Fertility preservation

Fertility Preservation Oocyte cryopreservation, Egg freezing, Sperm cryopreservation, Sperm freezing, Ovarian tissue freezing, Ovarian failure, Ovarian insufficiency, Testicular failure

1. What every clinician should know

Fertility preservation is the process by which either oocytes (eggs) or sperm undergo an intervention to preserve their use for future attempts at conception. Fertility preservation is considered for patients who may undergo destruction of oocytes (eggs) or sperm leading to infertility.

Individuals at greatest risk of needing to consider fertility preservation techniques are men and women with cancer undergoing chemotherapy or radiation.

According to the American Cancer Society, approximately 852,630 women in the United States are newly diagnosed with cancer. The probability of a woman developing an invasive cancer is 1 in 18 from birth to age 49. These data combined with the fact that more women are surviving their cancer diagnosis have led to more discussion and implementation of fertility preservation techniques. Young women with breast cancer or males with testicular cancer, for example, have a 5-year survival of over 90%. The 5-year survival rate in children and youth with cancer has increased from <30% to approximately 80%. As survival increases, patients desire to include future childbearing into their life plan and various studies note the importance of being able to have children as a key factor in determining their satisfaction with life.

For females, fertility preservation may also be considered to defer reproductive aging, however, the American Society for Reproductive Medicine recommends caution in this setting and there is scant data regarding outcomes. Fertility preservation may be discussed in women who will be undergoing surgical removal of both ovaries or anticipated chemotherapy for other medical reasons that may impact future fertility.

For males, the American Cancer Society notes that estimated new cancer cases in males in the U.S. approaches 836,150. The probability of developing invasive cancer in males from birth to 49 years old is 1 in 30 and from 50 to 59 years old is 1 in 16.

The focus of fertility preservation is currently on individuals with cancer, and most recent advances have surrounded such treatment in women.

Once a diagnosis of cancer has been made, discussion regarding fertility preservation should occur as early as possible so that referral to appropriate specialists can occur prior to starting treatment. The historically established means of fertility preservation are sperm and embryo cryopreservation. Mature oocyte cryopreservation is no longer under experimental status. Other methods, however, are gaining wider acceptance, but still need to be performed under IRB-approved protocols, such as in vitro maturation of oocytes and ovarian tissue freezing in females. Other options include laparoscopic oophoropexy and laparoscopic radical trachelectomy for certain indications. Parents may elect to have children undergo fertility preservation if it is likely to provide benefit to the child. In this situation, IRB protocols often include an assent signed by the child. Males can also be considered for experimental protocols that involve testicular tissue cryopreservation or testicular sperm extraction.

Offspring of patients with cancer conceived after fertility preservation do not have an increased risk of cancer unless they have an underlying genetic syndrome. Preimplantation genetic diagnosis (biopsy of embryos to look for certain genetic diseases) if an inherited cancer is present, can be performed.

The main goals that involve future fertility in women are as described in The New England Journal of Medicine: improve patient-specific life preserving treatments, identify and reduce the threat that cancer treatment poses to fertility, expand safe and effective options for fertility treatment, and create symptom-management plans for patients who lose endocrine function for the gonads as a result of cancer treatment.

A reproductive health assessment should be performed on all patients of childbearing age to determine their goals and to have the opportunity to consider fertility preservation techniques, if desired. In premenopausal breast cancer patients, only 51% felt that their fertility concerns were addressed adequately.

The most common indications for fertility preservation include breast cancer, cervical cancer, cancers of childhood and youth, patients planning bone marrow transplant or stem cell transplant, planned bilateral oophorectomy, planned pelvic radiation, planned chemotherapy for noncancer diagnoses such as severe lupus glomerulonephritis or other autoimmune or hematological diseases.

Ethics of fertility preservation and reproduction in cancer patients

Medical providers should be aware of the adverse effects of cancer treatment on fertility. With increased number of cancer survivors, future fertility is an important issue and should be addressed.

