Female Fertility Preservation Research

Medical research provides the foundation for decisions about treatment and procedures for patient care.  The reports of research are published in research journals and distributed to the medical community.  For this reason, research articles are frequently filled with medical terminology and tedious descriptions of methods used to conduct the research.  PORF is providing three ways to find pertinent information that may inform parents and patients who are interested in preserving fertility after cancer treatment:  1) a brief overview of the literature related to pediatric Oncofertility research; 2) a short annotation for each article that is referenced on this website; and 3) a link to the complete article.

Overview of Literature

It is clear from research studies that certain treatments for cancer result in damage to the ovaries of women and young girls.  The research that quantifies the damage to ovaries by such treatments as chemotherapy and radiation therapy has been conducted with mature women.  However, we have to infer that immature girls experience similar damage as a result of some treatments.  Physicians can tell parents in advance of treatment how likely their prescribed treatment is to cause damage to the ovaries, or to immature ovarian tissue.

Studies have also found that damage to ovaries occurs very soon after the treatment begins.  For this reason, researchers have concluded that procedures to preserve fertility need to be completed prior to the initiation of cancer therapy.  Once again, the data that led to this conclusion were collected from mature female cancer patients.  Studies involving pediatric patients have not been completed.

For these reasons, all interventions to preserve fertility in children treated for cancer are experimental.  They are research studies that may well benefit the study participants, but are limited to those patients who have access to a medical facility that participates in the study.  While there are no guarantees that participation in the study will result in fertility restoration, significant progress has been made and documented through research reports.

For young girls anticipating cancer treatment, the most promising procedure for restoring fertility is cryopreservation of ovarian tissue.  Since the pre-pubertal girl does not have fully developed ovaries, ovarian tissue from one ovary is removed from the child prior to cancer treatment.  This tissue is cut in sections and frozen for future use.  Some of the tissue is used by the researchers as part of their ongoing studies into Oncofertility.

Researchers have demonstrated that the ovarian tissue, once thawed, can be successfully implanted into the same child after treatment is complete.  The implantation of ovarian tissue in adult woman has to date resulted in 24 successful pregnancies and live births.  However, studies have not yet demonstrated success with pre-pubertal tissue removal and replantation.

A major concern for researchers has to do with the nature of the cancer diagnosis and its potential impact on the tissue preserved for Oncofertility use.  If the cancer is systemic, such as leukemia, there is a danger that cancer cells may be contained in the preserved tissue.  For this reason, researchers are currently developing bioengineering techniques to separate ovarian follicles from the rest of the ovarian tissue.  This has the potential for allowing the essential ingredients of fertility to be implanted in the patient without the danger of reintroducing cancer cells.

Because of the groundbreaking studies currently being conducted, researchers recommend that ovarian tissue be harvested and preserved prior to cancer treatment.  The potential for these studies to result in standard care is very high.

One of the most recent developments is the cryopreservation of Oocytes, especially in post-pubescent females.  The practice of cryopreserving oocytes is so powerful that it approximates the cryopreservation of embryos in terms of pregnancy.  The preservation of oocytes does require hormonal stimulation prior to oocyte collection, which may compromise its effectiveness for newly diagnosed cancer patients.  Also, oocyte preservation is likely not an option for very young pre-pubertal patients.  However, this option adds to the options available for newly diagnosed cancer patients and their physicians.

Although the term Oncofertility causes most to think about preserving the potential for pregnancy in the future of cancer survivors, it may well mean much more to the pre-pubertal female patient.  The preserved tissue may prove useful in the maturation process if implanted at the time of puberty.  Adult women have experienced a resumption of menses at approximately three months after ovarian tissue is replanted.  This means that tissue may well be available as a source of estrogen and progesterone, vital hormones for the development and maintenance of skin, bone, and vessels throughout the body.

This brief overview of the research published on the topic of pediatric Oncofertility is by no means complete.  Rather, it is intended to communicate pertinent information that may help parents make an informed decision about their daughter’s future fertility.  Questions that parents may have as a result of considering this information can be a source of discussion with your child’s physicians and nurses.

Article Annotations

“Fertility preservation for young patients with cancer:  who is at risk and what can be offered?”

W Harrish, B Wallace, Richard A. Anderson, D. Steward Irvine
http://oncology.thelancet.com vol 6 April 2005

 

This article, published in 2005, is an overview of options available to boys and girls facing treatment for cancer.  It is not a report of primary research.  Since the article is at least ten years old, it is more historical in its significance for families making decisions about fertility preservation today.

