The Disease

Reproduction is a basic drive of all species of animals, and humans are no exception. Indeed, producing children and raising a family is a fundamental aspect of the lives of most people. The inability to reproduce (infertility) is not only a devastating problem for many affected couples, but it is also common. For example, one frequently used clinical definition of subnormal fertility is the failure to achieve a pregnancy after a two-year period of trying. According to this criterion, it is estimated that approximately 20% of couples in the United States are subfertile.

Infertility can result from a variety of causes, which can affect either the female or the male partner. Many cases are due to anatomical defects in the Fallopian tubes, through which oocytes must travel from the ovary to the uterus. Some women are infertile (or subfertile) because of hormonal disorders that result in the failure to produce normal metaphase II eggs. Other cases of infertility or subfertility result from a failure of the male partner to produce or ejaculate adequate numbers of normal sperm. In vitro fertilization (IVF), which was originally developed as a treatment for tubal defects, is now widely used in the treatment of both male and female reproductive disorders.

Molecular and Cellular Bases

The basic procedure of in vitro fertilization is to recover metaphase II eggs from the ovary and culture them together with sperm. Fertilization is assessed 12 to 18 hours later by microscopic observation to detect the formation of two pronuclei. Fertilized eggs can then be returned to the Fallopian tube or uterus. Alternatively, they can be maintained in culture for a few additional days, during which the early embryonic cell divisions take place.

In vitro fertilization was initially developed to bypass defects in the Fallopian tube, which present an obvious anatomical block to a natural pregnancy. As already noted, however, IVF is also effective for other reproductive disorders. For example, hormonal defects resulting in the failure to produce metaphase II eggs can be treated by administration of appropriate hormones to the female partner. This treatment results in the production of multiple eggs, which can then be fertilized in vitro, followed by the return of successfully fertilized eggs to the uterus.

IVF is also effective in treating cases of infertility resulting from failure of the male partner to ejaculate sufficient functional sperm to achieve fertilization in vivo. Moreover, a new procedure in which a single sperm is directly injected into an egg (intracytoplasmic sperm injection, or ICSI) can be applied to cases in which fertilization does not result from the standard in vitro coculture of sperm and eggs. Interestingly, successful fertilization by the ICSI procedure also requires stimulation of the surface of the egg in order to achieve egg activation.

The rate of pregnancy resulting from fertilization in vitro is similar to that observed in vivo. In particular, it is estimated that about 25% of ovulated human eggs naturally give rise to offspring in a normal fertile couple. Similar pregnancy rates are obtained following in vitro fertilization of eggs of young women with an anatomical block to pregnancy. Although lower pregnancy rates are obtained with eggs of older women or of women with hormonal defects, these reduced rates can be compensated for by the return of multiple fertilized eggs to the uterus. ICSI also yields a pregnancy rate of about 25%, suggesting that there are intrinsic limitations on the developmental capacity of human eggs, both in vitro and in vivo.

Prevention and Treatment

The first attempt at in vitro fertilization of human eggs was reported in 1942, but not until 1978 was the first IVF baby born. Since then, a variety of technical improvements have made IVF a standard treatment for infertility, and IVF has allowed tens of thousands of otherwise infertile couples to bear children. Although not successful for many couples, IVF has clearly had a major impact on a widespread medical problem.

In addition to its direct impact on the treatment of infertility, IVF offers new opportunities for the diagnosis and prevention of genetic disease. It is possible to remove one or two cells of an early embryo developing in vitro (usually at the eight-cell stage) without harming further embryonic development. Consequently, single embryo cells can be isolated and tested either for chromosomal abnormalities or for mutant alleles of any inherited disease gene that can be identified by PCR. It is then possible to select only the embryos carrying normal gene copies for transfer to the uterus. In combination with these methods of preimplantation embryo diagnosis, IVF thus allows couples carrying genes for inherited diseases to prevent the transmission of these diseases to their offspring.

Reference

Handyside, A. H. and J. D. A. Delhanty. 1997. Preimplantation genetic diagnosis: Strategies and surprises. Trends Genet. 13: 270–275.