Women have historically been the focus for development of new contraceptive methods. The National Institutes of Health, World Health Organization, and Institute of Medicine have stressed the need to develop nonhormonal, nonsteroidal male contraceptive agents. We report results from initial dose-ranging studies of a new indazole carboxylic acid analogue, gamendazole. An infertility rate of 100% was achieved in seven out of seven proven-fertile male rats 3 wk after a single oral dose of 6 mg/kg of gamendazole. Fertility returned by 9 wk in four of seven animals, with typical numbers of normal-appearing conceptuses. A fertility rate of 100% returned in four of six animals that became infertile at a single oral dose of 3 mg/kg of gamendazole. No differences in mating behavior were observed in either of the gamendazole-treated groups versus the control (vehicle-only) group. In the animals that showed reversible infertility, a transient increase in circulating FSH levels coincided with an initial decline in inhibin B levels after administration of gamendazole, but no other significant changes in circulating reproductive hormones were observed. Gamendazole inhibited production of inhibin B by primary Sertoli cells in vitro with a median inhibitory concentration of 6.8 thorn+/- 3.0 (SEM) (3/4)x 10(-10) M, suggesting that Sertoli cells are a primary target. A biotinylated gamendazole analogue revealed cytoplasmic and perinuclear binding of gamendazole in primary Sertoli cells. Gamendazole represents the most potent new oral antispermatogenic indazole carboxylic acid to date. Our results, however, demonstrate that additional dose-finding studies are required to improve reversibility and widen the therapeutic window before more detailed drug development of this potential nonhormonal male contraceptive agent can occur.

A novel potent indazole carboxylic acid derivative blocks spermatogenesis and is contraceptive in rats after a single oral dose.

GROTJAN† From the *Infertility Center of St Louis, St Lukeʼs Hospital, Chesterfield, Missouri; and †Serono, Inc, Rockland, Massachusetts. Between 1975 and 2003, a total of 4010 patients have undergone microscopic vasectomy reversal by 1 surgeon at 1 institution. Of these cases, 3904 had available records and 1735 were successfully contacted to obtain reliable long-term data. A total of 1556 (89.7%) were able to establish a pregnancy in their female partner, resulting in 2111 pregnancies. When there was no sperm in the vas fluid at the time of vasectomy reversal, vasoepididymostomy was performed rather than vasovasostomy. A total of 1581 patients underwent bilateral vasovasostomy; 1184 underwent vasoepididymostomy on one side and vasovasostomy on the other side; and 1139 underwent bilateral vasoepididymostomy. Of patients undergoing vasovasostomy, 2.1% had no sperm in the ejaculate postoperatively, and 10.3% of patients undergoing bilateral vasoepididymostomy had no sperm in the ejaculate postoperatively. Thus on average a patency rate of 96.2% in the total group of patients was achieved. When the vasectomy was less than 10 years prior to reversal, the patency rate was 98%. When the vasectomy was 10 or more years prior to reversal, the patency rate was 93%. Among all the patients, 77.7% had sperm counts greater than 5 million/mL postoperatively. Among patients undergoing bilateral vasovasostomy and those undergoing bilateral vasoepididymostomy, 92.5% and 84.3% eventually achieved a pregnancy, respectively. The pregnancy rate did not differ with patients that had a sperm count of greater than 5 million sperm/mL. The pregnancy rate for less than 5 million sperm/mL was 78.3% and when there was greater than 5 million sperm/mL the pregnancy rate was 91.9%. Although the duration of time between vasectomy and vasectomy reversal had an impact on preg

https://onlinelibrary.wiley.com/doi/pdf/10.1002/j.1939-4640.2004.tb03150.x

Microscopic Vasectomy Reversal 30 Years Later: A Summary of 4010 Cases by the Same Surgeon

Antifertility effect of chronically administered Martynia annua root extract on male rats.

Suppression of fertility in male albino rats following the administration of 50% ethanolic extract of Aegle marmelos

Background: Plants have served as a natural source of antifertility substances The reactivated interest in the evaluation of some lead plants for fertility prompted us to undertake studies on the antifertility potential of Aegle marmelos leaves Study Design: Fifty percent ethanolic extract from the leaves of A marmelos (AMLEt) was prepared The effect of A marmelos leaf extract on the reproductive system of male albino rats was investigated at three different doses, namely, 100, 200 and 300 mg −1 kg −1 day −1 for each rat for 60 days Recovery was also investigated after a withdrawal of 120 days Results: All the major accessory sex organs shed weight postadministration of the extract There was a marked reduction in motility and density of the sperm derived from cauda epididymis of the treated animals A marmelos reduced fertility of male rats by 100% at the 300-mg dose level Serum testosterone levels also decreased significantly in all the experimental groups The protein, glycogen and lipid peroxidation content of the testes was significantly reduced at the highest dose level; a highly significant increase in testicular cholesterol was observed along with a highly significant reduction in the sialic acid contents of testes, epididymis and seminal vesicles Blood tests did not point to distress in any of the vital organs Withdrawal of the extract restored all the altered parameters including organ weights, fertility, testosterone levels and tissue biochemistry to control levels after 120 days Conclusions: Taken together, it is inferred that the leaf extract of A marmelos (AMLEt) suppresses fertility in male rats Complete recovery of fertility was observed following the withdrawal of drug Absence of any deleterious effect on the vital organs points to the safe use of

