On the Promising but Partially Still Experimental Nature of Oocyte (Egg), Embryo and Ovarian Tissue Freezing to Preserve Female Fertility

OPINIONs 006: September 29, 2014

Summary

We in this OPINION discuss the concept of “fertility preservation.” It is based on the facts that (i) women are born with a limited number of follicles/eggs in their ovaries, which constantly decline from birth; (ii) as women age, the quality of their eggs also declines, leading to fewer pregnancies and more chromosomally abnormal pregnancies and miscarriages. The concept of fertility preservation evolved from attempts to interrupt this “ticking time bomb” by freezing eggs, embryos or ovarian tissue. Once frozen, eggs, embryos or follicles within frozen ovarian tissue no longer age. When thawed out years later, if they survive the thawing process, these eggs, embryos or ovarian tissues, therefore, represent similar pregnancy potential as they would have offered at time of cryopreservation (freezing). Fertility preservation is currently offered for two principal reasons: In so-called medically indicated fertility preservation, medical treatments (usually required as lifesaving procedures) threaten the integrity of ovarian tissue, usually resulting in the premature loss of follicles and eggs, leading to early menopause. Examples are chemotherapy or radiation therapy for cancers, but other treatments may also be toxic to ovaries. So-called social fertility preservation is different: here the reason for the procedure is that women are not ready to conceive but fear aging of their ovaries. They, therefore, want to preserve eggs, embryos or ovarian tissue in time. These two reasons for fertility preservation are based on distinct motivations and risk-benefit considerations. In some circumstances fertility preservation is, therefore, no longer considered an “experimental” procedure, while under other circumstances it is still classified as “experimental.” ThisOPINION will review in detail the concept of fertility preservation, with special emphasis on what CHR currently perceives as appropriate indications for female fertility preservation.


CHR issues this OPINION out of concerns about the increasing commercialization of fertility preservation, especially social fertility preservation and underutilization of medically indicated fertility preservation. As many women in developed countries increasingly delay childbearing into older age, the evolving concept of social fertility preservation has an important role to play. At the same time, this does not mean that every woman needs fertility preservation.

Unfortunately, commercial interests have in recent years co-opted many fertility centers into commercial enterprises, which are strongly incentivized financially to actively drive women into the process of fertility preservation. CHR is, therefore, concerned that potential abuses in the utilization of social fertility preservation will end up discrediting a very important, very valuable and potentially life-changing treatment opportunity for women who have reasons to delay their pregnancies. CHR is, however, equally concerned about the underutilization of the much less lucrative, medically indicated fertility preservation.

What is fertility preservation?

Though some recent studies suggest that follicles/eggs may be created in ovaries after birth, a large majority of experts still believe that women are born with all of their eggs. Indeed, starting while still in utero, follicle and egg numbers quickly decline. This loss of follicles/eggs actually ebbs after birth, and especially after menarche, when menstruation starts and regular cyclicity is established in most women. Follicle/egg loss is, however, relentless until menopause and likely even beyond because even in menopause women still have a few hundred follicles/eggs left in their ovaries.

With advancing age, women lose increasing numbers of follicles and their ovaries “age” in parallel. Ovarian age is, therefore, determined by how many follicles/eggs are left in a woman’s ovaries: the fewer, the older are her ovaries.

But loss of follicles/eggs is not the only sign of ovarian aging: With advancing female age the quality of follicles and eggs also deteriorates. Older women face a double insult on their fertility as they age: they produce fewer and fewer eggs of poorer and poorer quality. Not surprisingly therefore, female fertility declines with advancing age.

Recognizing this fact, increasing numbers of women are trying to preempt this aging process by pursuing fertility preservation, either by freezing eggs, embryos or even ovarian tissue containing follicles and eggs. If women pursue fertility preservation for purely social reasons, this process is called social fertility preservation.

Fertility preservation can, however, also become necessary for medical reasons, when, for example, a young woman is diagnosed with cancer, and requires chemotherapy and/or radiation therapy. Women with other medical problems, including autoimmune diseases or hepatitis, may also require life-saving medical treatments with drugs, which are toxic to ovaries and kill off follicles and eggs prematurely. This kind of fertility preservation, called medically-indicated fertility preservation, while technically in the laboratory involving the same egg, embryos and/or ovarian tissue freezing steps, is, of course, very different in practically all other aspects.

While social fertility preservation allows for careful deliberations and timely selection of a provider center where the process is to take place, medically-indicated fertility preservation is often an emergency, with very little time to consider options and/or select an appropriate provider because patients have to receive treatment right away. This difference in available time to make all the right choices also defines the informed consent process for both of these indications for fertility preservation.

Fertility preservation as an experimental procedure

Most authoritative professional bodies still consider social fertility preservation by cryopreserving eggs an experimental procedure. CHR concurs with this assessment.

Defining a medical procedure as “experimental” does not mean that this procedure cannot or should not be offered to the public. It just means that the procedure should be offered to the public as “experimental,” i.e., with appropriate and detailed explanation and written informed consent as to why the proposed procedure is not yet considered standard treatment. If with adequate explanations, a patient consents in writing to be treated with an experimental procedure (drug, device, etc.), such treatment is appropriate.

Social fertility preservation via egg freezing is, rightly, still considered an experimental procedure because adequate long-term data on the procedure are still lacking. An overwhelming majority of women who so far have undergone social fertility preservation via egg freezing have not used their frozen eggs yet. Nobody, therefore, really knows with any degree of reasonable probability how many eggs women at different ages (and with different remaining follicle/egg numbers in their ovaries) need to freeze to achieve a reasonable likelihood of establishing at least one successful pregnancy that reaches delivery with x% likelihood.

