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Nitrofurantoin sodium and nitrofurazone in certain critical concentrations have the ability to cause sperm immobilisation. Intraoperative vas irrigation with these solutions in 24 patients have produced sterility in the immediate postoperative period.
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The present state of male contraception is reviewed with reference to pharmacological methods only. Since spermatogenesis is the result of a long chain of endocrine mechanisms starting in the hypothalamus, any review of contraceptive techniques must follow these physiological links. Spermatogenesis itself involves different stages and each of them can be a target for pharmacological compounds. Although no drug is currently available that offers all the necessary guarantees required of a contraceptive, interesting interconnections have nevertheless emerged. In consequence there are grounds for moderate optimism as to the availability of a male contraceptive in the coming years.
Win 18,446, a bis(dichloroacetyl)diamine, is a drug that was previously shown to suppress spermatogenesis and to be an effective oral abortifacient in rats. The present study shows that the drug is capable of producing characteristic congenital malformations in high incidence, by a single treatment, and with high survival of fetuses to day 21. Gestation day 11 is the most sensitive time. The teratologies obtained after various schedules of treatment include malformations of the snout (100%), septal heart defects (100%) diaphragmatic hernias (100%), cryptorchism (100%), cervical pockets (100%) and absent or small irregular thymus (92%). Some of these data, namely of the heart, face and thymus, cluster in patterns that indicate that the action of the drug is upon a time-resistricted developmental process. These periods of sensitivity are subsiding or have ended before primordia of these structures appear, but they coincide with the proliferation and migration of those mesenchyme cells that will eventually form or contribute to the structures affected. It is postulated that the drug acts on these mesenchyme cells, or on the extracellular matrix that provides the necessary framework for their dispersal.
N, N1-bis (dichloroacetyl) diamine 1, 8-octomethylenediamine (WIN 18,446) is an experimental drug which was first investigated as a male contraceptive. It is soluble in lipid solvents but not in water. The administration of 1,200 to 1,600 mg/kg to pregnant rats on the tenth day of gestation produced multiorgan fetal malformations. Smaller doses, 400 to 800 mg/kg, especially if divided over 2 or 3 days, caused perinatal death. Thus, 60 to 100% of offspring of rats given WIN 18,446 on the tenth and 11th days of gestation died at birth or within 4 days (Taleporos et al., 78). The present study investigated such deaths. At doses of 200 mg/kg on day 10 or 50 mg/kg on days 10 and 11, 67% of offspring had defective or absent diaphragms, 48% had tracheobronchiomegaly with cystic lungs, and 67% had pleural hemorrhage. At doses of 100 mg/kg given on 1 day or 25 mg/kg each day for 2 days, 50% had tracheobronchiomegaly with cystic lungs and rudimentary acini. At lower doses (18.8 mg/kg X 2 or 12.4 mg/kg X 3), a majority of fetal lungs had rudimentary acini, thick septa, few capillaries, and wide cuffs of perivascular connective tissue. Thus, a chemical given during organogenesis produced dysgenesis of the respiratory apparatus. Varying the dose produced malformed lungs with persistently deficient acini which model such human lung faults as tracheobronchiomegaly (Mournier-Kuhn Syndrome; Mounier-Kuhn, '32), bronchiolar dysplasia (Wilson-Mikity Syndrome), and perinatal death with acinar failure resembling neonatal hyaline membrane disease.
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The newly available orally effective testosterone undecanoate (TU) was investigated as a possible means for male fertility control. One of 7 normal volunteers exposed to 80 mg TU three times a day for 10-12 weeks became azoospermic, the remaining showed slightly suppressed or unaffected sperm counts. The insufficient suppression of spermatogenesis in 6 out of 7 subjects may be due to the fact that testosterone levels are only sufficiently high to suppress gonadotropins for some hours after ingestion of the drug.
