Medically indicated fertility preservation
We here want to encourage colleagues in all pediatric and adult medical specialties to carefully consider the concept of medical fertility preservation whenever patients face treatments that might potentially endanger a young woman’s (or man’s) future fertility. Vitaly A. Kushnir, MD, Director of CHR’s Fertility Preservation Center (FPC), and other CHR physicians are available for emergency consultations 24 hours a day, 365 days a year, by calling (212) 994-4400. Just call CHR’s whenever an emergency arises (after regular hours you will be referred to an answering service).
In this second issue of Fertility Preservation News, we focus on the concept of ovarian tissue cryopreservation (rather than egg freezing), followed by orthotopic re-transplantation of cryopreserved ovarian tissue to ovaries or surrounding areas after cancer treatments or other cytotoxic therapies. While this approach is still considered experimental, data is rapidly accumulating to support its efficacy and safety.
Ovarian tissue cryopreservation requires that a part of an ovary or a whole ovary is removed during laparoscopy. The ovary is then dissected in the laboratory, where its outer layer (the cortex) is peeled off. The cortex contains all the primordial follicles, which are the most primitive and immature stage of follicles. Once the ovarian tissue is frozen, there are several options available for its future use, including auto-grafting, xeno-grafting, and in vitro maturation (IVM) of follicles from the graft.
The process we want to concentrate on here is auto-grafting: Once a patient is cleared for pregnancy, auto-grafting involves re-implanting surgically little strips of ovarian cortex where the ovary used to be. These implants in most cases become functional ovarian tissue, which again produces hormones and follicles, retrievable in an in vitro fertilization (IVF) procedure. If successful transplantation is accomplished, this technique, therefore, potentially offers a woman multiple chances of achieving pregnancy.
Ovarian tissue cryopreservation can be done prior to or, sometimes, even after gonad-toxic chemotherapy. A laparoscopy can be performed on an outpatient basis within hours of initial presentation, allowing patients to quickly preserve their fertility without delaying initiation of cancer care. It can also be performed in young pre-pubertal girls, i.e., in cases of childhood cancers.
The method’s potential shortcomings include the need for laparoscopic surgery under anesthesia, and the potential, fortunately mostly hypothetical, risk of transplanting cancer cells with the re-implanted ovarian cortex graft.
The most recent addition to the medical literature on the subject comes from Germany. In an article published in the December issue of Fertility Sterility, the official journal of American Society for Reproductive Medicine, Dittrich et al. report results of 20 orthotopic re-transplantations of cryopreserved ovarian tissue after cancer treatments,1 11 hematological, 4 breast, 3 anal and 2 ovarian site cancers. The mean age of patients was 30.5 years.
Ovarian tissue was removed from patients in Germany between 2005 and 2009 at various centers. Tissue was then in eight cases overnight transported before freezing. Cryopreservation in all cases was performed with slow freezing protocols. All patients received chemotherapy and/or radiotherapy, and 17 patients developed full primary ovarian insufficiency (POI). Re-transplantation of thawed tissue was performed on average 3.75 years after initial extraction.
Ovarian activity resumed in all but one patient. Seven patients conceived, with one miscarriage and four ongoing pregnancies. Four patients delivered healthy babies.
The most established technique for ovarian tissue cryopreservation is slow freezing. Virtually all established pregnancies have used slow freezing of ovararian tissue. Vitrification is an alternative technique, which is often used to cryopreserve human oocytes and embryos. It involves a much faster freezing process but requires higher concentrations of cryoprotectants.
When used for oocytes and embryos, vitrification produces a solid glass-like cell, free of ice crystals. Vitrified cells have, likely, somewhat higher survival rates and better development compared to slow frozen cells and embryos.
Many embryology laboratories, therefore, have abandoned slow freezing, the needed equipment and lost the required expertise. Vitrification is, however, inferior to slow freezing in preserving ovarian tissue because currently available cryoprotectants do not penetrate whole tissues sufficiently. CHR, therefore, currently vitrifies eggs and embryos but slow freezes ovarian tissue.
- What are the results of auto-grafting
To date, more than 30 live births have been reported worldwide from the transplantation of cryopreserved ovarian tissue.2 Likely the largest number of birth have been achieved at Israel’s >em>Sheba Medical Center at Tel Haschomer, where Prof. Dror Meirow heads up the Fertility Preservation Unit. CHR follows the Sheba protocols.
- Minimizing the risk of cancer recurrence
Prior to re-transplantation ovarian tissue fragments are analyzed for presence of malignant cells. This is typically done histologically. In some cancers with special predilection of cancer cells to spread to the ovary, advanced techniques, such as flow-cytometry and cytogenetics are used to minimize the risk of transmission of cancer cells through the surgical graft.
