Fertility preservation

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Fertility preservation is the effort to help cancer patients retain their fertility, or ability to procreate. Research into how cancer, ageing and other health conditions effect reproductive health and preservation options are growing. Specifically sparked in part by the increase in the survival rate of cancer patients. [1]

Contents

Indications

Fertility preservation procedures are indicated when it is predicted that there will be exposure to a cause of infertility, mainly cancer treatment but also ageing, sex reassignment surgery for those who identify as trans and conditions like Polycystic Ovary Syndrome (PCOS) or Primary Ovarian Insufficiency (POI).

Chemotherapy and radiotherapy

Chemotherapy and radiation treatments for cancer and autoimmunity conditions like Lupus [2] and Multiple Sclerosis [3] have the ability to affect reproductive health. The regimens that threaten ovarian and testicular function are mainly radiation therapy to the pelvic area and some types of chemotherapy. Chemotherapies with high risk include procarbazine and alkylating drugs such as cyclophosphamide, ifosfamide, busulfan, melphalan, chlorambucil and chlormethine. [4] Drugs with medium risk include doxorubicin and platinum analogs such as cisplatin and carboplatin. [4] On the other hand, therapies with low risk of gonadotoxicity include plant derivatives such as vincristine and vinblastine, antibiotics such as bleomycin and dactinomycin and antimetabolites such as methotrexate, mercaptopurine and 5-fluoruracil. [4]

These regimens attack rapidly dividing cells in the body, including healthy cells like sperm and those belonging to the ovarian follicle (egg). Depending on the dose and duration of administration, these therapies can have varying effects on reproductive health. [5] Surgery involving reproductive tissue affects reproductive function and fertility.

For some patients receiving chemotherapy or radiotherapy, the decrease or loss of reproductive function is temporary; many men and females, however, do not regain fertility after this treatment. The extent of the damage to ovaries resulting in diminished fertility can be associated with the chemotherapeutic regiment such as the combination of chemotherapy and radiotherapy (chemoradiation) where despite allowing a more effective treatment or reducing the risk of the cancer returning (adjuvant chemotherapy). [6] It has extensive associations with fertility damage than receiving either treatment individually. [7] Sometimes these patients experience symptoms resembling menopause (in females) or andropause (in men), which can indicate reproductive damage. In females this can be premature menopause of menopause in premenopausal women; this state can be permanent or reversible, dependent on many factors. [8]

A study indicated that fewer oocytes are recovered from cancer patients wanting to perform embryo preservation when compared with an age-matched control group, but the mean number of zygotes generated appears to be similar. [9] The same study found that, of 65 patients referred to the program, 28% declined to undergo embryo, oocyte, or tissue cryopreservation. 9% were found not to be eligible for medical reasons. Of the remaining 41 patients, 85% chose to cryopreserve embryos, 10% chose to cryopreserve oocytes, and 5% chose to undergo ovarian tissue freezing. [9] No serious clinical sequelae resulted from participation. [9]

Prior to females undergoing these treatments, a testing for the level of anti-Müllerian hormone (AMH) is useful in predicting the long-term post-chemotherapy loss of ovarian function, in turn predicting the need for fertility preservation strategies in the future. [10]

Ageing

Increasing age in females is directly associated with decreasing reproductive potential. This can be the result of many factors such as the amount of eggs available and their overall reproductive quality. [11] Fertility preservation, such as ovarian tissue or oocyte cryopreservation, may also be used to prevent infertility, as well as birth defects, associated with advanced maternal age.

Males also have decreasing fertility as they age, however this is associated with a problem in sperm quality as opposed to the overall sperm count. These changes can be attributed to the reduction in testosterone males experience when ageing. [12]

PCOS

Polycystic Ovarian Syndrome is the most prevalent endocrine disorder females experience during prime reproductive age.