The article is easily understood by the non-medical reader.  However, some of the medical jargon can be a bit daunting.  The reader should understand that some of the information presented has become dated.

One of the most important points addressed in this article has to do with the ethics of fertility preservation.  The authors make the following important points:

  1. Attempts to preserve fertility should not promote unrealistic expectations.
  2. Attempts to preserve fertility should not have undue adverse effects to the patient.
  3. Attempts to preserve fertility should not have undue adverse effects to subsequent offspring of the patient.

The authors also stress the legal and ethical importance of securing informed consent.  They point to the emotional stress of the circumstances surrounding the cancer diagnosis and treatment plan as complicating the fertility preservation decision.

PORF recommends this article for its historical value, as well as for the important ethical and legal issues that it addresses.

“For patients who have not yet started puberty, options for fertility preservation remain entirely experimental at present.  Optimism for these patients in the future lie with continuing research efforts.”


 

“Dynamics and mechanisms of chemotherapy-induced ovarian follicular depletion in women of fertile age.”

Mikkel Rosendahl, M.D., Claus Yding Anderson, D.M.Sc, Nina le Cour Freiesleben, M.D., Anders Jual, M.D, D.M.Sc, Kristine Lossl, M.D., Ph.D., and Anders Nybee Anderson, M.D., K.M.Sc

Fertility and Sterility Vol 94, No. 1, June 2010

 

This article reports on primary research designed to determine the impact of chemotherapy on ovarian function in mature women.  As with most primary research reports, the opening statement and the final paragraphs of the report are most user-friendly to the non-medical reader.

Two important conclusions were reached by the authors of this study:  1) chemotherapy exerts an immediate toxic effect on growing ovarian follicles; and 2) pretreatment ovarian follicular reserves may be used to individualize a patient’s risk of chemotherapy induced ovarian failure.

These findings complement studies that found that increased age of a patient correlates to a diminished follicular reserve.  This would suggest that younger patients who have a larger pool of follicular reserve may be able to undergo more chemotherapy without becoming infertile.  It is important to note that this study had a research population of 16 women with and average age of 30 years.  The age range was 19-35 years.  This means that all study participants were mature women.  This causes PORF to believe that similar studies should be conducted on pre-pubescent girls.  In the absence of such studies, it would be inappropriate to generalize these findings to the pediatric population.

In the meantime, the conclusion by these researchers that chemotherapy’s toxic effect was immediate in important.  Because of the immediacy of the toxic impact, procedures to preserve fertility in all female cancer patients must currently be undertaken prior to the administration of the first chemotherapy treatment.

“…chemotherapy exerts an immediate toxic effect on the granulosa cells of growing follicles.”  P.165


 

“In Vitro Oocyte Maturation and Preantral Follicle Culture from the Luteal-Phase Baboon Ovary Produce Mature Oocytes.”

Min Xu, Asgerally T. Fazleabas, Ariella Shikanov, Erin Jackson, Susan L. Barrett, Jenny Hirshfeld-Cytron, Sarah E. Kiesewetter, Lonnie D. Shea, and Teresa K. Woodruff

Biology of Reproduction 84, 689-691 (2011)

 

This article is important in that it marks a stage of research that may lead to fertility preservation in humans.  It is a report of primary research involving baboon ovarian follicles.  The researchers found that baboon follicles can be cultured in vitro to produce competent oocytes.

The historical significance of this article is important to PORF.  Since the study report was published in 2011, it is foundational to research currently underway by these researchers and others.


 

“Initiation of puberty in mice following decellularized ovary transplant.”

Monica M. Laronda, Adam E Jakus, Kelly A. Whelan, Jason A Wertheim, Ramille N. Shah, Teresa K. Woodruff

Biomaterials 14 February 2015
This is a report of primary research conducted at Northwestern University and published in 2015.  It is a fundamental study that may pave the path for engineering an artificial ovary to replace ovarian tissue destroyed by treatments for cancer and other diseases.

As with most reports of primary research, the non-medical reader can easily be confused by the “Materials and methods” section of the document.  However, the “Introduction” and “Conclusions” are easy to understand.  The “Discussion” is interesting, albeit closely related to the more tedious “Materials and methods” section.

In introducing this study, the authors highlight the importance of the ovary as a source of hormone generation.  While we mostly think of the ovaries as organs for reproduction, the authors assert additional ovarian function.  “Ovarian hormones also significantly influence bone, skin, breast, vessels and additional endocrine tissues.”  Therefore the restoration of this function is critical throughout the life span of the woman treated for cancer as a child.

