The preceding section has suggested the importance of the development of contraceptive procedures that meet the personal and cultural needs of people with different economic, social, and religious backgrounds. The social acceptance and individual motivation necessary for continued voluntary fertility regulation depend to a large extent upon the ease of use and the effectiveness of contraceptive procedures. The diverse needs among people throughout the world require development of a variety of methods and procedures.
Some effective methods of preventing reproduction are unacceptable—methods that remove or destroy the organs (testes or ovaries) that produce germ cells (sperm or ova) or permanently prevent the germ cells from leaving the body. Thus, castration is a completely effective method, but cannot be regarded as acceptable. The same end-result may be secured by the application of irradiation and by the use of some chemical substances, but these techniques are equally unacceptable.
Also effective, when properly executed, is surgical occlusion of the gonadal ducts—vasectomy in the male and salpingectomy in the female. Such procedures do not interfere with hormone production and in some cases it has been possible to restore fertility by reuniting the ducts. Acceptance of this method of preventing reproduction appears to be increasing in some parts of the world; for example, vasectomy is widely used in one state of India and in Korea, and undoubtedly it will be used even more widely in the future.
Short of such final methods, there are various well-known temporary techniques of contraception that can be used selectively by individual couples—diaphragms, condoms, various types of jellies, creams and foams, coitus interruptus, and periodic or total abstinence. All these methods operate on the simple and direct principle of preventing the sperm from physically meeting the egg, and they may all be considered, in greater or lesser degree, as mechanical means of contraception.
These procedures can and do affect the birth rate to varying degrees in accordance with the extent of motivation, proper use, and the skill of the individuals concerned. Obviously, the effectiveness of such methods varies widely depending upon the individual couples using them; a recent study has shown that couples who have all the children they want are much more successful in their use than those who still want to add to their families on a spacing basis. A major drawback of most of these methods, of course, is that they are too closely related to the sexual act itself; for that and other reasons they may not provide sufficient effectiveness for the large majority of people in the world.
For the majority we need simpler and less-demanding methods than are now available—methods consonant with weak motivation, inferior educational attainment, ignorance of biological processes, and other cultural differences. Development of better methods of this kind requires greater knowledge, which can be acquired only through bio-medical research.
Our present knowledge of the reproductive process in human beings is meager, and the study of reproduction does not receive the attention it deserves. We do know that human reproduction is exceedingly complex and is based upon the integration of many essential processes. Indeed, one might well wonder that reproduction is accomplished at all! In the normal course of events, the process of reproduction frequently does fail, as evidenced by human sterility and spontaneous abortion. The knowledge that would enable all couples to enjoy the fulfillment of parenthood by producing children, and to achieve a sense of personal responsibility in limiting the size of their families to the number of children desired, would contribute substantially to human happiness.
In devising methods for voluntary physiological regulation of fertility, the reproductive processes susceptible to interference must be considered. There are several major steps at which physiological reproductive mechanisms are subject to control. Blocking any one of these steps will effectively prevent reproduction, since each step is essential. These steps are:
production and release of the pituitary gonadotrophic hormones,
stimulation by gonadotrophic hormones of egg and hormone production in the ovary and of spermatozoa and androgenic hormone production in the testes,
ovulation and passage of the egg into the oviduct,
transport of spermatozoa into and through the epididymis and physiologic maturation of the spermatozoa,
passage of spermatozoa through the vas deferens to the ampulla,
suspension of spermatozoa in the seminal plasma during ejaculation,
passage of spermatozoa through the cervix,
ascent of spermatozoa through the uterus and oviducts and acquisition by the spermatozoa of fertilizing capacity,
pentration of the ovum by one spermatozoon and formation of the zygote,
cleavage and early development of the zygote during passage through the oviduct,
preparation of the endometrium of the uterus for reception of the blastocyst,
entrance of the zygote into the uterus and formation of the blastocyst, and
implantation of the blastocyst in the endometrium, and maintenance of continuing embryonic development.
Attention is now being given to each of these steps by investigators, but accelerated and expanded effort is essential if we expect to devise a sufficient variety of regulatory methods quickly enough to affect significantly the world’s population growth rate.
METHODS CURRENTLY MOST PROMISING
At the present time, four methods of great promise have been developed. These are the inhibition of ovulation, the inhibition of zygote development, the inhibition of spermatogenesis, and the action of the newly developed intra-uterine devices.
