial function in the pubertal rat following local testicular irradiation.

The dose- and time-related responses of the irradiated seminiferous epithelium in the pubertal rat have been investigated. The threshold dose for Sertoli cell dysfunction, as assessed by serum androgen binding protein (ABP) concentrations, was estimated to be 5 Gy. A significant reduction (to less than 50% of control levels) in serum ABP was observed at 8 weeks post-irradiation, with further reductions at later times (24 and 36 weeks). Serum follicle-stimulating hormone (FSH) was elevated to between 130 and 175% of control at only 2 weeks post-irradiation, but recovered with time. Normal FSH levels seemed to be related to recovery of spermatogenesis, as assessed by counts of regenerating tubule cross-sections. The results indicate that the clonogenic spermatogonia and Sertoli cells of the pubertal rat testis are less sensitive to radiation than those of the adult.

Androgen-Binding Protein↗
PubMed1986

Ethylene dimethanesulfonate destroys Leydig cells in the rat testis.

Ultrastructural changes in the interstitial cells of the adult rat testis were studied up to 45 days after administration of a single dose (100 mg/kg) of the antifertility compound ethylene dimethanesulfonate (EDS). Most Leydig cells showed degenerative changes 12 h after treatment. Twenty-four and 48 h after injection, all Leydig cells observed showed gross degenerative changes. At 4 and 14 days, intact Leydig cells could not be identified in the interstitial spaces. Twenty-one days after treatment with EDS, small Leydig cells were visible, and at 45 days, Leydig cells appeared normal. The seminiferous epithelium appeared morphologically normal until 4 days after injection of EDS, when slight abnormalities were observed. At 14 and 21 days, the seminiferous epithelium was grossly abnormal, but at 48 days, spermatogenesis appeared normal. Twelve, 24, and 48 h after treatment, large quantities of material, presumably from dead Leydig cells, were observed within the macrophage cytoplasm. The predominant cell in the interstitial space 4 and 14 days after EDS was the macrophage. Inclusions from the dead Leydig cells within the cytoplasm of the macrophages had almost disappeared. LH receptors (hCG binding) in testicular homogenates were consistent with the cytological changes in Leydig cells. Receptor concentration was low at 24 h and was almost zero at 4 days. This change was accompanied by a decrease in serum testosterone to castrate levels by 2 days. The responses of the endocrine system to destruction of the Leydig cell by EDS, as monitored by serum FSH, LH, and testosterone, were slower than those after castration, indicating that the response to EDS reflects the time required to kill the Leydig cell rather than direct impairment of the steroidogenic pathway. These experiments demonstrate that Leydig cells can be specifically destroyed by a cytotoxic drug. The availability of a specific cytotoxic agent for Leydig cells offers further opportunities to study the interrelationships between the Leydig cell and the seminiferous tubule.

Animals↗
PubMed1986

Inhibition of testicular LDH-X from laboratory animals and man by gossypol and its isomers.

The inhibitory effect of (+)-, (-)-, (+/-)-gossypol and (+/-)-gossypol acetic acid upon testicular cytosolic LDH-X was measured in vitro. Gossypol acetic acid (0-100 mumol/l) inhibited LDH-X prepared from the testes of the mouse greater than rabbit greater than human greater than rat greater than hamster. There was no relationship between inhibition and in-vivo antifertility activity. LDH activity measured in vitro in serum of men and hamsters was unaffected by gossypol. Gossypol and its isomers were non-competitive inhibitors of human and hamster LDH-X with respect to the coenzyme NADH, competitive inhibitors of human LDH-X and noncompetitive-competitive inhibitors of hamster LDH-X with respect to the substrate alpha-ketobutyrate. Co-incubation with human serum albumin or poly-L-lysine but not lysine protected human and hamster LDH-X from gossypol.

Animals↗
PubMed1985

Inhibition of intestinal smooth muscle function by tamoxifen and clomiphene.

