Inhibition of spermatogenesis in gerbil (Meriones hurrianae) hedgehog (Hemiechinus auritus collaris) and mice after methallibure (ICI 33828) treatment

The effect of methallibure (ICI 33828) on spermatogenesis was studied in the gerbil, hedgehog, and mouse. Injection of ICI 33828, at a dose of 100 mg/kg for 10-25 days, caused testicular lesions in the gerbil and hedgehog, and spermatogonia were absent in the seminiferous e pithelium. Distinct hypertrophy of the Leydig cells was evident. Acces sory sex gland activity was suppressed. It is possible that ICI 33828 impairs testicular androgen production and luteinizing hormone (LH) activity, as suggested by reduced seminal veisicle weight and reduced concentrations of DNA and RNA. Levels of follicle stimulating hormone and LH were considerably reduced. Both adult male gerbils and hedgehogs were rendered sterile by ICI 33828 at the dose studied, while mice were relatively unaffected.     

Chemical sterilization of males - successful inhibition of spermatogenesis in langurs (Presbytis entellus entellus dufresne) after metopiron (SU-4885, Ciba) administration.

1. Daily administration of metopiron (SU-4885, Ciba) (10 mg/kg body wt. for 30 days) produced a massive atrophy of the spermatogenic elements. The pachytene primary spermatocytes have been implicated as the main site of damage. Seminiferous and Leydig cell shrinkage was conspicuous. Epididymal and vesicula seminalis structure and functions were severely affected. 2. RNA, protein and sialic acid contents of the testes, epididymides and seminal vesicles were reduced, whereas testicular cholesterol and enzyme phosphatase were elevated. 3. Marked reduction in the testicular glycogen was noticed. 4. Normal functioning of liver, kidney and general metabolic activities was revealed by clinical parameters (serum, transaminases, phosphatases, lipids, serum bilirubin, blood sugar and blood urea). Serum protein levels were low, whereas the serum cholesterol was elevated. 5. In conclusion: Metopiron (SU-4885, Ciba) at 10 mg/kg body wt. dose level did not cause severe damage to the vital organs but it produced an effective inhibition of spermatogenesis in male Presbytis in 30 days and thus induces an antifertility state.     

Reversible changes in the testes and epididymides of dog treated with alpha-chlorohydrin.

1. Chronic administration of alpha-chlorohydrin (8 mg/kg body wt for 30 days) caused lesions in the testis of dog. The changes in the germ cells were degenerative. The seminiferous tubule and Leydig cell nuclear diameter were reduced. 2. Epididymal cell height was greatly reduced and the stereocilia had disappeared completely. The lumen was devoid of spermatozoa. 3. Alpha-chlorohydrin administration inhibited the RNA and sialic acid contents in the testes and epididymides of dog. Total cholesterol and lipids/g of testes were increased significantly after alpha-chlorohydrin administration. 4. These effects were reversible. Repopulation of testis tubules occurred following a period of 100 days recovery in dog. Numerous spermatogonia and sperm develop and traverse the epididymides. The RNA, sialic acid, cholesterol and total lipids of testes and epididymides returned to subnormal levels. 5. The possibility of using alpha-chlorohydrin as male contraception is indicated.     

Control of the Indian mole rat with alpha-chlorohydrin: laboratory studies on bait acceptance and antifertility effects

Toxic and antifertility effects of feeding poison baits of a toxicant-sterilant, alpha-chlorohydrin, were studied against the Indian mole rat Bandicota bengalensis . It was found that 0.5% alpha-chlorohydrin bait was the most palatable formulation which delivered the amount of active ingredient equal to or more than MLD (82 mg/kg) to B. bengalensis in a single day's feeding. The rats suffered maximum mortality with this bait concentration both in no-choice and bi-choice feeding trials. Male survivors of 0.5% and 1.0% alpha-chlorohydrin baits showed functional abnormalities of their testes as revealed by loss in testicular weight, decrease in the diameter of seminiferous tubules and thickness of seminiferous epithelium and abnormally low levels of spermatogenic cells. Effect of the poison on epididymis became apparent by the presence of epididymal lesions in caput epididymides and low levels of sperm concentration, live sperms and sperm motility in the cauda epididymal fluid. Our findings on the acceptance and toxiccum-antifertility effects of feeding alpha-chlorohydrin baits suggest field evaluation of this poison for the management of B. bengalensis would be appropriate.     