Inhibition of ovulation
It is now well known that the cyclic use of a variety of steroid substances will inhibit ovulation with extreme effectiveness, as a result of the suppression of the gonadotrophic hormones. The preparations most used are a combination of a synthetic progestin and an estrogen—substances normally responsible for the build-up of the uterine endometrium prior to the implantation of the blastocyst. The oral ingestion of these agents for 20 days, beginning on the fifth day of the menstrual cycle, will effectively abolish the normal ovulatory cycle and substitute an artificial anovulatory cycle—one in which no eggs are released from the ovary. It is estimated that almost two million women in the United States now use oral contraceptives as their only means of regulating fertility, and it is likely that at least another two million are doing so in other parts of the world. At the present time there are two widely used preparations that are taken orally, and many more preparations are under development and study. Further investigation is needed, and is in process, especially on the possibility of serious side-effects from long-term ingestion of such compounds. Their cost is currently a barrier to wide distribution in the poorer countries, but there is hope that mass production can meet this problem. In addition, experiments are underway to develop a preparation that could be injected once a month, or even less frequently, and still provide continuous protection. The injectible agent may be combined with other substances that permit a slow but sustained release of the compounds over an extended period of time, thus replacing a daily oral regimen.
These substances appear to inhibit development of the cleaving egg (the zygote) during its transport through the oviduct. It appears that the recently fertilized egg is extremely vulnerable to diverse influences, both spontaneous and induced. It is estimated that death of early zygotes occurs, spontaneously, at least as frequently as once in four instances. The causes of this fetal wastage are numerous, and not well understood, but, in part, may be due to deleterious chemicals. It is well known that the cleaving eggs of many kinds of animals are very susceptible to inhibition by a wide variety of chemical substances. Some of these compounds have proved effective in preventing embryonic development in experimental animals when administered within three or four days after mating. Thus it is possible that a single pill, taken after coitus, will inhibit development of the egg, should fertilization occur. Animal studies have indicated that such compounds act directly on the young zygote and not primarily on physiological mechanisms in the maternal organism. Since numerous compounds which produce these or related effects are under investigation, it seems highly likely that effective agents, safe for human use, will become available. If so, they will have certain important advantages over the oral contraceptives presently available.
It has been known for approximately ten years that certain compounds of the nitrofuran and thiophene type are capable of inhibiting spermatogenesis in animals by halting this process at the primary spermatocyte stage, one of the early stages in the formation of mature sperm. This is a completely reversible phenomenon and does not involve the endocrine functions of either the testes or the anterior pituitary gland. Inhibition of sperm production by this procedure has a distinct advantage over the spermatogenic inhibition induced by the same compounds that prevent ovulation in females. Although these latter drugs are exceptionally effective in preventing maturation
of sperm cells, they cannot be regarded as acceptable contraceptives in the male since they also inhibit secretion of male sex hormones and hence lower libido and potency.
The nitrofurans and thiophenes have not been applied to human fertility regulation because the doses necessary for suppression of spermatogenesis have induced unpleasant side-effects. More recently a series of bis- (dichloroacetyl) diamine compounds has been synthesized. Although the compounds were developed initially for their amebacidal activity, studies of the testes of experimental animals showed the same kind of effects that had been observed earlier for the nitrofurans and thiophenes. Experimental tests in human beings demonstrated that spermatogenic inhibition can be achieved, and that the effect is reversible: Sperm production returned to pre-treatment levels about two months after treatment ceased. These observations, secured in two separate groups of volunteer institutionalized individuals, were sufficiently encouraging to suggest clinical studies on the contraceptive effectiveness of these compounds. When the trials were made, however, an unexpected side-effect quickly became manifest: Individuals ingesting the drugs experienced exaggerated responses to the peripheral effects of alcohol, which, though not serious, were unpleasant enough to suggest that general acceptance of this form of contraception would be unlikely.
Subsequent investigations have been directed toward development of compounds that will be effective antispermatogenic agents without unpleasant side-effects, and a number of preparations will probably be available soon for laboratory and clinical study. When one or more of these compounds can be proven effective and safe, another method will thus be added to the battery of contraceptive techniques, assuming its general acceptability.
Another group of compounds that seem promising at present are the dinitropyrroles, one of which has been particularly effective as an antispermatogenic in rats. A single oral dose, after exhaustion of sperm already formed, induces a period of infertility lasting four weeks, and an infertile state has been maintained indefinitely by administering single doses at four-week intervals. The process of spermatogenesis is halted at the primary spermatocyte stage, and it recovers when treatment is withdrawn.