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We have studied the effects of three known mutagens: vinblastine sulphate, mitomycin C and local irradiation of testes on the stage-specific DNA synthesis in the rat testis by using transillumination assisted microdissection of rat seminiferous tubules. It enables us to investigate the sensitivity of different types of spermatogonia and preleptotene spermatocytes to the genotoxic effects of these agents. According to our results, spermatogonia and preleptotene spermatocytes are quite resistant to the action of vinblastine at the treatment times and the doses used. After treatment with mitomycin C, type A2, A3 and A4 spermatogonia seem to be the first cell types affected, which shows itself as a reduction in the DNA synthesis at stages I, II-III, XIII-XIV of the epithelial cycle two and/or three days after the treatment. It also seems that they are mostly affected during the S-phase of their cell cycles. In addition, preleptotene spermatocytes are also sensitive to the action of mitomycin C when they are treated in the G1 phase of the cell cycle. The local irradiation of 3 Gy has severe effects on the spermatogonia of rat testis which can be seen already 18 h after the treatment and becomes more evident 42 and 66 h after the treatment as a reduction of DNA synthesis at stages XII-V. Type A spermatogonia (A1-A4) seem to be the most sensitive cell types to the action of irradiation. This study indicates that the novel method of stage-specific DNA synthesis in rat spermatogenesis allows detailed studies of sensitivities in differentiating spermatogonia to genotoxic agents.
In this study, immunochemical techniques were employed to examine the guinea pig (GP) testicular proacrosin-acrosin system. Monospecific polyclonal antibodies to the highly stable enzymatically active 34,000 molecular weight form of GP testicular acrosin were generated. Western blot analysis of acid extracts prepared from snap-frozen freshly excised GP testes revealed two major immunoreactive bands with mol. wts of approximately 62,000 and 48,000 and one minor band with an approximate mol. wt of 54-56,000. The 62,000 mol. wt molecule identified is in close agreement with the previously reported mol. wt for purified GP testicular proacrosin. Western blot analysis of different species of testicular acid extracts demonstrated the evolutionary relatedness of the proacrosin-acrosin systems since immunoreactivity was observed primarily with acid extracts from rodent species (rat, mouse and hamster) and not with extracts from evolutionarily less-related species (goat, ram and bovine). The majority of the cross-reactivity observed was characterized by immunoreactivity with the 62,000 and 48,000 mol wt molecules. The only species which exhibited cross-reactivity with the 54-56,000 mol. wt protein was rat. In addition, the iso-immunogenic and aspermatogenic properties of the 34,000 mol. wt form of GP testicular acrosin were examined. One out of five Hartley and one out of seven Strain 2 female GPs immunized and boosted with a total of 200 micrograms of purified protein exhibited increased levels of circulating anti-acrosin iso-antibodies. The antigenic specificity of the iso-antibodies observed in the two animals was verified by Western blot analysis. All other female animals, including two strain 13 GPs, exhibited very low or undetectable levels of such antibodies following immunization. One out of three male Hartley GPs immunized with 50 micrograms of the purified protein exhibited typical lesions of experimental allergic orchitis while none of a group of three animals developed lesions at a 5 micrograms dose. Taken together, these results suggest that the 34,000 mol. wt form of GP testicular acrosin is neither a highly potent iso-immunogen nor aspermatogenic autoantigen.
The effect of oral administration of N,N'=bis (dichloroacetyl)-1, 8-octamethylenediamine (WIN 18446) (200 mg/kg body weight/day, up to 30 days) on the testis of the Parkes (P) strain laboratory mouse was studied. The drug caused reduction in testicular weight and severe atrophic changes in the seminiferous tubules. A duration-dependent effect of the drug was observed on the germ cells. The drug had its initial impact on spermatids followed by spermatocytes, ultimately culminating in the Sertoli cell-spermatogonia syndrome. The drug-induced changes included exfoliation of germ cells, formation of multinucleated giant cells, and vacuolization of cytoplasm and displacement (towards the lumina of the tubules) of Sertoli cell nuclei. Even 75 days after drug withdrawal, testicular weight remained depressed and in 15 to 20% of the tubules there was incomplete recovery of spermatogenesis. Our data indicate that WIN 18446 induces sustained impairment of spermatogenesis by a direct action on spermatogonia or indirectly by affecting the integrity of the Sertoli cells. The Leydig cells remained unaffected in WIN 18446-treated mice.