Discussion of treatment plan should include:

• Risk of infertility with proposed treatment and referral to reproductive endocrinology and infertility specialists

• Estimates of risk of infertility should be attempted to be made and the patient counseled

• Overall prognosis for patient

• Prognosis applies to the ability for the patient to undergo a current procedure in the setting of a new cancer diagnosis and the future life expectancy (shortened lifespan is not a reason to deny cancer patients fertility options/treatment)

• Risks for delaying treatment (in the case of embryo or egg freezing)

• Effect of pregnancy on recurrence of disease

• There are currently no data to support increased risk of recurrence of disease if a patient becomes pregnancy

• Genetic screening, if indicated and use of PGD when appropriate

• Use of established versus experimental therapies (see management below)

• Discuss benefit to minors, if applicable, and their ability to give assent

• If the minor is able to understand the choice and refuses, then the procedure should not be done despite parental wishes

• If the minor it not old enough to give assent, then parents may consent to the procedure if it has minimal risk and is of expected benefit

• Ethics committee consultation is recommended

• Health risks to future offspring

• Concerns regarding well-being of future children born to cancer survivors should not result in their being denied access to fertility treatment

• Fertility preservation techniques

• Posthumous reproduction

If fertility preservation is used, then a clear plan for storage and disposition of gametes, embryos, or tissue should be documented.

2. Diagnosis and differential diagnosis

It is difficult to assess when or if a patient will become infertile and need fertility preservation. Consideration for fertility preservation counseling should be instituted early and should have a multidisciplinary approach. The most significant damage to the ovaries or testicles is incurred by radiation and alkylating chemotherapy agents.

There is no testing that can be completed to predict a patient’s fertility response to treatment. Infertility risk will depend on type, duration, and dose of chemotherapy; location and dose of radiation; location of surgery; cancer type; age of patient, and fertility status prior to starting treatment.

Risk of amenorrhea (a surrogate marker of ovarian failure) in females receiving chemotherapy can be assessed (Fertile Hope table available from the Fertile Hope website). These estimates are helpful in counseling patients, but are based on mostly cohort or case series or small nonrandomized trials.

Risk of azospermia in males can be estimated based on treatment type.

Before patients can undergo fertility preservation options, they must:

• Be medically cleared to proceed

• If female patient is >45 years old, patient may not qualify for fertility preservation with procedures such as egg/embryo freezing due to age-related ovarian changes. Uterine preservation with consideration of possible egg or embryo donation use in the future may be considered for women into the early 50s. No absolute specific age-cut offs are documented; therefore, a combination of medical judgment in addition to an ethics committee review would be appropriate on a case-by-case basis.

• Identify if patient is pre- or post-pubertal and then identify fertility preservation options accordingly

• In women, exclude pregnancy, subjects with FSH >15 mIU/mL or estradiol >75 pg/mL on second or third day of menstrual cycle. In case of immediate need for cancer treatment, no FSH or estradiol is required

• Exclude subjects who are simultaneously enrolled in other investigative studies that require medications, prescribe fertility medications, or otherwise prevent compliance

• Exclude patients with current diagnosis of gestational trophoblastic disease

Plan for patients considering fertility preservation:

• Counseling session

• History and physical exam

• Transvaginal ultrasound for females

• Preconceptual counseling

• Laboratory testing

• Females

• Day 3 FSH and estradiol (if able)

  Progesterone (if indicated)

  Pregnancy test

• AMH (anti-müllerian hormone)

• Consideration of FDA infectious disease screening labs as is done for oocyte donation (HIV 1 antibody and NAT, HIV 2 antibody, HIV type O screening, ABO and Rh type, hepatitis C antibody and NAT, hepatitis B surface antigen, hepatitis B core antibody [IgG and IgM], serologic test for syphilis, gonorrhea/chlamydia testing, blood type and Rh factor, genetic screening as indicated.)

Males

If sperm or embryo cryopreservation is anticipated: Because sperm and embryo cryopreservation are not considered experimental and its anticipated use is in a sexually intimate partner, there are few screening requirements for males. HIV screening is indicated and other infectious disease screening can be obtained as appropriate (i.e., for risk factors).

If testicular tissue freezing is planned: Consideration of FDA infectious disease screening labs for donated tissue may be considered (HIV 1 antibody and NAT, HIV 2 antibody, HIV type O screening, hepatitis C antibody and NAT, hepatitis B surface antigen, hepatitis B core antibody (IgG and IgM), serologic test for syphilis, gonorrhea/chlamydia testing, genetic screening as indicated, HTLV 1 and 2, and CMV (IgG and IgM).

Possible fertility outcomes after male cancer treatments can be normal fertility, temporary infertility, compromised fertility, or permanent sterility.