PCOS has a direct relationship with many health risks such as the development of Type 2 Diabetes, increasing insulin levels, obesity and increased waist size. females with PCOS usually experience anovulation (where they will not regularly release an egg). The link between infertility and PCOS is well documented [13] and so females may therefore seek fertility treatment like ovulation induction. [14]

POI

Primary Ovarian Insufficiency is defined as when ovarian function is stopped prematurely (before the age of 40). This is also known premature ovarian failure or premature menopause. Ovarian deficiency causes a reduction in serum oestrogen levels which can lead to infertility, giving a reason for females to seek fertility treatment.

POI can result in a long term risk of serious physical symptoms including bone fragility and heart problems. It has also been linked to psychological distress specifically in regards to fertility loss and the long term consequences of that. [15]

Methods

The main methods of fertility preservation are ovarian protection by GnRH agonists, cryopreservation of ovarian tissue, eggs or sperm, or of embryos after in vitro fertilization. [16] The patient may also choose to use egg or sperm from a donor by third party reproduction rather than having biological children.

Semen cryopreservation

Men hoping to preserve their fertility before undergoing treatment for cancer or another fertility-threatening disease can cryopreserve, or freeze, their sperm, which can be obtained through masturbation in post-pubescent boys and men. This is the most established fertility preservation method for males. For pre-pubescent boys, sperm can be obtained through testicular aspiration or electrostimulation and then stored for future use. Researchers are also looking at methods for cryopreserving testicular tissue samples so that they can be re-implanted into the body after treatment.

Cryopreservation of ovarian tissue or oocytes

Oocyte cryopreservation

Oocyte cryopreservation involves the extraction and freezing of a female's eggs, to preserve their viability for future use. This is often due to medical reasons such as females undergoing cancer treatment. It is also increasingly being used for elective fertility preservation in females who are not ready to become pregnant but who are conscious of their age-related decline in fertility. [17] This process is different to embryo cryopreservation, where mature eggs are fertilised in vitro (outside the body) with sperm from a donor or partner, and the embryo is frozen. The religious and ethical concerns and legislative restrictions surrounding embryo cryopreservation has prompted significant technical advances in oocyte cryopreservation techniques. Oocyte cryopreservation is now considered a well-established technique for fertility preservation in women. [17]

Embryo cryopreservation

Some female patients choose to have mature eggs extracted and fertilized outside of the body with sperm from a partner or donor. The resulting embryo is then frozen until the female's is in remission from disease. When the female's is ready to initiate pregnancy, the embryo is thawed and implanted into the uterus for maturation and birth. While this option is the most common fertility preservation method in females, it is not available to pre-pubescent girls, who do not have mature eggs that can be fertilized. females who do not have a partner will need to use donor sperm. Additionally, because this procedure requires a two-week period of hormonal stimulation to encourage egg maturation, it is not optimal for female patients who are diagnosed with hormone-sensitive cancers (such as breast cancer, ovarian cancer, etc.) or those who cannot delay cancer treatment. Alternative methods of hormonal stimulation using letrozole or tamoxifen may be used for females with hormone-sensitive cancers.

Ovarian tissue cryopreservation

Cryopreservation of human ovarian tissue has been successfully carried out around the world to preserve fertility in female cancer patients and in other pathologies where the patient is at increased risk of primary ovarian insufficiency. Most notably, this technique can provide an option for fertility preservation in prepubertal girls. Part of the ovary is removed, frozen and stored until after treatment. The tissue is then thawed and re-implanted. [18] According to a meta-analysis performed in 2017, the success rate of reestablishment of ovarian activity was 63.9%, [19] restoring normal fertility and endocrine function. Over 130 live births have been reported as of June 2017. [20]

Strips of cortical ovarian tissue can also be cryopreserved, but it must be re-implanted into the body to allow the encapsulated immature follicles to complete their maturation. Furthermore, ovarian tissue is fragile under hard freezing conditions and putting it back into the body carries the risk of re-introducing cancerous cells. In vitro maturation has been achieved experimentally, but the technique is not yet clinically available. [21] With this technique, cryopreserved ovarian tissue could possibly be used to make oocytes that can directly undergo in vitro fertilization. [21]

Third-party reproduction

Many patients diagnosed with a malignancy or another disease requiring treatment that may impair their fertility consider alternatives to bearing biological children, such as assisted reproductive technology (ART) using in vitro fertilization (IVF) with donor eggs or donor sperm. The resulting embryo can be implanted into the female's's uterus after her endometrium (the lining of the uterus) is stimulated with hormones to prepare for the development of the embryo.