The effect of methallibure (I.C.I., 33828) on the ovary of the carp, Cyprinus carpio

A study has been made on the effect of methallibure (I.C.I., 33828) on ;the ovary of Carp. C. carpio. Methallibure treatment may exert marked inhibitory influence on vitellogenesis in the fish and cause atresia of vitellogenic follicles, the oogonial proliferation is stepped up. The site and mode of action of methallibure is discussed.     

Effect of sodium nitrite on the alpha-chlorohydrin-induced lesion of the testis--epididymis complexin the rat.

Administration of vasodilator, sodium nitrite (20 mg/kg body weight), 30 min before alpha-chlorohydrin treatment (90 mg/kg body weight) prevented the chlorohydrin-induced lesion in rat testis--epididymis complex. However, administration of vasodilator 90 min after alpha-chlorohydrin treatment did not prevent the chlorohydrin-induced lesion in the testis--epididymis complex. These observations suggest that the testicular vasculature is involved in drug action.     

Effects of methallibure (I.C.I. 33828) on the female reproductive tract of the Indian Desert gerbil (Meriones hurrianae Jerdon).

Effects of methallibure (I.C.I. 33828) have been studied on the reproductive organs of female gerbils, Meriones hurrianae. Methallibure administration caused reduction of gonadal weight indicating suppression of pituitary gonadotrophins. In the ovaries of the treated females extensive atresia of follicles and of corpora lutea was observed. In addition methallibure interrupted the sex cycle, and a dioestrous vaginal pattern was retained throughout medication. A significant decrease in the level of RNA, protein and sialic acid in the uterus and vagina and of glycogen in the uterus was found. Histological and biochemical changes in the ovaries and uteri suggest a possible direct antioestrogenic action of the compound.     

Testicular and accessory organ degeneration induced by subcutaneous injection of quinacrine in the gerbil (Meriones hurrianae jerdon)

Quinacrine (an acridine homologue of chloroquine) administration (30 mg kg^?1 day^?1 for a period of 25 days) resulted in mass atrophy of the spermatogenic elements. Seminiferous tubule and Leydig cell nuclear dimensions were reduced. The luminal epithelium was severely damaged. The lumen of epididymides and was deferens were devoid of spermatozoa.Castration followed by quinacrine administration (30 mg kg^?1 for 25 days) denuded the tubules of the caput epididymides. Simultaneous testosterone therapy could not prevent the damage.Quinacrine administration depleted the concentration of RNA, protein and sialic acid in the testes, epididymides and seminal vesicles, whereas the total cholesterol concentration in the testes was elevated. Castration/ castration + quinacrine administration also brought about a significant reduction in the RNA, protein and sialic acid concentrations in the accessory sex organs. Simultaneous testosterone treatment prevented the action of quinacrine on the accessory sex organs and enhanced the production of RNA, protein and sialic acid in epididymides and seminal vesicles of castration/ castration + quinacrine treated gerbils.Serum transaminases (SGOT and SGPT) were moderately elevated, whereas haemoglobin/hematocrit/blood sugar/blood urea levels were in the normal range in quinacrine-treated animals.Histopathological examination of the liver did not show any damage.Leydig cell impairment and decreased production of RNA and sialic acid in the testes points to deficient androgen production following the administration of quinacrine hydrochloride.     

Inhibition of thyroid function and thyrotrophic activity following the administration of methallibure (ICI-33 828).

1. Goitrogenic action of methallibure (ICI-33828) has been studied in mice gerbil and hedgehog using thyroid weight and histological structure as an index. Liquefaction and vacuolation of thyroid follicles were most prevelant after methallibure administration. 2. The I131 content of the thyroid gland was significantly higher in the methallibure treated groups than in the controls. This denotes a decrease in the rate of discharge of thyroid hormone. 3. Protein bound radioiodine (Pb I131) was low after methallibure administration. 4. Methallibure administration brings about hypertrophy of pituitary thyrotrophs which is also reflected in the increased basophilic cell percentage in gerbil (control: 15.5 percent; methallibure: 22.8 percent). 5. It is concluded that methallibure acts on thyroid function both by a direct effect on the gland as well as by influencing pituitary thyrotrophic activity in enhancing I131 uptake.     