Females can have normal fertility, fertility followed by an early menopause, compromised fertility, or ovarian failure (menopause)

Consult services involved in fertility preservation may include:

• Medical oncologist, radiation oncologist, or other provider managing the primary disease process

• Reproductive endocrinology and Infertility specialist (REI)

• Maternal-fetal medicine (MFM, high-risk OB specialist)

• Genetic counselor

• Psychiatrist/psychologist

• Ethics committee

• Urologist

3. Management

For all patients desiring fertility preservation, options must be individualized.

The established methods of fertility preservation are embryo, oocyte, or sperm cryopreservation. Oophoropexy and radical trachelectomy can also be performed without IRB approval. Other forms of fertility preservation require IRB approval in a research setting.

There are female fertility preservation options (see, for example, Sonmezer et al., “Fertility preservation in female patients,” Fig. 3), male fertility preservation options and other options (see respective tiers).

The first step in evaluating a patient for fertility preservation is to assess the medical stability of the patient. The patient should be medically cleared by their medical oncologist, internist, primary care provider or qualified medical subspecialist.

The couple should then also have an MFM (high-risk OB) consultation to discuss potential complications in pregnancy.

A consultation with reproductive endocrinology and infertility is indicated as soon as the patient diagnosis is known. Options for fertility preservation can then be presented and discussed. Often these types of interventions are not covered by insurance plans.

The patient should also work with a psychologist if there is complex decision making. Ethics committee should likely be involved if there are questions regarding the treatment of a minor.

Female Fertility Preservation Options

• Embryo cryopreservation

• Oocyte cryopreservation (egg freezing)

• Ovarian tissue cryopreservation (ovarian tissue freezing)

• Ovarian tissue transplantation, orthotopic

• Ovarian tissue transplantation, heterotopic

• Laparoscopic oophoropexy (ovarian transposition)

• Ovarian suppression

• Radical trachelectomy (cervical cancer)

• Uterine transplantation

Radical trachelectomy (cervical cancer)

Radical trachelectomy is a laparoscopic procedure performed to remove the cervix in the setting of cervical cancer, sample the pelvic lymph nodes, and yet preserve the body of the uterus. This procedure can be offered to patients <40-45 years old, with stage 1A1 with vascular space invasion, 1A2, or 1B1 cervical cancers. To achieve greatest success, cervical lesions should be <2-2.5 cm with limited endocervical extension, and have no lymph node metastases. Approximately 10-12% of patients at the time of their surgery will be found to have more extensive disease and so the procedure is abandoned and completion of a radical hysterectomy or adjuvant radiation therapy is planned.

A cerclage is usually placed at the time of surgery.

Cervical cancer recurrence risk in appropriately selected patients is <5%, which is similar to results following radical hysterectomy.

C-section is indicated for delivery. Approximately 70% of pregnancies resulted in live birth, but of those 60% are premature. First trimester pregnancy loss is the same as the general population. There is an increased risk of second trimester pregnancy loss (9.5% versus 4%).

Routine post-pregnancy hysterectomy is not usually recommended, but there are no official guidelines regarding post-pregnancy hysterectomy. The decision for hysterectomy after pregnancy should be individualized. Patients with tumor size >2 cm are at higher risk of recurrence.

Ovarian Suppression

Ovarian suppression with GnRH analogues, such as Lupron, has been suggested as a possible fertility preservation option in patients planning for chemotherapy. Ovarian suppression is not indicated when radiation will be given.

This is one of the most debated topics in fertility preservation discussions. Protective effect was seen early animal studies and mostly nonrandomized evidence. Many others studies, including the German Hodgkin Study Group randomized trial, do not show an effect, or others indicate mixed results. A summary in peer-reviewed papers of patients receiving GnRH analogues versus controls revealed a rate of premature ovarian failure of 11.1% in the GnRH group and 55.5% in the control group, however, only one of these was a randomized trial (see Blumenfeld). Thus, a conclusive benefit of treatment with GnRH analogues has not been demonstrated. And, some authors suggest that since breast, ovary, and endometrium express GnRH receptors, that it cannot be determined at this point that GnRH analogues do not reduce the efficacy of chemotherapy either by effect on GnRH receptors or by inducing glutathione S-transferases.

GnRh analogues, however, can be helpful in decreasing menstrual bleeding during cancer treatments.