One of the primary concerns for reintroducing cryopreserved ovarian tissue is the danger of cancer cells being present in that tissue.  That eventuality does not apply to all cancer types.  However, cells from such common pediatric cancers as leukemia and Ewing’s sarcoma were found in this study to be contained in the preserved ovarian tissue.  This finding adds urgency to the need to find an alternative to auto-transplantation for girls diagnosed with certain cancer types.

This study found that a method for engineering ovarian tissue is successful in animals.  It also found that engineered tissue will stimulate puberty in mice.  Further, it concludes that the potential for engineering an ovary that will be free of any previously discovered disease is possible.

The data presented in this report, “provide the first steps toward creating an artificial ovary that functions as an endocrine organ and supports viable gametes.”

There is a critical need for additional research to bring this important proof-of-principle to widespread use in children treated for cancer and other diseases.  PORF is dedicated to providing funds to support this effort.

“Ovarian hormones also significantly influence bone, skin, breast, vessels and additional endocrine tissues.


 

“Children born after autotransplantation of cryopreserved ovarian tissue.  A review of 13 live births”

Jacques Donnez, Sherman Silber, Claus Yding Andersen, Isabelle Demeerstere, Pascal Piver, Dror Mierow, Antonio Pelticer, and Marie-Madeleine Dolmans

Annals of Medicine, 2011, 43:437-450
This article is not a report of primary research.  Rather it is a description of ten women who delivered a total of 13 healthy babies as a result of auto-transplantation of cryopreserved ovarian tissue.  Auto-transplantation is a procedure whereby tissue that was removed from the patient prior to ovary-compromising treatments is re-implanted into the same person.  Cryopreservation is the term used to describe the freezing and preserving of tissue between the time it is removed from the patient and re-implanted.

The article begins by describing three types of cryopreservation that are available to young girls and women who are about to undergo ovary-compromising cancer treatment.  The three options are:  embryo cryopreservation; oocyte cryopreservation; and ovarian tissue cryopreservation.  Because of PORF’s focus on pediatric cancer patients, we will address ovarian tissue cryopreservation, because it is the only option available to pre-pubescent girls and post pubescent girls who need to begin therapy as soon as possible after diagnosis.

The article describes ten case studies where cryopreserved ovarian tissue was auto-transplanted after being thawed, resulting in successful pregnancies and normal infant births.  While each of the women featured underwent some ovary-compromising treatment, not all experienced treatment for cancer.

It is important to note that the nature of the cancer diagnosis has a significant bearing on the availability of auto-transplantation of the cryopreserved tissue.  For example, patients treated for such blood-related cancers as leukemia run the risk of having metastatic disease in the cryopreserved ovarian tissue.  Despite this potential, the authors of this article suggest that cryopreservation of ovarian tissue remains an option.

There are options other than auto-transplantation that are available.  These include a procedure where individual ovarian follicles are cultured in vitro and a procedure where the tissue is implanted in a engineered solution called a scaffold.  Research is currently underway to refine these procedures and secure additional alternatives for patients whose tissue may be exposed to metastatic disease.

This article was published in 2011.  The authors conclude that ovarian cryopreservation should be offered to all young girls who are about to undergo ovarian-compromosing treatments of any kind.  They believe that the power of cryopreserved ovarian tissue to result in successful pregnancies is sufficiently powerful to warrant consideration by all patients and their parents.

This article is relatively easy for a non-medical person to read, especially if the reader focuses on the following sections:  “Introduction,””Key messages,”and “Conclusions.”  The “Discussion” section is interesting, but a bit more tedious for the non-medical reader.

This article also presents an historical foundation for Oncofertility research.  Published in 2011, it is old news in the world of Oncofertility research.  Even at this early date, the authors were suggesting that all girls who will be going through ovarian-compromising cancer treatment should be offered the option of cryopreservation.
“Cancer treatment takes priority over potential restoration of fertility, but offering the chance to preserve fertility may greatly enhance quality of life for cancer survivors.“


“Bioengineering the Ovarian Follicle Micro-environment,”

Lonnie d. Shea, Teresa K. Woodruff, and Ariella Shikanov.  The Annual Review of Biomedical Engineering, 2014 – 16:29-52
This comprehensive article presents a detailed description of the need for and progress toward bioengineering of ovarian follicles.  For purposes of PORF, the authors make at least six critical points:

  1. Most of the follicles contained in the ovary and ovarian tissue are at the most immature stage of development (primordial follicles).
  2. Primordial follicles have the greatest potential to survive cryo-preservation and transplantation.
  3. The ovarian tissue cryo-preservation preserves a large number of immature follicles.
  4. Transplantation of ovarian tissue, “could restore both endocrine function and produce a large source of follicles for recruitment into the
  5. growing pool over multiple cycles.”
  6. A critical concern for cryo-preserved ovarian tissue is the potential for cancer cells to be present in the preserved tissue.
  7. Isolation and transplantation of individual ovarian follicles, rather than intact tissue, has the potential to significantly reduce or eliminate the risk of reseeding disease.

Additionally, this article projects four areas for continued bioengineering research that promise opportunities for pediatric Oncofertility:

  1. Artificial ovary.
  2. Transplantation of oogonial stem cells.
  3. Systems biology analysis.
  4. Reproduction tract engineering.

This article is an important analysis of the opportunities for combining biomaterials technology and the field of reproductive biology.  Those non-medical readers of this article will likely find the following sections easiest to understand:  “Abstract,” “Introduction,” “Technologies for Ovarian Tissue or Follicle Transplantation,” and “Summary.”  The literature cited in this article is exhaustive and gives support to the substance presented.

Transplantation of ovarian tissue,“ could restore both endocrine function and produce a large source of follicles for recruitment into the growing pool over multiple cycles.”

 

“Pediatric and Young Adult Patients and Oncofertility”

Katherine E. Dillon, BA, Clarisa R. Gracia, MD, MSCE

www.Oncofertility.northwestern.edu

This article reviews the state of pediatric fertility preservation as of 2012.  While it is intended for health care providers, the article reinforces the position that in-depth discussion of fertility should be standard of care for all children contemplating cancer treatment.  The article goes so far as to precede the review with an “Opinion Statement,” fairly unusual for an article of this nature.

One important dimension of this review is its discussion of the potential for birth defects and for pregnancy problems from either the cancer, or it treatment.  While the discussion is relatively technical and cannot be generalized, the question it poses is certainly important to the overall discussion of fertility that should be had before treatment begins.

All sections of this article are worthy of review by the non-medical reader.  However, readers should not allow themselves to be intimidated by technical jargon.  The final paragraphs under each subsection in the following sections are particularly important:  “Treatment effects in females,” and “Treatment effects in males.”

PORF recommends this article as a reinforcement to the literature that has been reviewed in this section.

“Importantly, the ability to have biological children greatly effects the quality of life of childhood cancer survivors in adulthood; it has been demonstrated that a perceived loss of fertility is associated with lower marriage rates and increased divorce rates in this population.”

 

“Evidence-Based Recommendations for Fertility Preservation Options for Inclusion in Treatment Protocols for Pediatric and Adolescent Patients Diagnosed with Cancer”

Allison Fernbach, MSN, RN, CPNP, Barbara Lockart, MSN, RN, CPNP, CPON, Cheryl L. Armus, MSN, RN. FNP, Lisa M. Bashore, PhD, RN, CPNP, CPON, Jennifer Levine, MD, MSW, Leah Kroon, MN, RN, Genevieve Sylvain, RN, CPHON, and Cherly Rodgers, PhD, RN CPNP, CPON

This is a comprehensive article that consolidates the professional literature relative to fertility preservation as of 2014.  It is user friendly to non-medical readers and thorough in its review of the literature.  However, the full article, published in the Journal of Pediatric Oncology Nursing, is only available through subscription.  The content of this article, albeit more comprehensive in scope, is consistent with the literature review contained on this website.

“It is important to consider and discuss all available fertility options with patients at the time of diagnosis.”

 

“Oncofertility:  a grand collaboration between reproductive medicine and oncology”

Teresa K. Woodruff

This article chronicles the history of Oncofertility.  It is an important overview of the blending of two disciplines in modern medicine.  PORF recommends that all persons interested in the fertility side effects of pediatric cancer treatment read this article in it entirety.  Only one section, “Advances in ovarian follicle culture,” will prove challenging to the non-medical reader.  The pdf of this article can be found at:  http://www.reproduction-online.org/content/150/3/S1.full.pdf

“It is remarkable to think that less than a decade ago, I presented this kind of multidisciplinary collaborative effort to improve patient care as the future of medicine.  For many of our cancer survivors, that future is now, and they are the proud parents of children  they thought they might never not be able to have.”