Male reproductive effect of nickel sulphate in mice

Nickel sulphate was administered orally to adult male mice at dose level of 5 and 10 mg/kg body weight (5 days per week) for 35 days. There was no change in body weight. However a significant decrease in absolute and organ-to-body weight ratios of testes, epididymides, seminal vesicles and prostate gland was observed. The sperm abnormality, associated with decrease in sperm motility and sperm count was also observed. Significant alterations in the activities of marker testicular enzymes, viz. sorbitol dehydrogenase (decreases), lactate dehydrogenase (increases) and -glutamyl transpeptidase (increases) associated with histopathological changes in testes, epididymides and seminal vesicles, were also observed. Accumulation of nickel in testes, epididymides and seminal vesicles was also observed. The study reveals that the oral exposure to nickel may affect the histology of testes, epididymides, seminal vesicles and sperms morphology. These testicular and spermatotoxic changes may be responsible for observed male mediated developmental toxic effects.     

Effects of molybdenum on fertility of male rats

Sodium molybdate was administered orally to adult male rat at dose level of 10, 30, and 50 mg kg body weight (5 days per week) for 60 days. At higher dose levels significant decrease in absolute and organ-to-body weight ratios of testes, epididymides, seminal vesicles and ventral prostate was observed. The sperm abnormality, associated with decrease in sperm motility and sperm count was also observed. Significant alterations in the activities of marker testicular enzymes, viz. sorbitol dehydrogenase (decreases), lactate dehydrogenase (increases) and -glutamyl transpeptidase (increases) associated with histopathological changes in testes was also observed. Accumulation of molybdenum in testes, epididymides and seminal vesicles was also observed. The study reveals that the oral ingestion of molybdenum may affect the histoarchitecture of testes and sperm morphology. The testicular and spermatotoxic changes may be responsible for observed male mediated developmental toxic effects.     

Effects of flutamide on testicular involution induced by an antagonist of gonadotrophin-releasing hormone and on stimulation of spermatogenesis by follicle-stimulating hormone in rats.

The effects of combined treatment with an antagonist of gonadotrophin-releasing hormone (ANT) and the antiandrogen flutamide (FL) on spermatogenesis were studied in the presence and absence of exogenous follicle-stimulating hormone (FSH). After treatment for 2 weeks, the combination of ANT (RS 68439, 450-500 micrograms/kg per day, s.c.) with 10, 20 or 40 mg FL/day, s.c. was as effective as ANT plus the Leydig cell toxin ethane dimethane sulphonate (75 mg/kg per week, i.p.) in terms of reduction in weight of testes, epididymides and seminal vesicles. Thus, a daily dose of 10 mg FL/kg was sufficient to block the androgen action in the testes of ANT-treated rats. In a second experiment, rats received ANT and ANT+FL (10 mg/kg) alone or in combination with a highly purified human FSH preparation (5 or 10 iu, twice a day) for 2 weeks. FSH did not affect testosterone concentration or weight of epididymides and seminal vesicles, but ANT+FL markedly enhanced the ANT-induced reduction of testis weight, seminiferous tubule diameter and numbers of germ cells, as revealed by qualitative and quantitative analysis of testis histology. In the absence of FL, testis size and numbers of germ cells, including elongated spermatids, were increased by FSH. In the presence of FL, the effects of FSH were less pronounced with respect to the germ cells, in terms of both numbers of cells and the effective dose of FSH. Irrespective of treatment with FL, exogenous FSH increased the inhibin concentrations in serum, indicating that Sertoli cells remained responsive to FSH. From the present study it is concluded that (i) FL accelerates ANT-induced testicular involution, (ii) FSH has a role in adult spermatogenesis and (iii) the effects of FSH on advanced germ cells are influenced by androgens.     