Laparoscopic Oophoropexy (Ovarian transposition)

Laparoscopic oophoropexy/ovarian transposition is utilized as a fertility preservation technique when there is expected pelvic radiation without chemotherapy in premenopausal women. The goal is to move the ovary(ies) to a fixed point outside of the radiation exposure which would not be the normal anatomic location for these gonadal structures.

The ovary(/ies) and its blood supply is moved out of the pelvis to be at least 3 cm above the expected radiation field. Collaboration with radiation oncology is critical. The surgical procedure involves laparoscopically suturing the ovary with permanent suture to the lateral anterior abdominal wall. Titanium clips are placed at the site of transposition so that the location of the ovary can then be noted by the radiation oncologist.

Success rates vary between 15% and 90% depending on various clinical factors.

Ovarian tissue transplantation, heterotopic

This process involves using cryopreserved ovarian tissue and transplanting it to the subcutaneous tissue such as the forearm or abdomen.

Heterotopic transplantation can allow easier access to removal of ovarian tissue, if needed or if transplantation to the pelvis is technically too difficult.

There are reports in the literature of return of endocrine function and rare cases of ability to create embryos after heterotopic ovarian tissue transplantation. Only 2 live births have been reported. In one case, ovarian tissue cryopreservation had been performed 9 years prior to an IVF cycle which led to a twin delivery. The grafted tissue was then removed (original diagnosis was Stage 1C mucinous cystadenocarcinoma) (Kristenson, et al).

Ovarian tissue transplantation, orthotopic

This process involves using cryopreserved ovarian tissue and transplanting it to the pelvis providing the opportunity for natural conception; however, this is a more invasive transplantation procedure.

One of the largest case series documents 95 orthotopic transplantations in 74 women (Vander Ven, et al.) Additionally, approximately 65% of the transplants were active 1 year after transplant. Some authors note an endocrine recovery rate of 93% (Meirow, et al.)

Ovarian tissue cryopreservation (Ovarian tissue freezing)

Ovarian tissue freezing can be completed at any time during the menstrual cycle and does not cause a delay in chemotherapy. This process can be considered in pre- and post-pubertal patients who have a low risk of metastasis to the ovaries. This process is considered experimental. The ovarian tissue is obtained by laparoscopy and then cortical strips are prepared from the ovarian tissue and cryopreserved. Viability of the tissue can be retained approximately 70% of the time. It is not yet possible to cryopreserve an entire ovary.

Indications for ovarian tissue cryopreservation are listed (see Donnez et al, “Ovarian tissue cryopreservation and transplantation: a review,” Table no. 2).

A male partner is not required, however, the patient must be able to medical tolerate a laparoscopic procedure.

After the patient’s cancer treatment is completed, the ovarian tissue is thawed and transplanted. Transplantation should occur in close temporal proximity to when the patient desires pregnancy as the auto-grafts may not have an unlimited survival.

The disadvantage is that there is possibility of reintroducing malignant cells and an overall low success rate. The advantage is that this tissue can function hormonally similar to endogenous secretion of hormones from the ovaries prior to cancer treatment.

Oocyte cryopreservation (Egg freezing)

Oocyte cryopreservation is the process by which eggs themselves are cryopreserved. This has been technically challenging, as compared to embryos, because of the large water content of the oocyte which is prone to intracellular ice formation and spindle disruption. Mature oocyte cryopreservation is no longer considered to be experimental.

There are two methods to freeze eggs: Slow freeze and vitrification (fast freeze). Slow freeze has an approximately 2% live-birth rate per oocyte thawed and vitrification has an approximately 4% live-birth rate per oocyte thawed (patients usually have multiple oocytes available).

A male partner is not required.

Egg freezing often involves the freezing of mature eggs. This process can be completed on postpubertal females. It requires that gonadotropins are given to stimulate the growth of follicles which are then aspirated in an oocyte retrieval procedure. The eggs are then frozen and, at a time determined by the patient, the eggs can be thawed and used for IVF/ICSI. ICSI must be incorporated to help increase fertilization rates.

Egg freezing can also involve immature oocytes that are obtained from aspiration of ovarian follicles or from ovarian tissue. Immature eggs can undergo in vitro maturation either before freezing or after thawing. In vitro maturation can be performed for pre and post-pubertal girls. Theoretically immature eggs may be more resistant to cryo injury than mature eggs. The advantages to in vitro maturation are that immature eggs can be collected without ovarian stimulation, matured for 24-48 hours in vitro and then fertilized by ICSI. Implantation rates are two to three times lower than conventional IVF when using in vitro matured eggs.

