A Volkswagen for Him and a Mercedes for Her *
By Theodore M. Jackanicz
Presented to
the Chicago Literary
Club April 12, 2010
1. Introduction.
Several fellow Literary Club members have asked me if my title concerns matters of a divorce settlement between concerned parties. It does not. Nor does it concern the eight times I’ve visited Germany. In this presentation I will cover some of the research in contraceptive development I conducted in my professional life and also that of some of my colleagues at the Population Council, preceded by some background information in the field of reproductive endocrinology and contraceptive technology. The title acknowledges that a woman’s reproductive system is far more sophisticated than that of us men, and I must confess a degree of envy at this difference. Some of the women in the audience might chuckle at this admission. Perhaps if I had dealt first hand with women’s reproductive issues as they have, I might express less enthusiasm, but certainly the sense of awe would continue.
The need for reversible, relatively inexpensive and simple contraceptives represents one of the most important challenges all societies face today; currently the world population is approaching seven billion individuals and estimates for 2050 range from 9 to 11 billion. Sterilization is a permanent and effective solution, but most useful in older couples who have reached their desired family size. In men (i.e. the Volkswagen) this vasectomy process, is comparatively simple, fast, inexpensive and
*
© by Theodore M. Jackanicz (all rights reserved)
usually free of major side effects, since a man’s reproductive system is relatively exposed. Sterilization in women is much simpler than several decades ago, but still when compared to men, requires more time, more elaborate medical facilities, costs more and entails greater risks of side effects. Again, the Mercedes reference seems appropriate, and thus the need for reversible methods becomes more obvious. Moreover, individual contraceptive users differ with regard to the desirable features of a contraceptive method; this quest to develop a variety of methods, not unlike managing an enormously complicated cafeteria, has occupied scientists in the field of reproductive endocrinology since the mid-twentieth century.
2. General
Background.
Traditional barrier methods keep sperm from reaching an egg, or to use more scientific terminology, from fertilizing an ovum. Men have used condoms for hundreds of years, and thanks to the valiant efforts of Margaret Sanger, an early family planning advocate, diaphragms for women enjoyed increased usage beginning in the 1920s. These were the two principal reversible methods until the introduction of oral contraceptives and intrauterine devices (IUDs) in the 1960s.
Over the past fifty years, pharmaceutical companies manufactured and distributed a variety of oral contraceptives, but virtually none of them chose to develop relatively inexpensive, simple to use, long-acting methods. This fell to the Population Council and other non-profit groups, whose target audience was a less affluent audience, principally in the so-called developing world. John D. Rockefeller III, one of the grandsons of John D. Rockefeller, founded the Population Council in New York City in 1952. The five Rockefeller grandsons had a variety of professions: Nelson and Winthrop were politicians, David a banker, Laurence an investment banker and a resort developer and John D. III, the eldest, was a professional philanthropist, with a deep interest in population issues. John D. III provided seed money for the Population Council, with the goal of addressing population matters, with both basic and applied biomedical research at a time when government and industry did not consider this a proper area of concern. Research is now supported by government funding (e.g. National Institutes of Health and United States Agency for International Development- USAID) and a variety of private foundations. Much of the research and development at the Population Council was conducted in association with the International Committee for Contraception Research (ICCR), a network of clinical investigators on six continents established in 1970, that tests new methods and devices. The strategy involves developing a method in the New York laboratories, adapting it for human usage, testing it sufficiently to prove its safety, ensuring the lack of serious side effects, determining contraceptive effectiveness, obtaining approval from the United States Food and Drug Administration and ultimately finding a pharmaceutical partner who would mass manufacture the device in a factory setting. The Population Council has negotiated contracts, which provided a new method at a minimal margin above cost in the developing world, while the pharmaceutical company could market the method in industrialized countries at a larger profit. In some cases USAID would purchase devices in bulk at the discounted price and provide them to local family planning agencies at no cost.
3. Background Endocrine Information.
Before discussing contraceptive development, some background is necessary in the field of endocrinology in which a hormone is produced in one gland or organ and transported thru the bloodstream to another target organ, to interact with specific receptors (usually proteins) that bind the hormone and facilitate its action. We will just consider the reproductive systems, not other endocrine entities such as the thyroid or adrenal glands.
