Millennium Update Future Trends in Human Infertility and Infertility Treatment
If you have any questions, you may call us at (314) 576-1400.
By Dr. Sherman J. Silber
Based on decades of experience in reproductive and genetic research, and in the clinical application of infertility technologies to the treatment to many thousands of infertile couples, we predict some shocking future developments in human reproduction.
There are 4 million babies born in the United States each year. However, there are an additional 6 million infertile couples in the United States who cannot conceive without medical help, and only 60,000 in vitro fertilization (IVF) cycles are performed each year. Fewer than one percent of infertile couples who need treatment receive it.
However, if the cost of IVF treatment were not an impediment, many millions of couples would be undergoing IVF. This has already occurred in countries like Israel and Australia, where such treatment is subsidized. In the future, at least 30 percent of babies will be born as a result of this technology, rather than as a result of sexual intercourse.
What is the reason for this problem? In modern society, many couples delay childbearing until they are in their thirties. Infertility affects 2 percent of couples in their early twenties, 25 percent of couples in their mid-thirties, and more than 40 percent of couples in their late thirties and early forties. Therefore, if most people who need IVF can gain access to it, 25 percent of all couples of childbearing age might eventually be undergoing IVF. Furthermore, 30 percent of those couples are likely to have multiple pregnancies, resulting in two or three children. Therefore, it is probable that as couples continue to put off childbearing, at least 30 percent of babies will be conceived from IVF; rather than from sex.
Sperm production in the male of every species is controlled by a variety of genes, mostly on the Y chromosome, some of which were originally identified by pioneering research conducted by doctors at the Infertility Center of St. Louis and at Massachusetts Institute of Technology.
About 30 million years ago, when apes began to develop, one of the major sperm production genes, called "DAZ", was translocated from chromosome 3 to the Y chromosome. In human beings and great apes, the Y chromosome has collected a variety of sperm production genes over many millions of years. Throughout primate evolution, genes that increase male fitness — including sperm production — have translocated from autosomal (non-sex-related) chromosomes to the Y chromosome.
According to emerging concepts of the evolution of the Y chromosome, this occurs because genes that promote characteristics that are preferentially beneficial to one specific sex and are antagonistic to the other sex accumulate in regions close to the sex-determining gene. The Y chromosome is a desirable environment for male fitness genes because most of the chromosome does not recombine with its partner, the X chromosome — meaning that genes located on it are not exchanged by "cross-over" with like genes on the X. The Y thus harbors specific genes, and protects them from further recombination, providing these genes with a safe place in which to amplify and not be carried in the women. But the Y chromosome has a very unstable structure because of the lack of "gene repair" that normally occurs when chromosomes recombine. This spells problems for our reproductive future.
The human male is known to have the worst sperm count of any mammalian species, with the exception of the gorilla, possibly because the fragile location of these sperm production genes lies on the Y chromosome. The process of recombination "repairs" chromosomes. Since genes on the Y do not recombine, the chromosome degenerates. Thus, the Y chromosome — which makes the male a male — deteriorates with each succeeding generation. It is not a very safe place for sperm production genes.
A recent French study suggests that there has been a slight decline in human sperm counts in every year that it has been carefully documented. Speculation on the reasons for the decline has raised questions about the effect of environmental toxins, estrogen-fed beef, or even statistical bias in studies due to geographic differences in sperm production rates among different populations of men.
It is very clear, however, that sperm production is genetically controlled, and that humans are genetically programmed to have a declining sperm count (see section above). Increasing sophistication of male infertility treatment allows us to help men with low or zero sperm counts father children by extracting a few sperm from their testicles and injecting them into eggs in a laboratory, so that once fertilized, the eggs can be then placed into the woman's uterus.
The Infertility Center of St. Louis and its research partners first demonstrated that the genes that control sperm production in the human are transmitted to male offspring via intracytoplasmic sperm injection (ICSI) procedures. Therefore, the infertility dilemma of the modern era is that we are adding to the overall problem of infertility by allowing otherwise severely infertile or sterile men to produce children who will have the same problem as their fathers. On a positive note, research on male infertility may lead eventually to a genetic cure.