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We studied the antifertility effects of a potent gonadotropin-releasing hormone agonist, D-Trp6-Pro9-N-ethylamide-LHRH (LHRHA) in eight normal men, who received daily subcutaneous injections for six to 10 weeks. Plasma testosterone levels fell substantially in all eight. Plasma 17-hydroxyprogesterone and serum estradiol-17 beta levels decreased concordantly with plasma testosterone. Impotence developed in five men between the sixth and seventh weeks of treatment, with resolution in each case within two weeks of stopping treatment. Serum gonadotropin levels also fell during treatment, briefly rebounding above basal levels when therapy ended. Sperm density and motility fell t a nadir during the seventh to 18th week after therapy. In six subjects sperm levels fell to 6 X 10(6) sperm per milliliter or less, and in the other two they decreased 70 and 86 per cent below basal mean values. Sperm density returned to pretreatment levels in all men during the 10-to-14-week recovery period. These results are consistent with LHRHA-induced pituitary "desensitization" but do not exclude a direct inhibitory effect of LHRHA on testicular steroidogenesis and spermatogenesis.
The relationship between decreasing spermatogenic activity and fertility, pregnancy outcome and the progeny is poorly understood. To study this relationship a model where testosterone is given by a sustained release device is used. Adult male Sprague-Dawley rats received empty or testosterone-filled implants measuring 0.5, 1.0, 2.0, 3.0, 4.0 and 8.0 cm. On Day 90 and again on Day 104 each male was exposed to two females in proestrus. Twenty days later the females were killed. Corpora lutea, implantation sites, resorptions and live normal and abnormal fetuses were counted. Sperm counts in the caput-corpus region of the epididymis in the 3.0-, 4.0- and 8.0-cm testosterone treatment groups were 12.6%, 3.0% and 29.9% of control, while those in the caudal region were 19.8%, 4.0% and 50.8% of control, respectively. The number of females with spermatozoa in the vagina after breeding was significantly diminished only in animals treated with the 4.0-cm testosterone implants (control, 95.8%; 4.0-cm, 50%) while the number of pregnant females per sperm-positive females was markedly reduced in the females mated with both the 3.0-cm and 4.0-cm testosterone implants (control, 82.6%; 3.0-cm, 10.0%; 4.0-cm, 7.7%). There was no effect on the numbers of corpora lutea, on the incidence of pre- or post-implantation loss, malformations, or on the numbers of pups/litter. Individual animals with a decrease in caudal epididymal spermatozoal reserves to less than 5 million, however, are infertile. A decrease in epididymal spermatozoal reserves mediated by testosterone does not cause an increase in teratogenicity in the resultant progeny.
The combination of an initial injection of 1000 mg of depot medroxyprogesterone acetate and 500 mg of testosterone enanthate, followed by monthly administration of 150 mg and 500 mg of the same drugs, was tested in 10 healthy males aged 28 through 39, with pre-treatment sperm counts of 50 x 10(6)/ml or more. Eight of the subjects achieved azoospermia, and the sperm counts of the other two declined 0.09 ad 5 million/ml. This last subject was highly refractory to treatment as his sperm density recovered to 27 million sperm/ml at the 6th month of continuous therapy. FSH was severely depressed during the entire treatment period. LH fell to 30--40% of normal values in the first two months and then showed a slow recovery during maintenance treatment. Testosterone measured one month after each injection was between 10 and 30% of pre-treatment values. Three of the subjects had increased libido and potency, none had decreased sexual drive or potency. All subjects gained weight with the average gain being 6 kg. The increase in the dose of testosterone enanthate to 500 mg/ng did not improve the results as compared to previous trials using lower doses of TE.