Others

In females requiring local pelvic radiation therapy may benefit from surgical transposition of the ovaries to a site remote from maximal radiation exposure. [22] [23]

The use of GnRH agonists for ovarian protection during chemotherapy is suggested to benefit the ability to ovulate, but benefits in terms of e.g. pregnancy rate are lacking. [22]

Table 1: Main Options of Fertility Preservation

MethodProcessAdvantages and DisadvantagesFurther Considerations
Oocyte cryopreservation
  • Halt GAHT (gender affirming hormone therapy) and carry out ovarian stimulation with transvaginal oocyte retrieval. [24]
  • Cryopreserve mature oocytes. [25]
  • No sperm necessary at time of retrieval, can be used later for fertilisation. [24]
  • Clinically available. [25]
  • Has to be carried out after puberty. [25]
  • Invasive procedure. [25]
  • Those with female partners, donor sperm may be required, the embryo can then be transferred to the partners uterus. [25]
  • Individuals with male partners can use partner's sperm but will need a surrogate to carry the embryo. [25]
Embryo cryopreservation
  • Halt GAHT and carry out ovarian stimulation to harvest oocytes. [24]
  • Fertilisation of mature oocytes and embryo cryopreservation. [25]
  • Clinically available. [25]
  • Need sperm at time of oocyte retrieval. [24]
  • Has to be carried out after puberty. [25]
  • Invasive procedure. [25]
  • Those with female partners donor sperm may be required, the embryo can then be transferred to the partners uterus. [25]
  • Individuals with male partners can use partner's sperm but will need a surrogate to carry the embryo. [25]
Ovarian tissue cryopreservation
  • Can be carried out at the same time as sex reassignment surgery. [25]
  • Surgical extraction of ovarian tissue for cryopreservation. [25]
  • Can be carried out before and after puberty. [24]
  • No sperm necessary at time of retrieval. [25]
  • Clinically available. [25]
  • Don't need to halt GAHT. [24]
  • Cryopreservation of either an ovarian cortex biopsy or the whole ovary, then the thawing and maturation of the follicles at a later date. [24]
  • Reimplantation of the tissue and the use of IVF. [25]

Adverse effects

Compared with the general population, people with cancer have a higher risk of arterial thrombotic events such as stroke, myocardial infarction and peripheral arterial embolism. This risk has a potential to be further increased in females undergoing controlled ovarian hyperstimulation for fertility preservation, but is usually only associated with cases of ovarian hyperstimulation syndrome (OHSS). On the other hand, venous thromboembolism rarely occurs unless a pregnancy is achieved, and is therefore usually not particularly relevant in the stage of oocyte retrieval. [26] Therefore, the recommended controlled ovarian hyperstimulation protocol for in females with cancer is an antagonist protocol using a GnRH agonist for final maturation induction, in order to decrease the risk of OHSS. [26] When used in conjunction with oocyte or embryo cryopreservation, using GnRH agonist rather than hCG for final maturation induction has no evidence of a difference in live birth rate (in contrast to fresh cycles where usage of GnRH agonist has a lower live birth rate). [27] Anticoagulant prophylaxis is recommended to be administered only to selected subgroups of females such as those with other risk factors of hypercoagulability or those who do develop early OHSS. [26]

Fertility preservation in transgender men

Transgender men should be given the opportunity to have counselling on preserving their fertility before undergoing any type of medical transition, otherwise they may be unable to have biological children in the future. [24] This is important as individuals may start their transition at a young age where they have no interest in future children, however half of adult trans men do wish to have children. [28] Suppressing puberty in paediatric patients does pause the development of fertility, however this is reversible. [29] Some fertility options in adults trans men present problems as they may require stopping hormone treatment for around 3 months  to carry out the procedure, [28] as well as multiple transvaginal ultrasounds (a probe entering and scanning the inside of the vagina) - both of which may be distressing for a transgender individual. [30] Various methods of fertility preservation are detailed in the table above.