On a physiological basis, women and men share a host of endocrine similarities. Both men and women possess a specific area at the base of the brain, the pituitary gland, which synthesizes and secretes the same two specific protein hormones follicle stimulating hormone (FSH) and luteinizing hormone (LH) that target the sex glands. In the case of women, it’s the ovaries and in men the testes.
In men the protein hormones FSH and LH stimulate testosterone production in the testes, and in our Volkswagen like design, we just keep producing sperm from the onset of puberty (10 to 12 years of age) until death, albeit at a lesser pace as we age. A colleague who studied structure and development of sperm with an electron microscope began collecting and analyzing his own sperm in his early twenties and continued until retirement in his late sixties, categorizing their gradual decline in both quantity and quality as he aged. He relates this as a somewhat sad story.
In women, of course, the reproductive process proceeds in a more sophisticated, synchronized fashion where the FSH and LH protein hormones regulate ovarian secretion of two steroids: estradiol and progesterone. An infant girl is born with all the ova (several hundred thousand) she will ever possess; only a small percentage of these ova (perhaps 400) will mature, be released from her ovaries and potentially be fertilized during her reproductive years, that could theoretically range from age 14 to 45. Each month a few ova start to develop as the circulating FSH hormone levels begin to rise. By about day 10 of the cycle, usually only one dominant follicle reaches maturity and at mid-cycle, about day 14, ovulation occurs as an ovum bursts from the rupture point of the follicle and is swept away in a stream of follicular fluid into the nearby opening of the oviduct, reminiscent of a ball gliding into a catcher’s mitt.
Fertilization occurs shortly after the time of ovulation as sperm ascend the fallopian tubes in search of their query, the ovum, which is traversing the oviduct toward the uterus. Sperm can live for several days in the female’s tract, but the ovum is fertilizable for only about 24 hours. Incidentally, of the millions of sperm which are released into the female tract, only a few thousand (the most fit) make their way into the uterus and only a few hundred make it to the fallopian tube, the arena of fertilization, to attempt to fulfill their destiny.
Five days after fertilization, (~day 19 to 20 of the cycle) the fertilized ovum attaches to the wall of the uterus from which it will obtain nutrients for further development. Meanwhile the uterus has undergone changes to provide a protective and supportive environment by increased estrogen exposure during the first half of the menstrual cycle, the interval prior to ovulation. Subsequently ovarian steroid production switches to the other female steroid hormone, progesterone, which increases the thickness of the inner uterine wall. At this point under progesterone influence, in a nonfertile month the ovary would fail to receive hormonal notice of a. pregnancy, would begin decreasing progesterone production, the uterine wall would slough off and menstruation would begin. In the event of a successful pregnancy a protein hormone (human chorionic gonadotropin--HCG) produced by the fertilized ovum stimulates the ovary to continue progesterone production to nurture the new resident of the uterus until the embryo (a later development stage of the fertilized ovum) can begin producing sufficient progesterone on its own. This sequence of events, as noted above, prohibits menstruation, which would empty the uterus of this fragile new entity. The detection of the protein hormone HCG is the basis of modern pregnancy test kits. The continued progesterone environment not only prepared the uterine lining for the implantation of a fertilized ovum, but also prevented uterine contractions and blocked a subsequent ovulation, which would have drastically altered the woman’s hormonal balance resulting in an unfavorable environment for the fertilized ovum.
The synchronization of the maturation, release and fertilization of the ovum in combination with the preparation of the uterus as a suitable site for implantation results from the perfectly timed sequence of hormone release. To be more specific, after ovulation, the ovarian steroid hormones blood levels increase to signal the pituitary gland to drastically decrease protein hormone (i.e. FSH and LH) production, thus preventing another ovulation at that time, which would compromise a successful pregnancy. But if the cycle is infertile, blood steroid levels decrease, and FSH and LH begin rising, in preparation for the next cycle and menstruation ensues.
Returning again to male aspects of the reproductive process, a man’s reproductive system does not function in a cyclical mode; sperm develop continuously from spermatogonia, the precursors of sperm, for the entire life of the individual. The sperm developmental process lasts about ten weeks, as the maturing sperm pass thru microtubules of the testes, which if stretched out would extend a mile or so. Spermatogenesis requires LH and FSH, the same protein hormones women produce, but in this case, instead of the progesterone and estradiol a woman’s ovary synthesizes, the male testes produce testosterone. The ultimate change in sperm structure enabling them to fertilize an egg occurs within the female reproductive tract, into which millions of sperm are released. Only tens of thousands actually reach the cervix, a few thousand enter the uterus, and a few hundred spermatozoa swim as far as the fallopian tubes, where one of them may fertilize an ovum.