The mere fact that we cannot determine for our patients with reasonable certainty what their outcome chances will be, once they decide to thaw out their frozen eggs, defines for CHR social fertility preservation via egg freezing as an “experimental” procedure.

Though most authoritative professional bodies agree with CHR on this issue, many IVF centers unfortunately do not and treat social fertility preservation via egg freezing as a fully established procedure. Their patients, in our opinion, do not receive appropriate information and informed consent. As already noted before, CHR is concerned that this will lead to overactive recruitment of women into social fertility preservation via egg freezing, and to commercial excesses like “egg freezing parties,” recently widely advertised by one company.

It should, however, also be noted that medically-indicated fertility preservation via egg freezing is by most authoritative professional bodies no longer considered “experimental.” And, here, CHR agrees as well!

The difference between these two assessments lies in what in medicine is called the risk/benefit ratio of a procedure. In women at risk of suffering irreparable damage to their ovaries within weeks to months, it is of course different from the risk/benefit ratio of a woman considering social egg freezing at age 35. When a 35 year old woman is suddenly diagnosed with breast cancer, she will likely find herself under the knife within days or at most weeks, sometimes to be followed (or at other times even preceded) by radiation and/or chemotherapy that will annihilate her ovarian function. The young breast cancer victim has nothing to lose if she freezes her eggs; she can only gain in comparison to imminently losing all of her ovarian function from radiation and/or chemotherapy.

It is simply not fair to patients to treat both of these situations as equal, and this is the reason why social fertility preservation via egg freezing, rightly, is still considered “experimental,” while medically indicated fertility preservation via egg freezing is considered standard treatment (and, unfortunately, still not pursued aggressively enough by the medical community).

Different options for female fertility preservation

Female fertility can be preserved via egg freezing, through the freezing of embryos (which, of course, requires from the woman a commitment to a specific sperm contributor and, therefore, represents in most cases a satisfactory option only for stable couples) and/or through the cryopreservation of the woman’s ovarian tissue (which has to be surgically extracted).

We already addressed fertility preservation via egg freezing. Similarly, embryo freezing can represent an option for social or medically indicated fertility preservation. Because embryo freezing has been successfully practiced for over 30 years, this technique of fertility preservation is no longer considered “experimental.” The reason for this is not only the long experience with embryo cryopreservation: Once an embryo develops in the IVF laboratory, we have the ability to assess with reasonable certainty that embryo’s chance to lead to pregnancy.

CHR, therefore, considers embryo freezing as the safest method of fertility preservation and recommends that even single women, who often have a difficult time committing to a sperm donor to produce embryos, consider this option by freezing at least a minimum number of good quality embryos, in case their frozen eggs later turn out to thaw poorly.

The third method of fertility preservation is universally still considered “experimental.” It involves the freezing of tissue from the so-called ovarian capsule, which requires a surgical procedure, called a laparoscopy. In this procedure, a varying amount of tissue is removed and cryopreserved. Depending on the patient, this can be part of one ovary, a whole ovary, or, in rare cases, both ovaries.

The removed tissue is dissected into small pieces or strips, which contain large numbers of very immature follicles and eggs, the so-called primordial follicles a woman is born with, and these tissue strips are then frozen. Using this technique, hundreds to thousands of these very primitive eggs are frozen, a drastically larger number than can ever be produced via egg retrievals, even in repeat in vitro fertilization (IVF) cycles.

Once a patient is cleared for pregnancy, some of these tissue strips can be thawed out and be surgically reimplanted where the ovary usually sits. The body usually accepts at least some of the transplants, and the very immature follicles, after proper hormonal stimulation, start to grow and turn into mature follicles, which contain mature eggs. These eggs can then be retrieved like in a routine IVF cycle, can be fertilized with the partner’s sperm and resulting embryos can be transferred into the uterus. A small but rapidly increasing number of pregnancies have already been reported using this technique1-3. Nevertheless, this technique, even in cancer patients, is still considered “experimental.” Though CHR is one of only very few IVF centers licensed to cryopreserve ovarian tissue, we fully agree with this designation.

The freezing of ovarian tissue offers, however, additional, and potentially highly rewarding future opportunities because of the abundance of follicles/eggs this cryopreservation method produces. The problem, however, is that, as of this moment, we are not yet able to culture to maturity very primitive primordial follicles and/or their very primitive eggs in the laboratory. Science is, however, getting close to reaching this goal and, once it is reached, it will revolutionize IVF because of the abundance of follicles and eggs it will offer to the IVF process without the need for expensive fertility drugs.

Conclusions

Fertility preservation offers life-changing opportunities for women but, like all medical treatments, requires cautious and responsible utilization by health care providers and other interested parties. CHR is concerned about the rapid commercialization of social fertility preservation, while the much less lucrative medically indicated fertility preservation appears underserved by the medical community.

CHR issues this OPINION to publicize these concerns.

References

  1. Macklon KT, Jensen AK, Loft A, Ernst E, Andersen CY. Treatment history and outcome of 24 deliveries worldwide after autotransplantation of cryopreserved ovarian tissue, including two new Danish deliveries years after autotransplantation. J Assist Reprod Genet 2014; Sep 12, [Epub ahead of print]
  2. Imbert R, Moffa F, Tsepelidis S, et al. Safety and usefulness of cryopreservation of ovarian tissue to preserve fertility: a 12-year retrospective analysis. Hum Reprod 2014;29:1931-1940
  3. Meirow D, Ra’anani H, Biderman H. Ovarian tissue cryopreservation and
    transplantation: a realistic, effective technology for fertility preservation. Methods
    Mol Biol 2014;1154:455-473