The Inaugural Issue of CHR’s Fertility Preservation News

Posted on Nov 12, 2014

From the Fertility Preservation Center that is always reachable [by calling 212-994-4400]

With the inaugural publication of this new monthly newsletter, Center for Human Reproduction (CHR) is pleased to formally introduce the center’s expanded Fertility Preservation Center (FPC), which was officially inaugurated with the GrandRounds presentation at CHR by Prof. Dror Meirow from the Sheba Medical Center at Tel Haschomer, Israel, on October 14.

Dr. Kushnir became the Medical Director of Fertility Preservation Center at CHR. Vitaly A. Kushnir, MD, pictured on the left, has assumed the position of Director of CHR’s FPC, after attending a special training program in oncologic fertility preservation during the summer at Prof. Meirow’s center in Israel, which is likely the leading oncofertility center in the world.

CHR, of course, has been offering fertility preservation for social and medical reasons for years. Likely because CHR has resisted the commercialization of social egg freezing—unfortunately quickly accelerating in many places in the U.S.—our social egg freezing program has been very successful in attracting patients over the last few years.

With a more expansive effort in oncofertility and other medical areas where toxic drugs to ovaries are in use, we now hope to expand this success into medically indicated fertility preservation. CHR is, of course, fully licensed to cryopreserve oocytes and is among only a handful of centers licensed by New York State to preserve ovarian tissue (i.e., ovaries).

This newsletter, therefore, will not only go out to CHR’s usual mailing list of Obstetricians & Gynecologists and Reproductive Endocrinologists & Infertility Specialists but to a variety of appropriate specialties within internal medicine, surgical oncology and pediatrics, where medications with potential ovarian toxicity are in use.

Through this newsletter, we want to encourage our colleagues within all of these medical specialties to carefully consider the concept of medical fertility preservation whenever they have patients facing treatments that potentially endanger a young woman’s (or man’s) future fertility. Dr. Kushnir and other CHR physicians are available to colleagues for emergency consultations 24 hours a day, seven days a week by phone, whenever an emergency may arise. Please just call CHR’s above noted telephone number. After regular hours, it will refer you to our 24-hours answering service. CHR offers fertility preservation services around the clock 365 days a year!

To women who seek to preserve their fertility for social reasons, we can only point out that CHR is known worldwide as a “center of last resort,” serving women from all over the world, who often have repeatedly failed elsewhere. The relevance of this lies in the fact that women who want to preserve their fertility do not just want to freeze eggs; they want to freeze good quality eggs, and CHR knows how to maximize egg quality.

We, therefore, encourage women who are considering freezing their eggs for the purpose of social fertility preservation to set up an appointment with Dr. Kushnir or one of the other CHR physicians. Even if, for whatever reason, they later choose to have their eggs cryopreserved elsewhere, they will find that the consultation was worth the effort and cost since our staff will present unvarnished facts, options and cost estimates. Consultations can be in person, via telephone or via Skype, and can be set up by calling the above listed phone number.

An Overview of Fertility Preservation Options

Fertility preservation was initially developed for young patients undergoing gonad-toxic therapies. However, in recent years increasing delays in child bearing to later reproductive years have created demand for social fertility preservation. Serial improvements in cell and tissue cryopreservation techniques have led to the emergence of a bio-banking industry, which aims to meet these demands.

Two very distinct patient populations with radically different needs utilize fertility preservation. We outline here the currently available options for both: Medically indicated and social fertility preservation.

Fertility preservation for women

fertility_preservation Fertility-sparing treatments can be offered to women in a variety of clinical situations, either “elective,” when fertility preservation is usually pursued for social reasons or “non-elective,” when fertility-preserving treatments are used to avoid damage to the ovaries from what is called “iatrogenic” (i.e., medically induced) causes.

Embryo cryopreservation (banking) is the most established fertility preservation technique. It has been successfully utilized for decades with many hundreds of thousands of births resulting from it. Embryo banking requires that a woman of reproductive age undergo in vitro fertilization (IVF), which entails ovarian stimulation with fertility drugs and subsequent egg retrieval. Retrieved oocytes are then fertilized by sperm from a spouse, significant other or semen donor.

Embryo banking, therefore, is an option only if a woman is willing to commit to a given semen provider. Many single women considering social fertility preservation are not interested in embryo banking for this reason. It is, however, an excellent, and probably still the best, method of social fertility preservation for couples in stable relationships.

Since ovarian stimulation requires approximately two weeks, some newly diagnosed cancer patients may not have the option of undergoing an IVF cycle before cancer treatment has to be initiated. Even if enough time for such a cycle is available, a single cycle may not yield enough embryos for cryopreservation (freezing). Studies have documented that only approximately 8 embryos are typically cryopreserved per treatment cycle in cancer patients, which may not be enough to achieve a later pregnancy. Therefore, additional IVF attempts or additional fertility preservation techniques like ovarian tissue freezing (see below) may be required to reach an adequate level of reasonable certainty that enough fertility potential has been preserved.

