2015 Group Project 5

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2015 Student Projects 
2015 Projects: Three Person Embryos | Ovarian Hyper-stimulation Syndrome | Polycystic Ovarian Syndrome | Male Infertility | Oncofertility | Preimplantation Genetic Diagnosis | Students
2015 Group Project Topic - Assisted Reproductive Technology
This page is an undergraduate science embryology student and may contain inaccuracies in either description or acknowledgements.

Oncofertility

Oncofertility refers to the medical field that bridges the specialties of oncology and reproductive endocrinology with the purpose of maximizing the reproductive potential of cancer patients and survivors.

Infertility

Infertility refers to an inability to conceive after having regular unprotected sex. Infertility can also refer to the biological inability of an individual to contribute to conception, or to a female who cannot carry a pregnancy to full term [1] .

Sexual dysfunction is a common consequence of cancer treatment, affecting at least half of men and women treated for pelvic malignancies and over a quarter of people with other types of cancer. Problems are usually linked to damage to nerves, blood vessels, and hormones that underlie normal sexual function.Innovations in cancer treatment such as robotic surgery or more targeted radiation therapy have not had the anticipated result of reducing sexual dysfunction [2] .Some new and effective cancer treatments, including aromatase inhibitors for breast cancer or chemoradiation for anal cancer also have very severe sexual morbidity.Men frequently have erectile dysfunction (ED) related to damage to the autonomic nervous system and/or reduced circulation of blood to the penis. Hormonal impairment of sexual function is less common. Women, in contrast, are able to overcome damage to autonomic nerves if genital tissues remain structurally intact and estrogenized. Female sexual dysfunction is frequently associated with sudden premature ovarian failure or direct effects of radiation fibrosis or scar tissue causing pain with sexual activity [3] .


Beside Chemotherapy, other treatment can affect the ability to have a child such as targeted and biologic (immune) therapies, Bone marrow or stem cell transplant, Radiation therapy and surgery.

Targeted drugs

These drugs attack cancer cells differently from standard chemo drugs. Use of these medicines has increased a lot in recent years, but little is known about their effects on fertility or problems during pregnancy. Bevacizumab (Avastin) is one exception – studies have found that this drug can cause ovarian failure, and some women’s ovaries never recover. Another group of drugs that are of concern are targeted drugs called tyrosine kinase inhibitors (TKIs) such as imatinib (Gleevec), which cause birth defects in lab animals. At this time the recommendation is that women/men talk to their doctors before becoming pregnant while taking TKIs.

Bone marrow or stem cell transplant

This usually involves high doses of chemo and sometimes radiation to the whole body before the transplant. In most cases, this permanently stops a woman’s ovaries from releasing eggs and it prevents a man from making sperm.

Radiation

Radiation treatments use high-energy rays to kill cancer cells. Radiation works by damaging the genes (DNA) in cells. Genes control how cells grow and divide. When radiation damages the genes of cancer cells, they can’t grow and divide any more. Over time, the cells die. This means radiation can be used to kill cancer cells [4] .These rays can also damage a woman’s ovaries. For a woman getting radiation therapy to the abdomen or pelvis, the amount of radiation absorbed by the ovaries will determine if she becomes infertile. High doses can destroy some or all of the eggs in the ovaries and might cause infertility or early menopause. Even if the radiation is not aimed right at the ovaries, the rays can bounce around inside the body and might still damage the ovaries. When radiation is directed inside the vagina, the ovaries absorb a high dose of radiation. Radiation to the uterus can cause scarring, which restricts flexibility and blood flow to the uterus. These problems can limit the growth and expansion of the uterus during pregnancy, and increase the risk of miscarriage, low-birth weight infants, and premature births. Sometimes radiation to the brain affects the pituitary gland. The pituitary gland normally signals the ovaries to make hormones, so interfering with these signals can affect ovulation (the release of eggs from the ovaries). This might or might not affect fertility depending on the focus and dose of the radiation. Women may be fertile when they start getting radiation treatments, but it’s important not to become pregnant until treatment is completed because radiation can harm the fetus [5] . Radiation to a man’s testicles can affect his fertility. Radiation at high doses kills the stem cells that produce sperm.Radiation is aimed directly at the testicles to treat some types of testicular cancer and childhood leukemia for example seminoma, a type of cancer of the testicle, which involves radiation to the groin area, very close to their remaining testicle. Even when a man gets radiation to treat a tumor in his abdomen (belly) or pelvis, his testicles may still end up getting enough radiation to harm sperm production.Sometimes radiation to the brain affects the pituitary gland. The pituitary gland normally signals the testicles to make hormones, so interfering with these signals can affect sperm production and cause problems with fertility [5] ,[6] .