Related Research Articles

<span class="mw-page-title-main">Ovary</span> Female reproductive organ that produces egg cells

The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus. There is an ovary found on the left and the right side of the body. The ovaries also secrete hormones that play a role in the menstrual cycle and fertility. The ovary progresses through many stages beginning in the prenatal period through menopause. It is also an endocrine gland because of the various hormones that it secretes.

<span class="mw-page-title-main">In vitro fertilisation</span> Assisted reproductive technology procedure

In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro. The process involves monitoring and stimulating a patient's ovulatory process, removing an ovum or ova from their ovaries and letting sperm fertilise them in a culture medium in a laboratory. After the fertilised egg (zygote) undergoes embryo culture for 2–6 days, it is transferred by catheter into the uterus, with the intention of establishing a successful pregnancy.

Cryobiology is the branch of biology that studies the effects of low temperatures on living things within Earth's cryosphere or in science. The word cryobiology is derived from the Greek words κρῧος [kryos], "cold", βίος [bios], "life", and λόγος [logos], "word". In practice, cryobiology is the study of biological material or systems at temperatures below normal. Materials or systems studied may include proteins, cells, tissues, organs, or whole organisms. Temperatures may range from moderately hypothermic conditions to cryogenic temperatures.

<span class="mw-page-title-main">Ovarian follicle</span> Structure containing a single egg cell

An ovarian follicle is a roughly spheroid cellular aggregation set found in the ovaries. It secretes hormones that influence stages of the menstrual cycle. At the time of puberty, women have approximately 200,000 to 300,000 follicles, each with the potential to release an egg cell (ovum) at ovulation for fertilization. These eggs are developed once every menstrual cycle with around 450–500 being ovulated during a woman's reproductive lifetime.

Fertility medications, also known as fertility drugs, are medications which enhance reproductive fertility. For women, fertility medication is used to stimulate follicle development of the ovary. There are very few fertility medication options available for men.

<span class="mw-page-title-main">Oocyte cryopreservation</span> Procedure to preserve a womans eggs (oocytes)

Oocyte cryopreservation is a procedure to preserve a woman's eggs (oocytes). This technique has been used to enable women to postpone pregnancy to a later date – whether for medical or social reasons. Several studies have shown that most infertility problems are due to germ cell deterioration related to aging. The procedure intends that the woman may choose to have the eggs thawed, fertilized, and transferred to the uterus as embryos to facilitate a pregnancy in the future. The procedure's success rate varies depending on the age of the woman, with the odds being higher in younger, adult women.

<span class="mw-page-title-main">In vitro maturation</span> Artificial maturation of harvested immature egg cells

In vitro maturation (IVM) is the technique of letting the contents of ovarian follicles and the oocytes inside mature in vitro. It can be offered to women with infertility problems, combined with In Vitro Fertilization (IVF), offering women pregnancy without ovarian stimulation.

<span class="mw-page-title-main">Cryopreservation</span> Process to preserve biological matter

Cryopreservation or cryoconservation is a process where biological material - cells, tissues, or organs - are frozen to preserve the material for an extended period of time. At low temperatures any cell metabolism which might cause damage to the biological material in question is effectively stopped. Cryopreservation is an effective way to transport biological samples over long distances, store samples for prolonged periods of time, and create a bank of samples for users. Molecules, referred to as cryoprotective agents (CPAs), are added to reduce the osmotic shock and physical stresses cells undergo in the freezing process. Some cryoprotective agents used in research are inspired by plants and animals in nature that have unique cold tolerance to survive harsh winters, including: trees, wood frogs, and tardigrades.