As
noted above, a woman may ovulate some 400+ times in her life.; each of these
ova would produce a unique individual.
And considering as noted earlier, that several hundred sperm could find
their way to the vicinity of a newly released ovum, each “hoping” to
successfully merge with the ovum, the number of possible individuals each of us
might have become on the fateful occasion that our parents conceived us (400 X
300= 120,000 or 1 X 300=300) staggers the imagination. It is no wonder that one sees similarities,
but yet significant differences among siblings.
4. The Contraceptive
Revolution.
The two most significant changes in modern contraceptive methodology were the oral contraceptive and the rediscovery of the intrauterine device (the IUD) in the 1960s. The pill arose through the efforts of Dr, Gregory Pincus at the Worcester Foundation for Experimental Biology in Shrewsbury, MA , who frequently conversed with birth control pioneer Margaret Sanger; Sanger constantly reminded Pincus of the need for improved contraceptive methods. Pincus received both financial assistance and synthetic potent progesterone-like steroids (termed progestins) from the former G.D. Searle Co. of Skokie, for studies in laboratory animals. After successful safety tests the candidate drugs were tested in human subjects, initially to treat infertile women and in women with very irregular menstrual cycles, and only subsequently for contraception. Several other pharmaceutical companies also developed synthetic progestins that proved effective in laboratory animals followed by trials in human clinical studies. More than fifty oral contraceptive products have been marketed with a variety of different progestins, dose combinations with a synthetic estrogen and administration under several different usage schedules. The main change over the years has been a lowering of steroid dosage in order to minimize side effects, while maintaining effectiveness.
The oral contraceptive functions by ovulation suppression. When a woman takes a progestin, usually on a 21-day schedule, her ovary will not release an ovum, as her hormone status is similar to that of the second half of her cycle, as if she had already ovulated. Her reproductive mechanism is designed not to ovulate twice in a cycle, so in effect her system is fooled into thinking the ovulation for the month has already occurred. Estrogen is added to improve the regularity of the menstrual cycle, and it also increases the contraceptive effectiveness of this method. Some women have used the pill successfully and others have not because of side effects. Some find it difficult to remember to take a pill each day, while others incorporate pill ingestion into their daily routines. In the final part of this presentation, I will address these issues.
Ernst Graefenberg was the first to study intrauterine devices (IUDs) in his patients in Berlin in the 1930s inserting flexible rings of catgut and/or silver into the uterus. An interesting anecdote concerns Graefenberg, a Jew being demoted from his hospital chairmanship in 1933, subsequently not fleeing Nazi Germany even though friends had advised him to do so; he was jailed on dubious charges, Margaret Sanger ransomed him and in 1940 Graefenberg immigrated to New York to continue his medical practice and lived there until dieing in 1957. With the limited use of the IUD, and intervening war years, the method fell into disuse until scientists, clinicians and statisticians at a 1962 Population Council sponsored conference reexamined the IUD data and decided to move forward. The first device was an all plastic curved form invented by Dr. Jack Lippes (the Lippes Loop). Because of the shape, women frequently experienced cramps and excessive menstrual bleeding. Investigators at the Population Council developed T shaped devices, which were very well tolerated, as they conformed to the shape of the uterus. When copper, which had been shown to be an effective and safe contraceptive in animal studies was fastened to the T-frame, the device became a very effective contraceptive. Subsequently an assortment of copper bearing devices of varying shapes were developed by individuals at non-profit groups and later, pharmaceutical companies. The most effective copper device is the Paragard (referred to as the Tcu-380A during our laboratory development), which has an effective lifetime of 10 years. Two Population Council ICCR investigators developed the Mirena IUD, which releases micro levels of a synthetic progestin into the uterine cavity and has an effective lifetime of five years..
Both devices are very effective and well accepted by most women. With either the copper or progestin-releasing device, sperm motility decreases markedly and their ability to fertilize an ovum declines dramatically. Neither device has been shown to interfere with implantation of the fertilized ovum into the uterus, what some would consider abortion, and thus a prohibition for some potential users. The advantage of an IUD is that a woman need visit a family planning facility only one time to have a long period of infertility that can be reversed easily. The method is much more commonly accepted in Europe and Asia than in the United States. After the problems with the poorly designed Dalkon Shield IUD in the 1970s, significant litigation followed and all United States pharmaceutical companies terminated IUD manufacture and marketing. The Population Council negotiated an agreement with a venture capital group to establish a small company that would manufacture and distribute the copper IUD, which was later named Paragard.