How many embryos should be cryopreserved will vary between patients, and will depend on the age of the patient, her functional ovarian reserve (FOR) and, ultimately, how much certainty of pregnancy the woman wants to have once she decides to attempt conception later in life. In most women, CHR recommends cryopreservation of at least 20 embryos at young ages, and even more in women in their late 30's and early 40's.

ovu_induction Oocyte (egg) cryopreservation (banking), in comparison to embryo banking, is a relatively new technique of fertility preservation. Like embryo banking, this technique requires that a woman undergo ovarian stimulation (of approximately two weeks) and egg retrieval. Retrieved eggs ****are, however, not fertilized with sperm as in embryo banking but immediately cryopreserved.

Though a much more recently developed technique of fertility preservation, oocyte banking in young cancer patients is no longer considered experimental. Even though we do not know yet enough about long-term outcomes, we know enough about the alternative in these patients (which is to lose all ovarian function and future fertility chances from chemo and/or radiotherapy) to know that the risk-benefit ratio of the procedure favors oocyte cryopreservation, however small the chances of pregnancy later may be.

However, that is not the case when oocyte banking is performed for social reasons. Here, the process is still considered experimental because outcomes are not yet well-defined enough to offer patients guidance and reliable advice for an obviously elective procedure. Unfortunately, this fact is not always well communicated to patients.

It is a reason why social fertility preservation is usually not a covered benefit in insurance plans, though interestingly, Apple and Facebook recently announced at least partial coverage within their corporate medical plans (for more detail see below).

Since oocytes are very large cells, it is still technically challenging to cryopreserve and thaw them efficiently compared to embryos, which consist of much smaller individual cells. Vitrification is probably the most effective technique to freeze eggs. Worldwide, several hundred to thousand children have been born from thawed oocytes so far. Though still considered experimental, social egg banking—at least in the U.S.—has become by far the most frequent utilization of egg freezing.

How many oocytes should be frozen to preserve fertility will also vary with female age at time of egg freezing and her FOR. CHR recommends cryopreservation of at least 30 oocytes for young women and even more in women in their late 30s. Like with embryo banking, egg banking in most women will require more than one egg retrieval in order to generate a reasonable likelihood of pregnancy later in life.

Ovarian tissue cryopreservation is also still considered an experimental technique. It can be coupled with in vitro maturation (IVM) (see below for detail) of oocytes at time of tissue collection.

In this method of fertility preservation, a part of an ovary or a whole ovary is surgically removed. The ovary is then dissected in the IVF laboratory, where its outer layer (the cortex) is peeled off. It contains all the primordial follicles, which are the most primitive and immature stage of follicles (also called resting follicles). This is the stage at which follicles are when a woman is born. From birth on until menopause, women lose follicles. Most of this loss occurs because these resting follicles are steadily “recruited” after menarche on a 3- to 5-month-long journey of follicle and egg maturation until, every month, only one of these follicles reaches ultimate maturity and releases a mature egg during ovulation.

Current medical knowledge does not yet allow for IVM of primordial follicles. At the present time, we can only mature follicles at later maturation stages to full maturity of eggs in the laboratory. It is, however, reasonable to assume that the ability to culture primordial follicles to full maturity will be obtained over the next few years. Once that is achieved, thousands of primordial follicles will be available for IVM after ovarian tissue preservation, changing the whole concept of IVF.

Until IVM of primordial follicles becomes available, ovarian tissue preservation can, however, lead to pregnancies in a very different way: Little strips of the ovarian cortex can be surgically reimplanted into women where the ovary used to be once the patient is cleared for pregnancy. These implants in most cases become functional ovarian tissue, which again produces hormones and follicles, retrievable in an IVF procedure.

Dozens of births have so far been achieved worldwide with this approach. This technique, therefore, potentially offers a woman multiple attempts of achieving pregnancy if successful transplantation is accomplished.

Ovarian tissue cryopreservation can be done prior to, or sometimes even after, a gonad-toxic therapy. It can also be performed in pre-pubertal girls. The method’s shortcomings include the need for laparoscopic surgery as well as the potential (and mostly hypothetical) risk of transplanting cancer cells with the reimplanted ovarian cortex graft, when tissue is transplanted into cancer survivors.

In vitro maturation of oocytes (IVM) is a relatively new technique in IVF, in which immature eggs are matured in the laboratory. It allows retrieval of immature oocytes without prior ovarian stimulation. Oocytes can then be matured in the laboratory and subsequently either fertilized with sperm and/or cryopreserved. CHR now uses IVM routinely in women with low FOR (LFOR) to maximize available egg and embryo numbers. Women with LFOR often produce disproportionally many immature eggs.