Ovarian tissue cryopreservation is cryopreservation of tissue of the ovary of a female.

Semen cryopreservation is a procedure to preserve sperm cells. Semen can be used successfully indefinitely after cryopreservation. It can be used for sperm donation where the recipient wants the treatment in a different time or place, or as a means of preserving fertility for men undergoing vasectomy or treatments that may compromise their fertility, such as chemotherapy, radiation therapy or surgery. It is also often used by trans women prior to medically transitioning in ways that affect fertility, such as feminizing hormone therapy and orchiectomies.

Cryopreservation of embryos is the process of preserving an embryo at sub-zero temperatures, generally at an embryogenesis stage corresponding to pre-implantation, that is, from fertilisation to the blastocyst stage.

<span class="mw-page-title-main">Oncofertility</span>

Oncofertility is a subfield that bridges oncology and reproductive research to explore and expand options for the reproductive future of cancer survivors. The name was coined in 2006 by Teresa K. Woodruff at the Oncofertility Consortium.

The Fertiprotekt network is a cooperation of university centres, hospitals and practices. It was founded in Germany in 2006. The network now extends to all German-speaking countries and currently units ca. 100 institutions in Germany, Austria and Switzerland.

Ovarian follicle activation can be defined as primordial follicles in the ovary moving from a quiescent (inactive) to a growing phase. The primordial follicle in the ovary is what makes up the “pool” of follicles that will be induced to enter growth and developmental changes that change them into pre-ovulatory follicles, ready to be released during ovulation. The process of development from a primordial follicle to a pre-ovulatory follicle is called folliculogenesis.

Cancer in adolescents and young adults is cancer which occurs in those between the ages of 15 and 39. This occurs in about 70,000 people a year in the United States—accounting for about 5 percent of cancers. This is about six times the number of cancers diagnosed in children ages 0–14. Globally, nearly 1 million young adults between the ages of 20 and 39 were diagnosed with cancer in 2012, and more than 350,000 people in this age range died from cancer.

Cryopreservation of testicular tissue is an experimental method being used to preserve fertility in pre-pubescent males, or males who cannot produce sperm, to allow them the option of having biological children.

<span class="mw-page-title-main">Artificial ovary</span>

An artificial ovary is a potential fertility preservation treatment that aims to mimic the function of the natural ovary.

<span class="mw-page-title-main">LGBT reproduction</span> Theoretical biological reproduction by LGBT people

LGBT reproduction refers to lesbian, gay, bisexual, and transgender (LGBT) people having biological children by means of assisted reproductive technology. It is distinct from LGBT parenting, which is a broader cultural phenomenon including LGBT adoption. In recent decades, developmental biologists have been researching and developing techniques to facilitate same-sex reproduction.

<span class="mw-page-title-main">Side effects of radiotherapy on fertility</span>

The side effects of radiotherapy on fertility are a growing concern to patients undergoing radiotherapy as cancer treatments. Radiotherapy is essential for certain cancer treatments and often is the first point of call for patients. Radiation can be divided into two categories: ionising radiation (IR) and non-ionising radiation (NIR). IR is more dangerous than NIR and a source of this radiation is X-rays used in medical procedures, for example in radiotherapy.

<span class="mw-page-title-main">Ovarian stem cell</span>

Ovarian stem cells are oocytes formed in ovarian follicle before birth in female mammals. They do not form post-natally, and are depleted throughout reproductive life. In humans it is estimated that 500,000–1,000,000 primordial follicles are present at birth, decreasing rapidly with age until roughly age 51 when ovulation stops, resulting in menopause. The origin of these oocytes remains under discussion. The publication of a study in 2004 proposing germ cell renewal in adult mice sparked a debate on the possibility of stem cells in the postnatal ovary. An increasing number of studies suggest that stem cells exist within the mammalian ovary and can be manipulated in vitro to produce oocytes, but whether such ovarian stem cells have the potential to differentiate into oocytes remains uncertain.

References

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  21. 1 2
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