DNA-biological target of radiation.jpg

Image showing that the biological target of radiation in the cell is DNA [4] .


Surgery

Surgery on certain parts of the reproductive system causes infertility. For some cancers, a hysterectomy is part of the treatment. A hysterectomy is surgery to remove the uterus either through the vagina or through a cut made in the abdomen. Once the uterus is removed, a woman cannot carry a child.The ovaries might be removed (oophorectomy) at the same time the uterus is taken out. Without ovaries, a woman can’t get pregnant because she no longer has any eggs [7].In some women with early stage ovarian or cervical cancer, surgeons try to save one ovary, if possible, to preserve eggs, which might still allow a woman to become pregnant. Keeping at least one ovary also preserves the hormones that prevent menopause symptoms like hot flashes and vaginal dryness [7]. Some women with small cervical cancers can have a surgery called a trachelectomy, which removes the cervix but leaves the uterus behind so a woman can carry a pregnancy. Sometimes surgery can cause scarring in the fallopian tubes. These scars may block the tubes and prevent eggs from traveling to meet the sperm. This means they can’t become fertilized and move on to the uterus to implant in the lining. This is similar for men as well as surgery on certain parts of the reproductive system can cause infertility. These following surgery can cause infertility in men:

Surgery for testicular cancer The surgical removal of a testicle or orchiectomy is a common treatment for testicular cancer.As long as a man has one healthy testicle, he can continue to make sperm after surgery. (Less than 5% of men develop cancer in both testicles.) But some men with testicular cancer have poor fertility because the remaining testicle is not truly normal [8] .

Testicle removal (both testicles) for prostate cancer Some men with prostate cancer that has spread beyond the nearby area may have both testicles removed to stop testosterone production and slow the growth of prostate cancer cells. This is called a bilateral orchiectomy. These men cannot father children unless banked sperm before surgery [9] .

Surgery to remove the prostate (radical prostatectomy) For men who have prostate cancer that has not spread beyond the gland, surgery to remove the prostate gland and seminal vesicles is one of the treatment options. The prostate and seminal vesicles are the parts that produce semen. Whether the prostate is removed through a cut in the abdomen (belly) or in the perineum (the area behind the testicles and in front of the anus), this surgery leaves men with no semen. Surgery to remove the prostate also can damage the nerves that allow a man to get an erection, causing erectile dysfunction (ED). This means he cannot get an erection sufficient for sexual penetration. Even If the person can get an erection, if there’s no semen coming from the penis during orgasm. Therefore, he cannot conceive a child during sex [10] .

Surgery to remove the bladder (cystectomy)

Surgery to treat some bladder cancers is much like a radical prostatectomy, except the bladder is also removed along with the prostate and seminal vesicles. The testicles still make sperm, but the vas deferens (the paths the sperm take to the urinary tube) are cut. With sexual stimulation, men can still have the feeling of orgasm, but no fluid comes out of the penis and the sperm cannot get out and as a result they cannot conceive a child during sex [11] .

Surgery that interferes with erection and ejaculation

A few types of cancer surgery can damage nerves that are needed to get an erection and ejaculate semen. They include removing lymph nodes in the pelvis, which may be part of the surgery for testicular cancer and some colon cancers. Nerves are often damaged when removing lymph nodes, and this can cause problems with erections and ejaculation. Sometimes surgery can completely paralyze the prostate and seminal vesicles, which normally squeeze and relax to move the semen as a man’s climax begins. After these operations, a man still makes semen, but it doesn't come out of the penis at orgasm (climax). Instead it either shoots backward into his bladder which is called retrograde ejaculation or does not go anywhere.In cases of retrograde ejaculation, medicines can sometimes restore normal ejaculation of semen. The seminal vesicles contract, the internal valve at the bladder entrance closes, and semen is ejaculated from the penis at orgasm. For example in the USA, ephedrine sulfate is the most common medicine used to restore normal ejaculation. Because it does not help everyone and may only work for a few doses, ephedrine sulfate is usually prescribed only for the fertile week of the woman’s cycle.To improve this condition several methods are available.Fertility specialists can gather sperm from these men using several types of treatments including, electrical stimulation of ejaculation or sperm aspiration surgery [12] ,[13] .