Especially in women with polycystic ovaries (PCOS), this technique can avoid the need for ovarian stimulation with fertility drugs. In women who quickly have to enter a gonad-toxic medical treatment and, therefore, do not have time for an IVF cycle with ovarian stimulation, this technique sometimes is performed prior to initiation of therapy. We also noted above that IVM is often done in combination with ovarian tissue preservation. Thousands of children have been born following IVM; however, pregnancy rates are significantly lower than with standard IVF.

Medical ovarian suppression with GnRH-agonists and -antagonists in conjunction with chemotherapy has been reported to help preserve FOR in young women with high starting ovarian reserve. However, outcomes are highly variable depending on patients’ age, FOR and gonad toxicity of the selected treatment regimen. Other treatments have also been reported successful in reducing damage to ovaries from chemo- and/or radiotherapy. No definite treatment to accomplish this goal has so far been established.

Fertility-sparing surgical and medical treatments for women with gynecological cancers

These treatment options are disease-specific, and are performed by gynecologic oncologists, usually before radiotherapy is administered.

Ovarian transposition is performed laparascopically prior to pelvic irradiation, moving the ovaries surgically out of the pelvis. This can help preserve both fertility and ovarian endocrine function.

Radical trachelectomy (removal of only the cervix and not the whole uterus) for early stage cervical cancer can be utilized to preserve the uterus and ovaries and allow future fertility in cases of cervical cancer. When surgical margins of the removed surgical specimen are clear of cancer, the procedure is curative. While the risk of preterm delivery is increased in subsequent pregnancies, most women are able to carry to term.

surgical Ovarian cystectomy or unilateral oophorectomy, along with lymph node biopsy, can be utilized to spare the contralateral ovary and uterus in cases of borderline ovarian malignancy and early stage ovarian cancer confined to one ovary. Recurrences are rare in properly staged patients with no residual disease.

Hormone therapy for early stage endometrial cancer can be successful with systemic or local high dose progestin treatment. Pregnancy should be established shortly after regression of the malignancy. After completion of pregnancy, a hysterectomy with comprehensive staging is typically performed.

Fertility preservation in men

Sperm cryopreservation, the most established technique, has been utilized for decades in post-pubertal males prior to gonad-toxic therapies. In recent years sperm cryopreservation has, however, also been utilized in other situations, including prior to military deployment and prior to elective sterilization via vasectomy.

Semen cryopreservation can be done rapidly; it is relatively inexpensive and widely available in most areas. Multiple vials of washed sperm are cryopreserved for later use. In men with no sperm in the ejaculate, sperm can often be extracted from the testicle or from the urine in cases of retrograde ejaculation.

Shielding of the testes is an established technique in patients undergoing radiation therapy and should be utilized whenever feasible.

Fertility preservation in pre-pubertal children

Ovarian and testicular tissue cryopreservation techniques are considered experimental but are, due to the high probability of primary disease survival at such young ages, frequently utilized. Since research is progressing rapidly in both young females and males, these options should be discussed with the family prior to initiation of gonad-toxic therapies. Thawed tissue can be later utilized for either autologous transplantation or for potential in vitro maturation of gametes.

Important general considerations for fertility preservation

Fertility preservation techniques require a very detailed informed consent process. The patient’s and, where applicable, the family’s desires for later disposition of cryopreserved gametes and/or tissues have to be carefully documented during this process. Specifically, the disposition of cryopreserved cells and/or tissues in cases of incapacity, death, and divorce should be addressed.

Ethical practice of medicine requires that patients be clearly informed about what treatment options are considered established and which are still considered experimental. Informed consents have to reflect the status of each proposed treatment.

Further required are realistic assessments of later successful reproduction for each proposed treatment and/or fertility preservation method, assessment of likely required number of treatments and expected costs.

Direct communication between treating oncologist/oncologic surgeon and/or other medical specialists and the expected provider of fertility-preserving treatments are essential, and will ensure that patients receive the best possible coordinated care in consideration of both treatment perspectives.

Apple and Facebook pay for their employees’ social fertility preservation

Apple and Facebook, two of the nation’s biggest companies by market value, made front-page news last month and conquered the blogosphere. They did so not because of new products they introduced to the market or because of unexpected earning reports but for extending the medical insurance coverage to their female employees to include social fertility preservation via egg freezing.