The recent revival of interest in the use of intra-uterine devices is a highly significant development. Although intra-uterine devices are scarcely a physiological method for fertility regulation, in the usual sense, they probably operate by means of physiological mechanisms. At present they represent a rather good possibility for use in a relatively cheap and acceptable procedure. A variety of improved devices is now available, including several constructed from plastics and rings formed from silkworm gut, nylon thread, and stainless steel. Some of these can be inserted into the uterine lumen without dilation of the cervix, thus facilitating their use. The record for effectiveness and acceptability of each of these devices appears to be exceptionally good; several thousand women are currently using one or another of these devices in experimental programs under careful clinical supervision.
For many years, the medical profession has questioned the use of intra-uterine devices; more recently, however, they have been the subject of renewed interest, centering upon those manufactured with inert plastics. Current investigations have indicated strongly that these devices are both safe and effective in preventing reproduction. The mechanism of their action is as yet unknown, and studies are being undertaken to acquire that important knowledge. In view of the potential importance of this means of contraception for mass application, providing safety and effectiveness over a long period with a single insertion, it deserves the most serious and careful consideration.
METHODS OF FUTURE PROMISE
Inhibition of implantation
It was noted above that some compounds inhibit early development of the fertilized egg or zygote. Attention is also being directed toward compounds with the capacity to inhibit implantation of the blastocyst in the endometrium. This effect might be accomplished by a substance that interferes with the action of progesterone, so that the proper preparation of the tissue lining the uterus would not occur,
or by a substance that would interfere with mechanisms essential to the implantation process.
Control of hypothalamic factors
It is now recognized that a neurohumoral factor that originates in the hypothalamic area causes the pituitary to secrete two gonadotrophic hormones necessary for stimulating ovulation and spermatogenesis. It is highly probable that, as our knowledge of this hypothalamic-pituitary relationship is extended, it will be possible to interfere selectively with the secretion of either of the two gonadotrophic hormones—the follicle-stimulating hormone (FSH) and the luteinizing hormone (LH). It would be desirable to be able to inhibit FSH selectively so as not to interfere with LH, which is the hormone essential for the production of other hormones that are important for maintaining the sex drive. Thus it would be possible in either sex to inhibit germ-cell production without causing a decrease in the production of sex hormones.
One of the most challenging areas of current investigation is designated as immuno-reproduction. Most of the proposed procedures for the immunological control of fertility are based upon the classical principle of disease control by vaccines—the development of antibodies against the causative agent. Theoretically it is possible, by the application of such immunologic procedures, to interfere selectively with any one or all of the processes related to reproduction. Some immunologists believe, for example, that it should be possible to develop a vaccine (as in the recent development of polio vaccine) to immunize females against spermatozoa, against reception of the fertilized ovum into the endometrium, and against the development of placental tissues. In the male, active immunization using testicular vaccines is known to prevent sperm development. The formed antibodies destroy and prevent further formation of sperm cells for extended periods of time. It might be possible to develop an immunizing vaccine that
would prevent the development of active sperm motility. It is also believed that it is possible to invoke an immunologic situation that would prevent fertilization. This latter type of regulation would be not only effective but also, in all likelihood, widely acceptable. There are numerous other possibilities for the application of immunologic principles to the control of fertility, and it is reasonable to anticipate the development of various methods of inhibiting fertility by induction of antibodies against substances involved in specific reproductive processes. When such methods are developed, it will be possible voluntarily to maintain an infertile state for any length of time desired by administration of occasional booster treatments. Immunologic procedures for controlling disease have a high degree of acceptability throughout the world; with further refinement, immunologic fertility regulation should also be well received.
Detection of ovulation
Any sure method for predicting ovulation would be extremely valuable in making the rhythm method of contraception more dependable and thus more acceptable to many people. Furthermore, the ability to predict ovulation almost certainly would permit effective treatment of some cases of infertility. Procedures now available reveal the occurrence of ovulation post factum, but obviously these are not applicable to the pertinent need. Claims have been made for a chemical method and for two methods of detecting incipient ovulation by use of “test” papers applied to the cervix or vagina, but impartial investigators have been unable to confirm the value of these procedures. Other studies now in progress may lead to more reliable methods; perhaps the most promising involves the application of immunologic procedures for determining changes in levels of the gonadotrophic hormones. Furthermore, at least three groups of investigators have shown independently that immunologic methods (antigen-antibody reactions) can be used to detect hormones related to the occurrence of pregnancy. Since each of the procedures depends upon the presence of a gonadotrophic hormone (chorionic gonadotrophin), it is reasonable to anticipate that progressive refinement of techniques may eventually provide a method of foretelling ovulation.