Another issue is cost: $200 or more for the device plus fees for the medical exam, which can vary depending on whether the medical service is at a private office (the most expensive), a clinic, or a Planned Parenthood facility (the least expensive). Moreover, not all insurance plans will cover the cost. One of the ironies of life appears when an insurance company will not pay the cost of an IUD. The Paragard copper IUD is mass-produced for about one dollar and lasts for ten years. It is provided to non-profit facilities overseas at a figure close to one dollar. While Viagra, which some insurance companies will cover, costs about ten dollars for one usage. So ten years of female contraception can cost one dollar, while one male use of Viagra is 10 dollars.
As popular as oral contraceptives have been, they require daily attention, induce side effects in some women (e.g. headache or nausea) and are relatively expensive. A cycle of pills costs at least $15-25 through pharmacies, can be ~$10 in generic form, but not all insurance plans will reimburse the charge. Sustained release methods in which the drug is delivered from a depot lasting for an extended time interval would address these problems. Examples include under the skin implants, injections, skin patches and vaginal rings. Due to time constraints, I will only discuss vaginal rings, a project on which I worked for a good number of years; many of the advantages of the ring apply to the other methods.
The 2 ¼” diameter vaginal ring is made of inert silicone rubber and is the reservoir from which a progestin and an estrogen are delivered into the woman’s vagina. The steroids are absorbed into the vaginal walls, pass into the blood stream and flow to the pituitary gland, the same target that oral contraceptive steroids seek.
A woman using a vaginal ring follows a schedule similar to that of a pill taker, inserting it into her vagina on day 7 of her cycle, keeping it in place for 21 days during which time she receives significantly less steroid than that delivered in an oral contraceptive over the same interval. During the 21-days of usage, the woman may wish to remove the ring prior to intercourse or for some other reason, but must be sure to reinsert it within two hours or steroid blood levels might fall enough to permit an ovulation. Since the ring is smaller than most diaphragms and its orientation within the vaginal vault is not critical, as with a diaphragm, most users leave the ring in place during intercourse. After 21 days of use, the woman removes her ring for 7 days at which time her menstrual bleeding begins. The same ring is reinserted on this 21/7 schedule for one year.
When ingesting a pill, the recipient must take enough drug, one might say an overdose, to last for 24 hours until the next pill. With a vaginal ring, a lower, more constant dosage is administered, with less potential for both immediate and for long-term side effects. Thus the woman only need address the usage schedule twice a month: once to insert the ring and once to remove it. Should the user forget to remove the ring and leave it in situ a few extra days, no harm results; if the woman forgets to reinsert the ring after the seven days of non-use have elapsed, she risks an ovulation, and thus a pregnancy. If the ring is reinserted sooner than the usual seven days out interval, e.g. if the woman’s menstrual bleeding ceases, that’s fine, too. The ring provides long-term continuous contraception, as do implants, IUDs, and injections, but it is under the user’s control, both an advantage and also a disadvantage: an advantage because some users wish to be in absolute control of their contraceptive method, but it’s a disadvantage because the method is easy to discontinue.
The Population Council recently completed a successful large scale, international, multi-centered clinical trial with a combination progestin and estrogen ring developed in my laboratory. Upon analysis of this data by the United States Food and Drug Administration, that organization should approve the use of our vaginal ring, hopefully in the next two to four years. Two weeks ago I visited New York to participate in the celebration of the Population Council signing a contract with a pharmaceutical partner that will assume the manufacturing, marketing and distribution of our vaginal ring in North America, after US FDA approval.
Approval by the USFDA is very important in that it will: (1) permit sale of the device in the United States. (2) Allow the US Agency for International Development to purchase the device (at slightly more than cost, probably a few dollars) for distribution to family planning programs in the developing world. By law, USAID may not distribute any drugs or devices the FDA has not approved, lest we be accused of passing off products not good enough or safe enough for consumption in the United States. (3) This will mean virtually automatic approval in those countries not having a food and drug authority. Currently a competing one-month vaginal ring is on the market. Because of this short usage interval and its high cost ($15-40 per ring), it is not a practical solution for the audience the Population Council wishes to serve.
