Reproductive Medicine: Its Potential and Challenges

2021/02/18

Reproductive medicine began as a medical treatment for couples struggling with infertility. Today, it has expanded beyond addressing infertility to include preimplantation genetic diagnosis for hereditary diseases and the application of germ cell technology in regenerative medicine, becoming broadly known as reproductive medicine. Throughout its history, Keio University has contributed significantly to its global development.

The history of reproductive medicine led by Keio University began with the active development and introduction of advanced technologies under Professor Kaichi Ando, centered around Professor Rihachi Iizuka and others. In 1949, the first live birth was achieved through artificial insemination by husband (AIH), and in 1958, a successful pregnancy resulting from the development of sperm cryopreservation technology led to the institution becoming a global mecca for reproductive medicine. Furthermore, in 1982, the Japan Society for Fertilization and Implantation was established at the Kitasato Auditorium in Shinanomachi for the purpose of in vitro fertilization (IVF) research, and Keio has played a leading role in its development. The number of children born through IVF technology has increased year by year, reaching a ratio of one in 16 live births, contributing significantly to measures against the declining birthrate.

In 1978, the world's first child was born via IVF in the UK, and over 40 years have already passed. Dr. Edwards was awarded the Nobel Prize 30 years later, shortly before his death, but IVF technology has further expanded medical options significantly. Following the securing of stable mature oocytes through ovulation induction, the evolution from laparoscopic surgery to non-invasive egg retrieval methods via transvaginal ultrasound, and long-term embryo culture, the 1990s saw the creation of intracytoplasmic sperm injection (ICSI) technology. This technique, where sperm is injected into an egg under a microscope, was developed for severe male infertility where conventional IVF is difficult, contributing greatly to the improvement of fertilization efficiency.

The cells used in reproduction are sperm, eggs, and fertilized eggs (embryos), but cryopreservation technology has advanced to stably secure these cells, including ovarian tissue. It has become common to cryopreserve surplus embryos when many eggs are retrieved through ovulation induction. In Japan, the first successful birth of twins from cryopreserved embryos occurred in 1989 at our affiliated facility, Tokyo Dental College Ichikawa General Hospital; currently, 70% of children born through IVF are brought about by cryopreserved embryos. Additionally, since cancer patients may lose reproductive function due to chemotherapy or radiation therapy, germ cells can be preserved prior to treatment. Because cryopreservation is maintained in liquid nitrogen at -196°C, long-term storage is possible, providing a means to enable pregnancy after recovery. On the other hand, the handling of preserved cells in the event of the individual's death after cell freezing has become an issue, giving rise to the new problem of posthumous reproduction using those cells.

Biologically, reproductive medicine is the process of leading an individual arising from cells to pregnancy, but its essence is the work of inheriting genes. New approaches in reproductive medicine have been taken to address the suffering of families with hereditary diseases. In the 1980s, the development of an artificial insemination method began for X-linked genetic diseases, where sperm carrying the X chromosome are centrifuged to prevent the birth of boys who might develop the disease. As this method leads to sex selection, many social opinions were voiced regarding its application. Furthermore, this led to the development of preimplantation genetic diagnosis (PGD) to prevent the onset of genetic diseases by analyzing genes at the embryo stage. This technology involves biopsying a portion of cells from an embryo created through IVF and analyzing them after sufficiently amplifying the genes. We succeeded in achieving Japan's first live birth using this method in 2004. This technology was also approved after extremely long ethical debates due to concerns about the selection of life, but to date, analysis of genes and chromosomes has been conducted for serious genetic diseases and the prevention of miscarriages. This field is expected to develop further, with research moving toward the introduction of technologies such as genome editing to modify disease-causing gene mutations and nuclear transfer, where the nucleus of an egg with many mitochondrial disease mutations is transferred into a healthy donor egg.

There has also been much discussion regarding reproductive medicine involving non-spouses, such as the donation of sperm, eggs, and embryos, as well as surrogacy. This began in 1949 at Keio University Hospital with the birth of the first baby girl through artificial insemination by donor (AID) for azoospermia. At that time, the process was initiated carefully while listening to social opinions. In recent years, challenges that cannot be easily resolved exist, such as the right to know one's biological parents (the right to know one's origins) and the issue of disclosure, but it is also a fact that there are no other alternatives. Egg donation has changed the concept of reproductive age. The oldest woman to give birth to twins using eggs donated by a young woman was actually 70 years old. Even postmenopausal women can become pregnant and give birth through the administration of hormonal agents, which significantly changes one's outlook on life. Addressing reproductive medicine for the LGBT community is also a challenge. Additionally, as a new endeavor, there have been reports of uterine transplants where women who have had hysterectomies receive a donor uterus to become pregnant, further increasing the available options.

Because reproductive medicine deals with the origins of life, there is no end to the debate over the diverse options brought about by technological development. It is a fact that sufficient discussion, including the scope of application, is necessary when introducing these technologies. Beyond that, for the sake of the people who need it, the development of safe and accessible medical care and the creation of a supportive environment are required.