Original research article Suppression of fertility in male albino rats following the administration of 50% ethanolic extract of Aegle marmelos

Long-term sequelae of tolnidamine on male reproduction and general body metabolism in rabbits

The ultrastructural changes in langur monkey epididymis prior to and following vasectomy or vasovasostomy were studied. The epididymal epithelium of the intact langur monkey was found to consist mainly of principal cells and basal cells and frequently apical or mitochondria rich cells were found. Besides these cells intraepithelial lymphocytes were also a consistent feature of the epididymal epithelium. Principal cells identified by means of the tuft of the stereocilia on their apical surface, bear well developed Golgi bodies, endoplasmic reticulum, vesicles, vacuoles and multivesicular bodies. This suggests their active involvement in absorption and secretion. Basal cells present at the base of the lamina bear a few cellular organelles and strong interdigitations with the adjacent cells. Apical or mitochondria rich cells were characterized by clusters of mitochondria in the apical region of the cell and few microvilli on their apical surface. Lymphocytes with a large nucleus and a pale rim of cytoplasm were also found at the base of the epithelium. Secretory and absorptive functions of principal cells of the epididymal epithelium were found to be increased after vasectomy, as indicated by bulging of the apical portion of the principal cells and membrane bound structure in the lumen. An extensive increase in the number of lysosomes, vesicles and vacuoles was also observed. An increase in the number of macrophages with spermatozoa remnants in the lumen of epididymis suggests that the principal mechanism for spermatozoa disposal following vasectomy is intraluminal endocytosis by macrophages. Changes following vasectomy persisted in vasovasostomized animals even after 12 months of recanalization, which may contribute to the failure of functional reanastomosis.

Ultrastructure of langur monkey epididymidis prior to and following vasectomy and vasovasostomy.

Tolnidamine (50 mg / kg body wt. / alternate day for 90 days; oral) was investigated for its contraceptive efficacy, causes of irreversibility, and side-effects by assessment of seminal characteristics and biochemistry, morphometry, libido and clinical investigations in adult male langur monkeys ( Presbytis entellus entellus Dufresne) . Semen weight, volume, colour, pH and libido remained unaltered. Sperm motility, vitality and morphology were impaired with the advancement of the treatment. Increased number of immature germ cells was also noted. Sperm density reduced to severe oligospermia following 45 days of treatment and remained low during recovery period. A marked reversible reduction in seminal GPC and magnesium levels was notieed, while other biachemical parameters remained unchanged. Irreversible changes in various morphometric data of Sertoli cells and spermatogonia were observed. Circulatory levels of testosterone fluctuated within pretreatment range. A significant but reversible elevation in serum creatinine was evident. The possible causes for irreversibility are the ever lasting alterations in the morphometry of Sertoli ceils and spermatogonia.

Studies on the Effects of Tolnidamine on Reproductive Functions in Langur Monkey

Studies on the ultrastructure of the vas deferens have been carried out in control, vasectomized (6 and 24 months) and vasovasostomized (12 months) langur monkeys (Presbytis entellus entellus Dufresne) Vas deferens epithelium of the control animals depicted four types of cells, viz the basal cells, principal cells, mitochondria-rich or apical cells and pencil or dark cells The basal cells were short, cuboidal in nature with prominent nuclei, and contained sparse cytoplasmic organelles The principal cells were characterized by the presence of nuclei with irregular outline and intranuclear electron-dense granules, well-developed Golgi bodies with prominent secretory vesicles, cisternae of rough endoplasmic reticulum, mitochondria, free ribosome particles, lysosomes and stereocilia in the cytoplasm, suggesting an active secretory role, as well as the absorptive functions of the cells The mitochondria-rich cells consisted of numerous mitochondria, and other cytoplasmic organelles were sparse The pencil cells were dark, slightly compressed and situated between the principal cells Vasectomy resulted in reduction of cytoplasmic volume and vacuolization of the cytoplasm, especially in the Golgi region of the principal cells Rough endoplasmic reticulum and mitochondria were poorly defined Vasovasostomy showed no appreciable improvement in the configuration of the cytoplasmic organelles The results suggest that a persistent reduced secretory activity of the cells following vasectomy and vasovasostomy might also be one of the factors responsible for unsuccessful vasovasostomy

S. Srivastava

Papers

Long-term sequelae of tolnidamine on male reproduction and general body metabolism in rabbits

Ultrastructure of langur monkey epididymidis prior to and following vasectomy and vasovasostomy.

Studies on the Effects of Tolnidamine on Reproductive Functions in Langur Monkey

Fine structure of the langur monkey vas deferens and possible role of changes following vasectomy in the success or failure of the vasovasostomy.