The acute in vitro effects of the oestrogen antagonists clomiphene (a racemic mixture) and tamoxifen were examined upon spasmogen induced contractions of the guinea pig ileum. Both oestrogen antagonists inhibited the contractions produced by acetylcholine, the muscarinic agonist beta-methylcholine, histamine and bradykinin in a manner which suggests non competitive antagonism. Concentration effect curves to each of the spasmogens were unaffected using 0.1 mumoles/litre of either of the oestrogen antagonists. Clomiphene at 1 mumole/litre reduced the maximum response to the spasmogens by 20 to 50%. Tamoxifen at the same concentration also inhibited the contractions but to a much smaller extent. Clomiphene at the highest concentration tested 10 mumoles/litre completely suppressed contractions to all the spasmogens. Tamoxifen at 10 mumoles/litre completely suppressed contractions to beta-methylcholine and bradykinin. A residue of a response to acetylcholine and histamine remained and this was abolished by raising the concentration to 100 mumoles/litre. The data indicated that clomiphene was more potent than tamoxifen upon the inhibition of the contractions of the ileum. The results demonstrate a non specific effect of the oestrogen antagonists upon smooth muscle function and do not substantiate early reports of specific anticholinergic activity. The possibility of these effects contributing to both the side effects and the antitumor activity of the oestrogen antagonists is discussed.

Acetylcholine↗
PubMed1985

Dose and time related responses of the irradiated prepubertal rat testis. I. Leydig cell function.

The testes of prepubertal rats were locally irradiated with 300 kVp x-rays to doses of between 1 and 15 Gy. Leydig cell function was assessed between 2 and 36 weeks post-irradiation. Dysfunction was observed at two weeks as evidenced by a reduction in serum levels of testosterone to between 40 and 70% of control, with a threshold dose of about 5 Gy. Endocrine deficiencies in the Leydig cell population were indicated at later times by increased serum levels of LH, although serum testosterone concentrations recovered to control levels. The elevations in serum LH increased with time suggesting progressive Leydig cell failure.

Age Factors↗
PubMed1985

Dose and time related responses of the irradiated prepubertal rat testis. II. Seminiferous epithelial function.

Dose-related effects of radiation upon the seminiferous epithelium were examined in the prepubertal rat. Marked damage to the spermatogenic cell populations was produced by doses of 5 Gy and above. As a result serum levels of FSH were increased, maximum changes being observed at 2 weeks, but levels remaining high even at 36 weeks after irradiation. Serum levels of androgen binding protein (ABP) were inversely related to serum FSH. Above a threshold dose of 5 Gy, serum ABP levels were reduced to between 30-50% of control values, possibly indicating damage to the Sertoli cells. Progression in the degree of testicular failure was indicated at 36 weeks after a dose of 15 Gy by further increases in serum gonadotrophins when compared to earlier times and by the absence of spermatogenesis.

Age Factors↗
PubMed1985

Influence of growth hormone, corticosterone, corticotrophin and changes in the environmental temperature on pituitary-ovarian function in the immature rat.

The influence of various endocrine and environmental factors on pituitary-ovarian function was studied in peripubertal rats treated with pregnant mare serum gonadotrophin (PMSG). Pregnant mare serum gonadotrophin induced ovulation in rats aged 27 days provided they weighed over 60 g. The response was preceded by a marked hypersecretion of LH which was detectable by radioimmunological and biological assay methods. In contrast, smaller rats of the same age did not ovulate in response to PMSG apparently because of the secretion of a pleiomorphic form of LH which, although immunoreactive, appeared to be biologically inactive. Ovarian function, assessed by response to exogenous gonadotrophins and by measurement of 125I-labelled human chorionic gonadotrophin binding, was normal despite the presence of the biologically inactive pleiomorph. Exposure of the small PMSG-treated rats to a high environmental temperature (39 degrees C) or treatment with corticosterone or GH altered the nature of the LH in the blood so that it was active in both assay systems and facilitated ovulation as also did ACTH. The results suggest that the abrupt change in the nature of the LH released by the pituitary gland essential for the initiation of ovulation may be affected by GH, corticosterone or a raised environmental temperature.

