Continuing Education Activity

As cancer survival rates improve in young men and women, fertility preservation becomes a topic that becomes relevant in malignant conditions. Additionally, several benign conditions may prompt women to consider their fertility preservation options, of which age-related fertility loss has gained popularity as more women choose to delay childbearing. Due to advances in assisted reproductive technologies, there are now a variety of methods to preserve fertility. This activity reviews the indications for fertility preservation in benign and malignant conditions and reviews fertility preservation techniques utilized by the interprofessional team.

Objectives:

• Review the benign conditions in women that may lead to the need for fertility preservation, and describe age-related fertility loss in women.
• Identify the role of fertility preservation amongst transgender men and women.
• Summarize the approach to fertility preservation in a patient with a new diagnosis of cancer and how cancer treatments may lead to a loss of fertility.
• Describe fertility preservation techniques and indications.

Introduction

There are a variety of benign and malignant indications for women that may cause a patient to seek fertility preservation counseling. Several benign conditions that may lead to early infertility include endometriosis, ovarian torsion, benign ovarian cysts, and premature ovarian insufficiency, which may be a result of genetic conditions such as Turner syndrome, Fragile X premutation, or galactosemia.

In addition, there are a variety of autoimmune medical conditions such as Lupus Nephritis and hematologic conditions such as sickle cell anemia and thalassemia that may require chemotherapy, radiotherapy, a combination of both chemotherapy and radiotherapy, and in some instances, even bone marrow transplantation.[1][2] These interventions for benign medical conditions may result in an early loss of fertility. Surgeries in the pelvis may also diminish a women's ovarian reserve and lead to issues with fertility.[3][4]

Function

There has been a trend over the past half-century of delaying motherhood. There is known to be age-related fertility loss for women, and thus with the delay in childbearing more women are now seeking oocyte cryopreservation and other fertility preservation techniques to have children at a later date.[5]

Another group to consider is the newly emerging population of transgender individuals at risk of infertility after pursuing gender-affirming surgeries or hormone therapy. The options for transgender preservation of fertility depend on the specific phase of transgender transition that the patient is undergoing. For transgender women, who were assigned male at birth, options before gender transition with hormones or surgery include cryopreservation of sperm or testicular tissue.[6] 

If puberty has already occurred, the patient may obtain semen from ejaculation or testicular sperm extraction (TESE). If TESE specimens are used, the sperm collected may only be used for in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), whereas if ejaculated sperm is used, it may be used for intrauterine inseminations (IUI) as well as IVF or ICSI. For prepubertal transgender girls who have not started gender-affirming hormones, the only option for fertility preservation is testicular tissue cryopreservation.[6] 

If a transgender woman has started hormone therapy with estrogen, the suppression of spermatogenesis is reversible after holding therapy for at least three months.[7] Thus they may discontinue estrogen treatment and cryopreserve sperm. If a transgender woman has undergone genital reconstruction, there are no options to reverse sterility.

On the other hand, options for fertility preservation in transgender men, who were assigned female at birth, include oocyte and embryo cryopreservation or ovarian tissue cryopreservation if they present before receiving hormone therapy or surgery. For these patients, controlled ovarian stimulation is used to obtain eggs for oocyte and embryo cryopreservation. If a transgender male has already started hormone therapy with testosterone studies, have recommended cessation of testosterone for at least three months.[8] There are a couple of case reports that demonstrate successful ovarian stimulation without testosterone cessation; however, until further larger studies are performed, the recommended practice at this time is for testosterone cessation.[9][10] 

A strategy to reduce the estrogenic symptoms from ovarian stimulation for this group is to use an antagonist protocol with the addition of letrozole.[11] Cryopreservation of ovarian tissue for these patients may be ideally performed at the time of gender-affirmation surgery and is the only option for prepubertal transgender boys.[6] This cryopreserved tissue may then be used at a later time for either reimplantation or to obtain immature oocytes and attempt in vitro maturation (IVM).

Issues of Concern

Malignant conditions are also a very common indication for an individual to seek fertility preservation. With improvements in cancer treatment, there has been a decrease in mortality, leading to a growing group of young woman survivors who wish to have children.[2] 

There are different degrees of damage to the ovaries based on the type of cancer treatment administered. The degree of gonadotoxicity depends on several factors, including the ovarian reserve when starting treatment, the patient's age at the time of treatment, the specific type of chemotherapy and or radiotherapy, and the duration and dose of the cancer treatment.[12] 

If a patient is older and has a lower anti-mullerian hormone level before starting a toxic cancer treatment, they will have increased risks of infertility [4]. Thus due to the wide range of effects, patients should be counseled on fertility preservation options in an individualized manner.

Patients who receive a new diagnosis of malignancy should be rapidly referred to a fertility specialist to receive fertility preservation counseling.[13] There should also be a multidisciplinary approach to treating newly diagnosed cancer patients with a team of oncologists, reproductive endocrinologists and surgeons, urologists, mental health professionals, and genetic counselors. It is also important to consider the patient's current health status as if a patient is too ill; they may not be a candidate to receive fertility preservation therapy. For patients that may be receiving pelvic radiation, the option of using a gestational carrier should be discussed.[14] 

Another option that is specific to women who will receive pelvic radiation is an ovarian transposition, where the ovaries are mobilized and affixed to a location in the abdomen free of radiation.[15] It is important to note that if a patient has ovarian transposition, it may prohibit future transvaginal oocyte retrieval and require a transabdominal approach. 