Effects of alpha-chlorohydrin and gonadectomy on the adenohypophysial cells of male rats and gerbils

The cytological changes occurring in the gonadotropic cells of the anterior lobe of the pituitary in 30 male rats and 30 male gerbils after administration of alpha-chlorohydrin were compared with those occurring following bilateral gonadectomy. A decline in the weights of testes and accessory sex glands and inhibited spermatogenesis were noted in rats and gerbils following alpha-chlorohydrin administration. Alpha-cholorohydrin changed the appearance of the delta-basilphils, cell cytoplasm showed fine granulation and vacuolization, and castration vacuoles appeared in many delta-basiphils of the anteroir lobe of the pituitary. The compound brought about transient changes resembling those of castration in the anterior lobe of the pituitary of male rats and gerbils. In gerbils, there was also a marked decrease in the number of acidophils. The results show that alpha-chlorohydrin exerts its effects on androgen-dependent structures, e.g., seminal vesicles, ventral prostrate, epididymides, and perineal complex.     

Effects of Methallibure (ICI 33,828) on the pars distalis of pituitary,testis and thumb pad of the green frog,Rana esculenta L.

Summary The influence of ICI compound 33,828 (1--methylallylthiocarbamoyl-2-methylthiocarbamoylhydrazine = Methallibure) on the pars distalis of pituitary, testes and thumb pads was investigated in the intact adult male green frog, Rana esculenta. Methallibure affected the gonadotropic basophils (particularly the B2 cells) of the pars distalis, which showed varying degrees of degranulation and underwent a notable decrease in their percentage. Within the testis this compound caused the arrest of spermatogenesis. The most uniform effect of Methallibure was observed in the thumb pads, which invariably showed regression of the epidermis and glandular epithelium. No histological changes occurred in the thyroid and adrenal glands and the B1 and A1 cells of the pars distalis remained unchanged cytologically. It is concluded, in concordance with the available data, that Methallibure is a non-steroidal antigonadotropic compound. The important question about its mode of action has been brought into discussion.Work supported by the National Research Council of Italy, and the Population Council (Grant No. M70.082 C) of New York.     

Effects of Malva viscus conzattii Greenm flower extract on testicular function of the house rat Rattus rattus Rufescens & the gerbil Meriones hurrianae Jerdon: a biochemical study

Extract of the flower Malva viscus conzattii (M. conzattii) was administered at a dose of 25/50 mg/day/animal to 30 healthy adult male gerbils and 30 adult male house rats to determine its effect on fertility. After 25 days' treatment fin l body weight, and the weights of testes, epididymides, seminal vesicles, and adrenal glands were measured. Testis, epididymides, and seminal vesicles were prepared for histological examination and total protein, RNA, sialic acid, and alkaline phosphatase activity were determined. Quantitative estimation of cholesterol was also made. While overall body weight remained stable during treatment, testicular weight in both animals was drastically decreased. A complete spermatogenic arrest in the testes was evident in house rats treated with 50 mg/day for 20 days and in the gerbil treated with 25 mg/day for 25 days. The seminiferous tubules showed marked degeneration, lined by 1 or 2 cell layers. Epididymides showed degenerative changes as well. RNA contents of the testes, epididydmides, and seminal vesicles of treated anials were significantly lowered as was sialilc acid content. Total cholesterol was increased significantly. M. conzattii causes an effective inhibition of spermatogenesis in gerbils and house rats in 25 states and induces infertility.     

Changes in the activity of acid glycosidases during posthatch development and regression after light reduction of Japanese quail testes and epididymides

