Sherman SILBER (USA)
For over 38 years Dr. Silber has originally developed all of the most popular fertility treatments used all around the world today.
He performed the world’s first microsurgical vasectomy reversal, as well as the first testicle transplant, in the 70’s and now in the current century, the world’s first ovary transplant. He was the first to develop the TESE and MESA techniques for retrieving testicular and epididymal sperm in azoospermic men. He headed the clinical MIT team that first mapped and sequenced the Y chromosome in infertile men and discovered the now famous DAZ gene for male fertility. His research includes also the study of reproduction and fertility in zoo animals and endangered species. Most recently he has perfected the preservation of fertility for cancer patients with ovarian freezing and transplantation and thereby figured out how to extend the reproductive biological clock of women.
Dr. Silber went to medical school at the University of Michigan, did post-graduate training at Stanford University, and then again at the University of Michigan. From 1967 to 1969, he provided medical care via the U. S. Public Health Service to Eskimos, Indians, and Aleuts. Then he taught at the University of Melbourne Medical School in Australia, and later at the University of California Medical School in San Francisco. He is a scientific collaborator at MIT in Cambridge, Massachusetts, at the Kato Clinic in Tokyo, and is a full professor at the University of Amsterdam, and at Sun Yat Sen University Medical School in China. His major clinical medical practice is at St. Luke’s Hospital in St. Louis, Missouri.
Abstract
Gamete and Embryo Freezing in Future Preservation Vs Ovarian Tissue Freezing
Ovary Tissue Cryopreservation
Worldwide there have been over 130 live births from frozen ovary tissue, but most have only been case reports. Nonetheless from the carefully tabulated series of young patients (i.e under 30 years old when frozen) in Brussels, Israel, and our center, live birth rates vary from 41% to 70%. Most are spontaneous pregnancies not requiring IVF. These were young women who had ovary cortex frozen prior to goonadotoxic treatment for cancer or other diseases. It is not known yet what the success rate would be for healthy women just wishing to delay childbearing. Patients almost always have return of ovarian function 5 months post transplant with regular menstrual cycling. AMH rises to very high levels as the FSH declines to normal or near normal. Four to eight months later, the AMH declines to very low levels. Nonetheless, the grafts remain functional for up to 5 years or longer. Thus ovary tissue cryopreservation, at least for young cancer patients, is a robust method for preserving a woman’s fertility. Another scientific benefit is that the results of ovary transplantation, whether fresh or frozen, give us insight into the mysterious mechanism of primordial follicle recruitment. Cortical tissue pressure is the key regulator of primordial follicle arrest in the fetus, recruitment in the adult, and indeed ovarian longevity.
Oocyte and Embryo Freezing
In most centers such as ours, for women under 38, with vitrification there is no significant difference in IVF results per transfer with fresh vs frozen embryos (59% versus 57%). Nonetheless, embryo freezing for preservation of fertility is seldom employed unless the woman is married and in a stable relationship. Even then, many women today would rather freeze their eggs than embryos in view of the modern frequency of divorce.
Freezing eggs was very problematic and mostly unsuccessful before the popularization (by Kuwayama) of vitrification around the turn of the century. Before vitrification the only option for cancer patients from 1996 until 2006 was to freeze ovarian tissue as advocated by Gosden. This was successful because the oocytes in primordial follicles are small (30 microns compared to 180), and arrested in early meiosis with no metaphase spindle. However for mature oocytes retrieved via ovarian stimulation, the slow freeze technique was very ineffective, because the water content of the mature oocyte could only be reduced from 70% to 30%, allowing enough some ice crystal formation still to damage the oocyte. The smaller oocyte in the primordial follicle, with no spindle could more easily tolerated this ice crystal formation inside the oocyte. However with vitrification, there would be no ice crystal formation at all to worry about. Therefore the larger mature metaphase 2 mature eggs could now be safely cryopreserved
The “intrinsic fertility” of the human oocyte very gradually drops somewhat from the late teens to the early 30s. But then at around age 35, there is a dramatic fall in fertility of 10% per year, so that by age 40 only about one percent of oocytes are capable of resulting in a live baby. Oocytes from a woman in her 20’s have as high as 30% chance of resulting in a live baby (this is only in natural cycle studies). Before oocyte vitrification, the awareness of this dilemma for the modern healthy woman would not encourage her to preserve her fertility against this decline because, to have her ovary removed and frozen seemed to aggressive and unproven. But oocyte freezing, once perfected by Kuwayama, seemed easier and less invasive than ovary tissue freezing.
Cobo verified this in her landmark paper in 2008 in a total of 47 oocyte donors and 57 recipients, with a frozen oocyte survival rate of 96%, and a pregnancy rate no different between fresh and frozen oocytes. Most of these oocytes were vitrified by Kuwayama. The oocyte to live baby rate was 6.5% quite similar to that of Patrizio with fresh oocytes. Nagy in 2009 showed the same good results in the U.S. Cobo computed that for a woman to have a 97% chance of having at least one baby, 40 oocytes needed to be preserved. But only 30 were needed to give an 84% chance. We advocated then that ASRM should remove the designation of “experimental” from oocyte freezing, as it is a proven technology. We are now advocating the same for ovarian tissue freezing.
Ovary Freezing Vs Oocyte Freezing
Although there have been over 130 babies born from ovary tissue cryopreservation for women, thus far very few have been born to cancer patients from oocyte freezing. This is only because it takes many years before these patients return to actually use their frozen tissue or frozen oocytes, and we have been doing ovary tissue freezing since 1996, 12 years longer than oocyte freezing. Nonetheless the advantages and disadvantages of each are obvious.
Cancer patients have little time to preserve their fertility, and Cobo showed that they need at least 30 frozen oocytes to have at least an 80% chance of having at least one live birth (40 oocytes to give them a 97% change). This means they certainly need more than one oocyte retrieval. Furthermore they will have no return of natural hormonal function even If they do get pregnant. Many leukemia patients will have already undergone initial chemotherapy and have no developing follicles to even respond to ovarian stimulation. However, many primordial follicles will have survived this initial chemotherapy, and can be preserved with ovarian tissue freezing. So in general we think ovary tissue freezing is the best approach for cancer patients.
For healthy women just wanting to put off child bearing, oocyte freezing may at first seem easier. But we still would want to do at least 3 cycles to give them some measure of assurance. In the United States this could add up to 45,000 dollars or more. A simple ovary freeze would be less than 6,000 dollars, and require just one simple procedure and no hormonal stimulation. Furthermore transplanting back ovarian tissue can give them hormonal function even after they might otherwise be in menopause 20 years later. Many female business executives and physicians have chosen this otherwise less popular approach.
So each woman will have to decide which method of preserving her fertility is most appropriate for her individual situation. But both ovary freezing and oocyte freezing today are established and successful technologies.