Clinical Significance

For postpubertal women who receive a new diagnosis of malignancy, their fertility preservation options include controlled ovarian stimulation with embryo or oocyte cryopreservation. Embryo cryopreservation may offer a prognosis on a live birth rate based on the patient's age, along with the number and quality of embryos with or without preimplantation genetic test results. Oocyte cryopreservation may be the preferred method if a patient does not have a committed male partner or does not wish to use donor sperm. Predictors for success with the use of mature oocytes include the age of the patient at vitrification and the number of oocytes cryopreserved.[16]

Women with a cancer diagnosis who desire future fertility should immediately undergo controlled ovarian stimulation with a gonadotropin-releasing hormone (GnRH) antagonist protocol regardless of the phase of the menstrual cycle to prevent a delay in treatment.[17] As the women may often be young, they should be triggered with a GnRH agonist for final oocyte maturation before retrieval to prevent the risk of ovarian hyperstimulation syndrome.[18] Additionally, to prevent venous thromboembolism and hyperestrogenemia in estrogen-sensitive cancers, letrozole or tamoxifen may be used during stimulation.[19] 

It is also recommended to cryopreserve the gametes before initiation of cancer therapy as there have not been any human studies examining the quality of embryos and oocytes following treatment with chemotherapy.[13] The use of GnRH analogs for ovarian protection during chemotherapy remains controversial and should not be used as an alternative to fertility preservation treatment.[20] 

In prepubertal girls with a new cancer diagnosis, the only option for fertility preservation is ovarian tissue cryopreservation, which is no longer considered experimental.[13] Ovarian tissue cryopreservation is also an option for women who cannot delay the start of cancer therapy to undergo ovarian stimulation with subsequent oocyte retrieval. Ovarian tissue cryopreservation involves removing ovarian cortical tissue and freezing it for future transplantation. Orthotopic transplantation, where the cryopreserved tissue is transplanted to a location within the pelvis, is a more successful method in humans than heterotopic transplant, where the cryopreserved tissue is transplanted to an area outside the pelvis such as the upper extremity. If there is a possibility that cancer cells are present in cryopreserved ovarian tissue, autologous transplantation is contraindicated due to the risk of reseeding cancer.[21] 

Additionally, if a patient underwent a bilateral salpingo-oophorectomy due to being a carrier of a BRCA mutation, it is not recommended that they have ovarian tissue transplantation given the increased possibility of having ovarian cancer.[13] Another option a BRCA carrier patient or a patient with limited time before receiving a gonadotoxic cancer treatment may consider is IVM, which is no longer considered experimental.[22] IVM is the process in which immature oocytes in the germinal vesicle or metaphase I stage are matured in the laboratory setting. Patients considering in vitro maturation should be counseled that there is a lower associated pregnancy rate compared to conventional IVF.[22]

Other Issues

Fertility preservation options specific to postpubertal men with a new cancer diagnosis include sperm cryopreservation before initiation of chemotherapy. Preferably two to three samples should be obtained. A male may be unable to ejaculate via masturbation for various reasons, including pubertal status, anxiety, hypogonadism, medications such as antidepressants and opioids, medical comorbidities such as diabetes, or neurologic issues, and underlying cancer.[13] 

In these circumstances, phosphodiesterase type 5 inhibitors, which are typically used to treat erectile dysfunction, may be used to help obtain a semen sample if there are no contraindications.[23] Additionally, penile vibratory stimulation can be used, which helps to trigger the ejaculatory reflex in a noninvasive manner. If penile vibratory stimulation fails, electroejaculation is another option that uses a transrectal probe and is typically performed with anesthetics.[24] 

Men may also experience retrograde ejaculation if they have diabetes, take antidepressant and antipsychotic medications, or have had prior surgery to the prostate or a retroperitoneal lymph node dissection. First-line treatment in these patients is the use of an alpha-agonist to restore antegrade ejaculation by tightening the muscles at the bladder neck and preventing semen from traveling into the bladder. If men have contraindications or fail to respond to alpha-agonists, another option is to alkalinize and collect the urine for processing viable sperm.[25] 

Additionally, there is the option for TESE with subsequent IVF or ICSI, as mentioned previously. In prepubertal boys, testicular tissue cryopreservation is still considered experimental and must be performed in the setting of a clinical trial.

Enhancing Healthcare Team Outcomes

Interdisciplinary teamwork is important with fertility preservation. In cases where a patient is diagnosed with cancer, collaboration amongst the oncologist and reproductive specialists is key. The American Society of Clinical Oncology released an updated guideline in 2013 stating that oncologists should address the possibility of infertility with their patients before cancer therapy is initiated and should refer the patient to reproductive endocrinologists.[26] [Level 2] 

In cases of elective fertility preservation, the reproductive endocrinologist needs to collaborate with the primary care physician. It is also important for the financial department to determine the funding for the patient through insurance or organizations that donate to patients with a diagnosis of cancer.