- The future
Reproductive medicine is rapidly evolving, and may in the foreseeable future permit in vitro maturation of oocytes from primordial follicles in the laboratory, without need for re-transplantation of cryopreserved ovarian tissue. This, of course, would make thousands of eggs available rather than the relatively small numbers, currently available to most patients after egg freezing, because every, even tiny, tissue graft contains large numbers of primordial follicles and eggs.
- Dittrich R, Hackl J, Lotz L, Hoffmann I, Beckmann MW. Pregnancies and live births after 20 transplantations of cryopreserved ovarian tissue in a single center. Fertil Steril. 2014 Dec 5. pii: S0015-0282(14)02305-X.
- Meirow D, Ra’anani H, Biderman H. Ovarian tissue cryopreservation and transplantation: a realistic, effective technology for fertility preservation. Methods Mol Biol. 2014;1154:455-73.
Social fertility preservation
Since the media disseminated recently considerable misinformation about elective (i.e. social) egg freezing, we here are attempting to offer some clarity in a question and answer format.
- Why should young women consider egg freezing?
Largely due to declining quality and quantity of eggs, female fertility declines with age. For most women peak fertility corresponds with peak functional ovarian reserve (FOR), i.e., number of growing follicles, at approximately age 25 years. Since women in developed countries increasingly delay pregnancies past peak fertility, they often encounter difficulties in conceiving once they decide that it is time to have a child. However, even some relatively young women may encounter difficulties in conceiving because approximately 10% of all women age their ovaries prematurely. Both of these patient populations, therefore, may benefit from early fertility preservation.
- When should women consider egg freezing?
CHR recently developed a risk-screening program for young women at ages 25-35 years, called What’s My Fertility, which is meant to identify young women at risk toward premature ovarian senescence, and gives them the opportunity to reconsider their reproductive planning if diagnosed at still young ages. We1 and others2 recently also suggested that young women should be offered risk-screening and counseling prior to initiation of long-term hormonal contraceptives.
In women already at young ages diagnosed with prematurely low FOR egg freezing may, of course, be of even greater urgency if they cannot advance their pregnancy planning.
In absence of risk toward premature ovarian senescence, social fertility preservation is primarily indicated for women who know that they will not pursue pregnancy before age 35 at the earliest. In such women the freezing of eggs at a young age makes sense, and the younger they are when they do it, the better. The ideal age for egg freezing is between the late 20’s and the mid 30’s.
- What is the process and what are the risks?
Egg freezing requires that the woman, in principle, undergo IVF. She will for approximately two weeks undergo ovarian stimulation with injectable hormones, followed by egg retrieval, performed on an outpatient basis under intravenous sedation. Instead of fertilizing each egg, as usually happens in a standard IVF cycle, all good quality eggs are here, however, cryopreserved.
The number of total eggs a woman should freeze will vary between patients but will be largely dependent on age: the older a patient, the more eggs she will have to freeze because of declining pregnancy chances per egg. Unfortunately, egg number obtained per cycle also decline with advancing female age. As women get older, they, therefore, require increasing cycle numbers to reach the desired egg number.
How many cycles a patient will need will depend on the number of good quality eggs on average frozen in one of her cycles.
The best technique for freezing eggs is, likely, vitrification which produces a solid glass-like cell, free of ice crystals.
Risks of ovarian stimulation and egg retrieval are generally low but include the possibility of ovarian hyperstimulation syndrome (OHSS) as well as retrieval and anesthesia related complications.
- Where should you begin?
The first steps are to assess the ovarian reserve and to determine whether there is increased risk for premature ovarian aging (see recent publications 1,2,3). This information will determine whether egg freezing or, possibly, another fertility preservation technique represents the best option of fertility preservation for that individual.
- Who do you need on your side?
To make an informed decision, patients need honest individualized information, based on up-to-date patient data. They, in addition, have to be openly informed about which fertility preservation options are considered established and which are still considered experimental.
The most important information patients have to receive is, of course, what their later chances of conception and delivery will be, once they want to make use of their frozen eggs. This, indeed, still requires very difficult, some would say impossible, prognostic assessments, which is the main reason why social egg freezing is still widely considered an “experimental” procedure.
- What are the costs?
Finally, patients require a realistic assessment of costs, associated with fertility preservation. They, of course, will depend on how many cycles of egg retrieval she will have to undergo. For patients with relatively low FOR, who require multiple cycles, CHR offers a 4-cycle Egg Freezing Package, which offers a significant discount compared to individual cycle pricing.
- Kushnir VA, Barad DH, Gleicher N. Ovarian reserve screening before contraception? Reprod Biomed Online. 2014; 29:527-529
- Seifer DB, Minkoff H, Merhi Z. Putting ‘family’ back in family planning. Hum Reprod. 2015; 30:16-19
- Gleicher N, Kushnir VA, Barad DH. Prospectively assessing risk for premature ovarian senescence in young females: a new paradigm. Reprod Biol Endocrinol. 2015; In press