Essential elements of informed consent for elective oocyte cryopreservation have been published by the American Society for Reproductive Medicine. Key information for patients includes description of ovarian stimulation and oocyte retrieval, methods that will be used for freezing, annual storage fees, and expected thaw-survival rate for oocytes and the possibility that none may survive. Consent also needs to include discussion of the need for ICSI in the future and these associated costs and should discuss clinic-specific outcome data.

It is important also to note that most women who cryopreserve oocytes prior to age 35 will never need or use them.

Embryo cryopreservation

Embryo cryopreservation is the standard technique by which gametes can be utilized in an attempt to preserve future fertility. According to CDC/SART data for 2014, thawed nondonor embryo transfers resulted in a 44% live birth rate for women under 35, 41% live birth rate for women 35-37 years old, and 35.2% live birth rate for women 38-40 years old. These data are reflective of mostly the infertility population, and thus no specific data for embryo cryopreservation as used in fertility preservation patients are known on a country-wide basis. Pregnancy rates would be expected to approximate the live birth rate for infertility patients.

Embryo cryopreservation requires a male partner unless the patient is prepared to use donor sperm. This process is similar to the IVF process used for infertility patients. Usually 2-6 weeks is necessary to complete a cycle depending on last menstrual period and response to gonadotropins. This time is needed to develop mature oocytes that are removed during the oocyte retrieval and then combined with sperm in the embryology lab to create embryos that are then frozen.

Embryo cryopreservation would not be an option for patients who are ethically opposed to freezing of embryos.

Uterine transplantation

Women who have congenital absence of a uterus or acquired absence (hysterectomy) or a non-functioning uterus are now able to consider the experimental technique of uterine transplantation for fertility.

The first human uterine transplant occurred in 2000, but the graft failed. The second human uterine transplant was performed in 2011 in Turkey without having a live birth reported. The first live birth following uterine transplantation occurred in 2014 in Sweden utilizing live donors. Since that time additional transplants have been successful.

The United Kingdom has plans to perform 10 uterine transplants over the next 2 years with brainstem dead, heart-beating donors. The United States completed its first transplant on February 24, 2016 at the Cleveland Clinic, but due to complications, the transplanted uterus was removed. The process of uterine transplantation for the US clinical trial (planned for 10 women) includes cryopreservation of at least 10 embryos, deceased donor uterus harvesting, uterine transplantation, stabilization of the transplant for 12 months, thawing and transferring of the embryos (one at a time), continuation of antirejection drugs during pregnancy, cervical biopsy monthly to monitor for organ rejection, caesarean delivery, and hysterectomy after one to two babies are delivered.

Male fertility preservation options include:

• Sperm cryopreservation

• Testicular tissue cryopreservation

• Testicular sperm extraction

Testicular sperm extraction

Testicular sperm extraction can be considered for pre- or post-pubertal males, but is considered experimental.

This technique has also identified sperm in 37% of men who had previously undergone chemotherapy and were deemed azospermic. In this situation a 42% live birth rate was obtained expanding the opportunities for reproduction in males status post cancer treatment.

Testicular tissue cryopreservation

Testicular tissue cryopreservation is an experimental technique that has been attempted in pre-pubertal boys. It is not yet efficient or safe for humans.

Sperm Cryopreservation

Sperm cryopreservation is a standard fertility preservation option for male patients prior to beginning cancer treatment. The technique is well-established and can be offered to post-pubertal boys and adults. A specimen is produced from the ejaculate. Frozen specimens can then be used years later for treatment. If sperm counts are low or there is a limited supply of sperm then IVF (in vitro fertilization) with ICSI (intracytoplasmic sperm injection) would be recommended. If sperm counts are adequate (>5 million total motile sperm in a washed specimen), then IUI (intrauterine inseminations) may be possible.

If an ejaculate cannot be obtained nor any sperm found in the ejaculate, then transrectal electroejaculation, epididymal sperm aspiration, or testicular sperm extraction can be considered.

Other fertility preservation options

• Donor oocyte (fresh donor egg or frozen donor egg bank)

• Donor sperm

• Donor embryo

• Adoption

• Foster parenting

• Child-free living

Cost of fertility preservation options

Table I provides approximate costs.