Adrenocorticotropic Hormone↗
PubMed1985

Leydig cell resistance to the cytotoxic effect of ethylene dimethanesulphonate in the adult rat testis.

Weekly doses of the Leydig cell cytotoxic ethylene dimethanesulphonate (EDS) were administered to adult male rats in an attempt to study the endocrine activity of the testis in the absence of Leydig cells. One week after the first dose serum testosterone and LH concentrations and seminal vesicle weights were close to levels in castrated rats and testicular human chorionic gonadotrophin (hCG) binding was severely depressed. These changes were maintained for a further week but subsequently began to return to, but did not achieve, control levels. After six weekly doses seminal vesicle weight and serum testosterone concentrations were significantly higher than in the castrated rats. Serum LH concentrations were declining towards control values at 4 weeks but had risen again at 6 weeks. Serum FSH concentrations were raised to about 50% of the value in castrated rats throughout the period studied. Testis weight and hCG binding, which initially fell, were partially restored at 6 weeks and spermatogenesis was recovering. The data show that responses of the testis to multiple doses of EDS are similar to those after a single dose. This apparent resistance indicates that the regenerating Leydig cells are functionally different from the mature Leydig cell. The similarities between the maturing Leydig cell seen after EDS destruction and those in the immature rat suggest that EDS will provide a valuable model for the investigation of Leydig cell physiology.

Animals↗
PubMed1983

The biological activity of a single dose of tamoxifen in the adult ovariectomized rat.

1 The peripheral and central activities of tamoxifen were studied in the ovariectomized adult rat, up to 16 d after a single dose of 7.0 or 0.7 mg/kg. 2 Food consumption and body weight were decreased; only food consumption returned to control values after 16 d. 3 The weights of the uterus and of the uterine luminal fluid were increased for up to 8 d. 4 Serum follicle-stimulating hormone (FSH) concentrations decreased, but only significantly 1 and 8 d after 7.0 mg tamoxifen/kg. Serum luteinizing hormone (LH) and prolactin concentrations were elevated for up to 4 d. 5 Lordosis behaviour was absent throughout the period studied. 6 Within 3 d of administration, tamoxifen partially antagonized the oestrogen-induced changes in uterine luminal fluid, prolactin and LH secretion and lordosis behaviour. 7 Tamoxifen did not alter oestrogen-induced changes in uterine weight, food consumption and body weight. 8 The experiments demonstrate that tamoxifen is active for up to 16 d after a single intraperitoneal dose; oestrogen agonist, partial agonist and antagonist activities were demonstrated. The duration and type of activity depends upon the dose of tamoxifen and the target tissue response examined.

Animals↗
PubMed1983

Fluprostenol-induced softening of the cervix of the pregnant rat.

Fluprostenol, an analogue of prostaglandin F2 alpha, administered s.c. to rats on day 18 of pregnancy increased cervical creep, or softness, by the following day. Doses of fluprostenol 100-fold larger were necessary to increase uterine contractions. Fluprostenol produced falls in serum progesterone concentrations, increases in 20 alpha-dihydroprogesterone concentrations, no changes in oestradiol or relaxin concentrations and a reduction in the ovarian human chorionic gonadotrophin binding capacity in vitro. Fluprostenol was less potent in inducing cervical softness when administered per vaginam, and a dose which produced softening in pregnant rats was ineffective in ovariectomized steroid-maintained pregnant or pro-oestrous rats. The findings suggest that cervical softening by fluprostenol does not result from a simple direct action on the cervix or by increasing uterine contractions, but rather by an indirect hormonal action mediated by the ovaries. The results with the lowest dose of fluprostenol indicate that cervical softening could be produced without a sustained fall in serum progesterone concentrations. Fluprostenol is much more potent at increasing cervical softness in the pregnant rat than prostaglandin F2 alpha or prostaglandin E2. With fluprostenol the ratio of dose to induce uterine contractility relative to that to produce cervical softness was greater than with these natural prostaglandins, indicating the greater selectivity of fluprostenol in the pregnant rat.

Animals↗