Androgens, GnRH antagonists, antibodies to sperm surface antigens, compounds that act on sperm maturation in the epididymis

Hormonal-based contraceptive approaches
Production of spermatozoa in the seminiferous tubules and of the male sex hormone, testosterone, by Leydig cells, depends on pituitary gonadotropins. The two pituitary gonadotropins responsible for testicular function are luteinizing hormone (LH) and follicle-stimulating hormone(FSH). These gonadotropins are regulated by the pulsatile release of the hypothalamic decapeptide gonadotropin-releasing hormone (GnRH). There is a finely tuned relationship between the testes and the pituitary-hypothalamic axis called negative feedback. It is based on the fact that testosterone or ovarian hormones administered to the male in large quantities will suppress pituitary-hypothalamic production and the release of gonadotropins which in turn will stop spermatogenesis. Historically, many combinations of androgens, progestins and estrogens have been utilized to stop normal pituitary function, an action that has been termed "pharmacological hypophysectomy.'' Figure

Recently, it has been shown that men injected with large doses of testosterone have a complete absence of spermatozoa in their ejaculates. This absence is termed azoospermia and is a highly effective contraceptive method. Testosterone-induced azoospermia occurs only in 60-70% of treated Caucasian men, but in a greater proportion of Chinese and Indonesian men (>90%). Most of the men who do not develop azoospermia become oligozoospermic and have very low sperm counts. Studies are now underway to ascertain whether severe, but incomplete, suppression of sperm production renders most of these men infertile.

Studies on GnRH have included development of synthetic derivatives that mimic (agonists) or oppose (antagonists) the action of GnRH. Agonistic compounds, when given in large doses, initially stimulate the pituitary gland to release LH and FSH but then suppress pituitary release of these gonadotropins, a phenomenon known as down-regulation. Despite this paradoxical decline in gonadotropin levels, agonistic analogs of GnRH have not been very effective at inducing azoospermia, at least at the doses used. However, exploratory clinical studies using GnRH antagonists in combination with androgens suggest that azoospermia can be reached more readily, and in a greater proportion of volunteers, than with any of the previous hormonal approaches. This data base must be substantially expanded before the true potential of this approach is realized. Two important factors must be kept in mind concerning the GnRH antagonist approach. First of all, androgen substitution therapy is needed because the use of antagonists leads to the loss of libido. Secondly, the current generation of antagonists is too expensive to be of practical contraceptive use. Figure

In addition to hormonal drug approaches, attempts are being made to utilize vaccines based on GnRH and FSH as potential male contraceptives. These approaches are in the early stages of clinical investigation and their full utility will not be known for several years.

Direct inhibition of spermatogenesis
Accidental observations have shown that the rapidly dividing cells within the seminiferous epithelium are exceedingly sensitive to a variety of chemicals. Unfortunately, the effect of many of these chemicals are not testes-specific and other end organs are affected, which can result in systemic toxicity.

The best known agent that directly affects the testes is gossypol, a yellow pigment found in cotton seed oil. It has been extensively studied in China and some other countries. This drug appears to have a very narrow safety margin and the effective dose must be closely controlled. Potassium metabolism and kidney function can be disturbed in individuals receiving this drug. Moreover, a relatively large proportion of men fail to regain their fertility after prolonged exposure.

Indinopyridines represent a category of drugs that rapidly disrupt spermatogenesis without affecting male sex hormone production. Experiments are underway in animal models to determine the specificity and reversibility of the action of these compounds. The mechanisms by which these compounds act is not known at this time.

Sperm antigen-based vaccines
Spermatozoa contain a number of unique chemical components that are not observed in somatic cells and which can be utilized as antigens in vaccine development. Many of these antigens arise during the early stages of spermatogenesis before the fully formed spermatozoon is released into the lumen of the seminiferous tubule. When a male is immunized with these sperm components, antibodies against them penetrate into the seminiferous epithelium and react with the antigens of the early sperm cells resulting in an immunologically-mediated inflammatory process. If severe, this process destroys the seminiferous epithelium leading to permanent infertility. Women are potential recipients of antisperm vaccines. Immunized women will produce antibodies that attack spermatozoa that enter the female reproductive tract after coitus, thus preventing fertilization of the ovum. Figure

Interference with sperm maturation
Spermatozoa acquire certain membrane components during their epididymal maturation process, after they are released from the seminiferous epithelium. These components have not been well characterized as yet, but, in theory, immunization against them should result in infertility although normal sperm production would continue.

Conclusions
Development of a practical male contraceptive agent is being studied by a number of investigators. Drug and vaccine approaches have had limited success to date and it appears unlikely that a male contraceptive will be available before the year 2000. A somewhat greater success may arise from methods that promote vasectomy as a contraceptive by making it more readily reversible.

Suggested Reading

Bernstein ME. Agents affecting the male reproductive system: effects of structure on activity. Drug Metab Rev 1984;15:941-996.

Nieschlag E, Behre HM, Weinbauer GF. Hormonal male contraception: a real chance? In: Nieschlag E, Halbernich UF, eds. Spermatogenesis -Fertilization -Contraception: Molecular, Cellular and Endocrine Events in Male Reproduction. Heidelberg: Springer; 1992:447-501.

Ray S, Verma P, Kumar A. Development of male fertility regulating agents. Med Res Rev 1991;11:437-472.

Swerdloff RS, Wang C, Bhasins. Male contraception: 1988 and beyond. In: Burger HG, de Kretser DM, eds. The Testis, 2nd edn. New York: Raven Press; 1989:547-568.

Waites GMH. Male fertility regulation: the challenges for the year 2000. Brit Med Bull 1993;49:210-221.

Wu FCU. Male contraception: current status and future prospects. Clin Endocrinol 1988;29:443-475.