Modem geneticists have concluded that most "germ line" mutations — mutations that are transmitted to succeeding generations — occur on the male side. Over millions of years, these mutations have led to the development of different species, and to evolutionary changes within species.
Mutations that lead to species evolvement and evolutionary change occur almost exclusively in men. The reason for this is that perhaps 100 to 200 million sperm are produced every day in the testes of the average fertile man. A woman has all the eggs she will ever have at birth. Mutations occur only when cells divide and produce inaccurate copies of genes. These "xeroxing" errors in DNA are most likely to occur when a lot of xeroxing is done. This is the reason that modern geneticists are discovering that mutations and evolutionary changes occur strictly via the male.
Since the female's egg does not undergo changes, the female becomes the stabilizer, counterbalancing the "unstable" male genome and preventing evolutionary change from occurring too quickly.
It is projected that by the year 2005, researchers will have mapped the entire human genetic sequence. Every day, new genes are identified that cause various illnesses. It is estimated that 100,000 genes are necessary to direct the construction of a normal human being. Research indicates that probably 60 percent of human genetic structure is not much different than that of the earthworm. About 98 percent of the structure is not much different from that of a laboratory rat.
Scientists' understanding of the genetic causes of disease means that doctors can examine the genes of an embryo produced via IVF, in order to determine whether the embryo has any major genetic illnesses prior to placing it into the woman. Couples can — and most do — choose to place only healthy embryos. This means that carriers of sickle cell anemia, Down's syndrome, cystic fibrosis, muscular dystrophy, and many other diseases can reproduce without worrying that their children may have these diseases.
Genetic testing of embryos produced via IVF raises ethical questions, of course. If Lou Gehrig's parents had had IVF, and the embryos produced had been screened for genetic diseases prior to placement in his mother's womb, might we never have had Lou Gehrig (or under similar circumstances, Stephen Hawking)?
Many women today don't want to marry and begin families until they are in their 30s. Others may have difficulty meeting men they want to marry. For many of these women, being married and having children may not be realistic until they are in their 40s.
Unfortunately, women's fertility declines rapidly in their late 30's and early 40's. One solution may be ovarian tissue freezing. At age 30, a woman can have one of her ovaries removed, and literally frozen and saved for the future. This will not cause her to have an earlier menopause, and in fact will have no discernible effect on her chances of having a baby naturally two years later, if she so desires.
However, if she wants to start a family at age 42, she can have her frozen ovary transplanted back into her body at a time when she would have been likely to run out of fertile eggs. She will then be 30 years old again as far as her fertility is concerned.
This is a very new procedure, still in developmental phases, thus far utilized primarily to help young women about to undergo radiation and chemotherapy treatments for cancer to preserve their future fertility. My colleagues and I performed St. Louis' first two ovarian tissue freezing procedures on young women with cancer in 1997 and early 1998.
Ovarian tissue freezing differs from egg freezing, which will not be widely available in the near future and has many flaws. Egg freezing requires a high level of ovarian stimulation to produce eggs and even so produces only 15 to 30 eggs per attempt, and less than 1 percent of those eggs can be frozen successfully. Many eggs are normally needed in order to get pregnant with IVF. Therefore, egg freezing doesn't hold much promise.
But with ovarian tissue freezing, one of a woman's two ovaries is removed in an outpatient procedure. The entire egg-containing outer layer is microsurgically separated in a thin enough layer to allow it to be frozen and preserved for later use. Once the woman is ready to bear children, the ovary, containing about 150,000 eggs, can be thawed and surgically replaced, allowing for natural conception to occur.
If many more babies are conceived via IVF in the future, does this mean we will have increasing incidents of genetic abnormalities? The incidence of abnormalities is no greater than what is found in a normal population. Massive follow up studies available now are very reassuring. Of course, occasional IVF babies do have congenital or genetic abnormalities, but the chance of this occurring is no greater than with naturally conceived babies.
If you have any questions, you may call us at (314) 576-1400.