6. Abortion
A few words about abortion, a politically charged issue, are appropriate. Personally, I am pro-choice. Visits to family planning clinics in Brazil, the Dominican Republic and the United States have reinforced this opinion for me.
Roussel, a French pharmaceutical company developed an abortion pill RU-486, also known as mifepristone. Under medical supervision, use of this method is safer and simpler than surgical abortion. No pharmaceutical company in the United States would distribute mifepristone, fearing economic reprisals from antiabortion groups. A product that would generate relatively small profits to a company would endanger sales of their mainline of pharmaceuticals. The Population Council tested the method in ICCR clinics to provide additional data for U.S. Food and Drug Agency approval, and subsequently found a venture capital firm that assumed the distribution of this method.
The same situation occurred with Plan B, the so-called morning after pill, best used within 24 hours after unprotected exposure to the risk of pregnancy. No pharmaceutical company wished to manufacture and distribute this product fearing reprisals from antiabortion groups. Incidentally, the method works by either preventing ovulation or thickening the cervical mucus and thus decreasing sperm motility, not by abortion. Again the Population Council sought a small venture capital firm that took over the manufacture and distribution of this method, which is now widely available.
Women have resorted to abortion for hundreds, if not thousands, of years when faced with an unwanted pregnancy. In some developing countries, where abortion is illegal, a major reason for admission of women to a hospital stems from infections due to abortion. Thus the question is not whether abortion should be prohibited. It is will women have access to abortion in a safe, environment or will it be in a setting where they are at risk for serious medical complications or even death?
7. What About Methods for
the Male?
Some of you may have noted that all the new methods described are for women. Is this a sexist plot? No!! Are men whining at being left out of their contraceptive responsibilities? No, again. To assess this issue, let’s recall the endocrine information presented in the beginning of this presentation; many more options are open for female contraception than for the male because there are more vulnerable points in a woman’s reproductive sequence. Only two possible aspects of male physiology lend themselves to treatment: One is interference with sperm transport, which has been addressed in the form of the condom and vasectomy, and no obvious alternatives to these methods appear on the horizon. The second possibility, to interfere with sperm production and maturation, is an area under active investigation in numerous animal studies and to a lesser extent human trials. To mimic the oral contraceptive effect on suppressing ovulation, a variety of testosterone analogs have been studied to suppress sperm production by oral administration, by injection and also implant routes. None works very well, as the steroid doses needed are far greater in men than that for women, so only the oral route is feasible, which drastically decreases the number of safe and effective drug candidates. The large quantity of a testosterone analog necessary would require monthly insertion and removal of an implant under the skin, a protocol acceptable to very few individuals and economically unrealistic.
Thus far no effective and safe testosterone analog has been developed. A completely different approach was, studied in China with gossypol, a component of cottonseed oil; this compound was shown to possess contraceptive properties, but the difference between an effective dose and a toxic dose was so narrow, that the method was abandoned. Furthermore, any male method centered on sperm suppression must take into account the ten-week time span of sperm maturation, requiring long intervals for testing a method. Even if a sperm suppression method were successful, couples would need an alternate contraceptive during the ten weeks that the sperm in the testicular tubules worked their way thru their mile long labyrinth in the testes. So the preponderance of female methods is not a sexist plot, but a practical issue.
8. Conclusion.
For the past 40 or so minutes you’ve patiently listened to a history of the Population Council, a quick course in reproductive endocrinology and a review of contraception. For most of us at our age, contraception isn’t as much of a concern as it once was, but our grandchildren will certainly have more options than we did. Our grandchildren may be upset with us for some environmental and financial messes they’re inheriting from us, but they’ll have a lot easier time limiting the size of their family than did earlier generations. And you can be sure that if we have a grandson, he will be going around in his Volkswagen, and if we have a granddaughter, she will be speeding about in her Mercedes.
References
1. Merck Manual, 18th Edition, (2006) p. 2069 for general discussion of reproductive endocrinology.
2. http://www.merck.com/mmhe/sec22.html Women’s health issues in current Merck Manual on-line edition for information similar to reference #1.
Two recent reviews of research in contraception:
3. R. Sitruk-Ware. Contraception 73 (2006) 215-222
4. J. Amy and V Tripathi. BMJ 2009;339:b2895 or on the web at:
http://www.bmj.com/cgi/content/full/339/aug07_1/b2895