This is, indeed, for a variety of reasons a remarkable development; we noted before, in describing the option of fertility preservation via egg banking that social egg freezing currently is still defined as an experimental procedure by authoritative professional organizations. Amy Klein, The New York Times’ “Fertility Diary” columnist, got this wrong in her October 16 blog on the subject, when she stated that the American Society for Reproductive Medicine had removed its experimental label. It did so only for medically indicated egg banking. Apple and Facebook, therefore, extended coverage to an experimental procedure.

The insurance industry will, most likely, view this news with horror because, if there has been one dogma in how the insurance industry has determined eligibility for coverage, then it is never to offer coverage for experimental treatments.

We foresee that this decision by Apple and Facebook will have major consequences including potentially the re-designation of social egg freezing as no longer experimental. In addition, Apple and Facebook’s action will have repercussions for other large employees, who frequently do not even offer coverage for standard infertility services, including IVF procedures.

Likely the most interesting and controversial commentary on the subject came from another New York Times writer, Claire Cain Miller, in the paper’s “Upshot” column. Miller wrote that these “workplaces could be seen as paying women to put off childbearing.” She also expressed fear that not delaying childbirth could then expose women to discrimination at the work place.

Amy Klein disagrees with Claire Cain Miller, and sees her concerns as “no good deed goes unpunished” comments, pointing out as an example that companies offering maternity leave, of course, do not pressure their employees “to have babies.” She considers the coverage offered by Apple and Facebook as an “elective” benefit, which she feels women will only utilize if they want to freeze their eggs and not on any company’s behest.

According to TIME Magazine’s Jessica Bennett, Facebook told NBC News that it has been offering a $20,000 egg freezing coverage under its “lifetime surrogacy reimbursement” administered by Aetna since the start of 2014. Not noted by the media, this is an almost laughable amount, considering the total costs of surrogacy: One surrogacy pregnancy (i.e., use of a surrogate to deliver somebody else’s pregnancy) in the U.S. will entail costs of approximately $60,000-100,000 or more. A $20,000 contribution from Apple, Facebook or other companies will, of course, be appreciated but will be only a relatively small contribution to overall costs.

Bennett, and the many others who have written on the subject in the media, also have failed to understand some other very important facts surrounding social fertility preservation via egg banking: First, egg banking has become an industry almost of its own, separate from standard fertility care. Commercial companies have entered the business often in cooperation with fertility centers, and have started commoditizing this form of fertility preservation in ways which CHR is uncomfortable with.

One of the excesses we have previously pointed out, “egg freezing parties,” recently also attracted attention from the media. We are also very uncomfortable with many of the cost quotes for egg banking cycles, published in various articles following the Apple and Facebook announcements. They are often highly misleading because they do not reflect additional costs that patients usually encounter. For example, before a patient’s ovaries are stimulated for egg retrieval, her ovarian function should be carefully evaluated. If this is done, it creates additional costs; if it isn’t, the patient runs a significant risk of inadequate stimulation.

Cost estimates used for marketing purposes often do not spell out clearly that most women will need multiple cycles and that the number of cycles required to accumulate adequate egg numbers increases with age because women produce fewer eggs per cycle, yet need more frozen eggs with pregnancy chances per frozen egg declining with age (the “double whammy,” as we call it at CHR).

In other words, if younger women are quoted the same costs as older women, we see this as misrepresentation, and if women are not individualized in their care based on age and FOR, they do not receive maximal care.

When Bennett and others quote “average egg freezing costs” at $10,000, they therefore, do not reflect reality. If a woman in her late 30s requires four cycles to cryopreserve an adequate number of oocytes, her costs will be a multiple of this sum. Just like the $20,000 Facebook offers as a lifetime benefit for surrogacy, so will this sum likely only be an inadequate amount to cover the costs of appropriate fertility preservation.

The excitement about Apple, Facebook and, per Bennett, also Citigroup, JP Morgan Chase and possibly soon Google and Microsoft, offering coverage for egg freezing should, therefore, be more muted. If women at these companies do want to freeze their eggs, they will incur significant additional out-of-pocket costs, considering the maximal contribution those companies are willing to offer per lifetime.

We cannot conclude these cautionary comments on social egg banking without repeating a very important point: social egg freezing is currently still considered an experimental procedure and we at CHR consider this designation to be highly appropriate. The most important reason why we consider this designation appropriate and, indeed important, is because when a woman comes to us for advice and asks how many eggs she should cryopreserve to secure a high likelihood of later success in conceiving at least one child, nobody can currently give her a reliable answer, because nobody has the necessary data to establish an appropriate predictive model.

Everybody, including we here at CHR, is just guessing; we, however, at least acknowledge the fact!

_Welcome again to the inaugural issue of

The CHR Fertility Preservation News,

where we fight for every egg and embryo

-The CHR_

Norbert Gleicher, MD, FACOG, FACS

Norbert Gleicher, MD, FACOG, FACS

Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned specialist in reproductive endocrinology, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.

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