In this study specific activities of four acid glycosidases: beta-N-acethylhexosaminidase (beta-HEX), beta-galactosidase (beta-GAL), alpha- and beta-mannosidase (alpha- and beta-MAN) were investigated in Japanese quail testes and epididymides during posthatch development and regression after light reduction. The specific activity of testicular beta-HEX and beta-GAL increased steadily during posthatch development and assumed maximum values for testes weighing 200-400 mg, when numerous spermatocytes appear in the testes of quail, and then decreased slowly. These enzymes showed much higher specific activity after 15 days of light reduction, and decreased to the control level after 30 days. Activity of alpha- and beta-MAN remained rather constant during testicular development and involution. The epididymal activity of the acid glycosidases was very low in immature individuals, whereas in sexually mature birds it was found to increase several-fold. Short photoperiod resulted in a decreased activity of these enzymes after 30 days to the values found in immature birds. A marked increase in the activity of acid glycosidases in the epididymides of sexually mature animals and a decrease in this activity during epididymidal regression indicate that these enzymes take part in reproductive processes. It is concluded that the activities of beta-HEX, beta-GAL, alpha- and beta-MAN in the development and regression of Japanese quail testes and epididymides change similarly as in mammals.     

Reproductive systems of the North Indian langur (Presbytis entellus entellus Dufresne)

The gross anatomy and histology of the gonads and accessory sex organs are described for male and female Presbytis e. entellus. The langur differs from other catarrhine monkeys in certain specialised characters. The “sexual skin” is not comparable to the true sexual skin of the Cercopithecinae which exhibits cyclical change during the various phases of reproduction; it is nevertheless fully developed in the adult male and serves as one of the secondary sexual characters. Certain aspects of the reproductive system strikingly resemble those of man. The combined testicular weight (0.07% body weight) is similar to the human (0.08%), and the male has ampullary glands. The cervical canal is straight like that of a baboon or man. The corpus luteum (except in the lactating female) is a hollow glandular structure. Extensive hemorrhage which always accompanies ovulation in the langur, does not appear to be a common phenomenon in any other catarrhine for which ovulation and the development of corpus luteum have been studied. The hemorrhagic remains are retained for a long time in the ovulated follicle. The ovary is characteristically large and averages 0.74 gm without corpus luteum and 1.57 gm with corpus luteum, a feature never reported in any other catarrhine monkeys. The pre-ovulatory follicle may attain a size of 14 × 14 mm.     

Antifertility activity and toxicity of alpha-chlorohydrin aromatic ketal analogues in male rats

The antifertility activity and toxicity of alpha-chlorohydrin and seven aromatic ketal derivatives were investigated in male rats. At a dose of 5 mg/kg injected intraperitoneally each day for 14 days, alpha-chlorohydrin and the methoxy benzaldehyde derivative (compound 2) produced complete infertility. The benzaldehyde derivative (compound 1) was 89% effective and the other five compounds 71-25% effective. All compounds except the least effective antifertility agent, the methylbenzaldehyde derivative (compound 3), reduced the motility of sperm recovered from the epididymis. None of the compounds caused a decrease in body or testes weight but some increased adrenal weight.     

Changes in the activity of soluble arylsulphatase during the post-hatch development and regression after light reduction of Japanese quail testes and epididymides

This study demonstrates that specific activity of soluble arylsulphatase (AS) during post-hatch development of Japanese quail testes is the highest for testes weighing from 20 to 200mg, and then decreases as the weight of testes increases, while AS activity per g of wet tissue decreases steadily for testes weighing over 20 to 30 mg. Total AS activity showed a steady increase with the increasing weight of testes. The highest increments in the enzyme activity concerned testes weighing up to 30 mg and those weighing from 30 to 150 mg. Mature animals with testes weighing from 2 to 4 g showed an equal level of total AS activity. Based on this data it is suggested that the changes found in the enzyme activity concern mainly arylsulphatase from Sertoli cells. Specific activity of AS in epididymides remains low until testes reach a weight of approximately 1g and then increases, reaching maximal values for epididymides from the testes of sexually mature animals. Testicular and epididymal regression induced by a short photoperiod (6L:18D) after 30 days of the experiment increases AS activity in the testes and reduces its activity in the epididymides to the values found in the early stages of development. Testes and epididymides in the earliest stage of post-hatch development are characterized by an elution profile of AS in which the form of the enzyme bound to the strong anion exchanger at pH 6.0 is predominant, while in mature animals the form of the enzyme unbound to the anion exchanger predominates in the testes and epididymides. After 30-day regression of the testes and epididymides, the form bound to the anion exchanger did not increase, which suggests that the organs do not return exactly to the stage before sexual maturity.