Fertility Drugs

Clomiphene or clomiphene citrate is recommended for those women with irregular ovulation which is the most fertility problems as a result of cancer therapy. This drug will reactivate the ovulation cycle.This drug acts as an inhibitor of the estrogen receptors in the brain. This blocking effect tricks the body into bumping up levels of two other hormones that are essential for ovulation. These two other hormones are: follicle-stimulating hormone (FSH) and luteinising hormone (LH).FSH causes the eggs to mature in the ovaries and make them ready for release. LH triggers the release of one or more mature eggs from the ovary follicles [14] .

Fertibella helps mothers to conceive their child in a natural. safe and easy way. Fertibella includes ingredient that are absolutely essential for a healthy and quick child conception, such as folic acid, progesterone, selenium and iron. Furthermore, Studies have shown that women who followed this treatment were 33 percent more successful within one month than the control group [15].

Follistim is used to treat infertility in women with ovulation problems, but do not have ovarian failure. Unlike the previous treatments that are to be administered orally, Follistim needs to be injected under the skin or into a muscle. The same product can be used to stimulate the production of sperm in men [15] .

Luteinising hormone (LH) and follicle-stimulating hormone (FSH) are types of gonadoptrophins. LH and FSH directly stimulate ovary to produce and mature eggs. Gonadotrophins are normally used for women with polycystic ovary syndrome (PCOS) who have not responded to other drugs or for women undergoing IVF. Gonadotrophins are also used for women donating their eggs and for egg freezing procedures [15] . Follicle stimulating hormone, can be taken as a course of injections over about 12 days. The injections cause ovaries to develop and mature egg follicles. The injections of FSH will be followed by a final injection of another hormone, called human chorionic gonadotrophin (hCG). hCG signals the release of egg (or eggs) after that they have just developed. while, Luteinising hormone stimulates the follicle to release the egg in a natural cycle, hCG is structurally similar to LH and has the same physiological effect on the ovaries causing final maturation and egg release [15] .

Risks of fertility drugs

Fertility drugs, like any drugs , come with potential risks and side effects such as drug reaction, Multiple births, Ovarian hyper-stimulation syndrome (OHSS), Birth defects , Ectopic pregnancy, Ovarian cysts and etc [16] .

Having a multiple birth is main health risk associated with fertility treatment. Mothers of multiples have more complications during pregnancy such as gestational diabetes , hypertension and miscarriages. One way to reduce the risk of multiple birth is to use single embryo transfer [16] .

OHSS – Ovarian Hyperstimulation Syndrome is a risk that is associated with fertility drug use and occurs when the ovaries become filled with fluid, which is then released into the uterus during ovulation.This release of fluid causes several complications including blood clots or kidney failure. This is due to taking mild fertility drugs such as clomiphene. One way to reduce this risk is to take a lower dose of fertility drugs and to monitor the fertility cycle closely [16] . Clomid (clomiphene) side effects are mild for most people. Because most of the estrogen receptors are blocked, this leads to some of clomiphene’s side effects like headaches, vaginal dryness and hot flashes. Most of the other side effects are caused by the ovaries becoming slightly enlarged [17] .

Ectopic pregnancy is a serious condition when an embryo implants outside the uterus, in the fallopian tube which is the most common site for this condition. Ectopic pregnancy can also develop in the ovary. It is important to note that the chances of an ectopic pregnancy would be higher in women having IVF, especially those with the problems affecting their tubes [16] .


Targeted Cancer Therapy Drugs

Chemotherapy

Chemotherapy is the use of anti-cancer drugs on the body to destroy and kill cancer cells. Chemotherapy can be applied with the use of only drug, or through a use of a variety of anti-cancer drugs at the same time, known as combination chemotherapy. The severity and types of anti-cancer drugs used is largely dependant on the type of cancer cells and degree of aggressiveness. Chemotherapy is also commonly used in conjunction with radiation therapy. [18]

Chemotherapy Treatment.jpeg

Chemotherapy drugs kill cells that are undergoing the process of dividing into 2 new cells – known as mitosis. Because cancer cells are rapidly dividing cells, and divide much more often then regular cells, they are more likely to be targeted and killed by the chemotherapy drugs. Each specific chemotherapy drug used kill cells in a different way, and the response is varied across the types of chemotherapy drugs. Some common mechanisms used to kill cancer cells are by damaging the part of the cell ‘s control centre that makes it divide – this often includes altering and/or disabling the checkpoint system in the cell cycle to ensure mitosis cannot complete. Other chemotherapy drugs work by interrupting the chemical processes involved in cell division. [19]


What are Cancer Cells?

Healthy, normal cells do not become aggressive cancerous cells instantly or overnight. The transformation into a cancer cell is a gradual and ongoing change in which these cells move further and further away from a healthy, regulated and functioning cell until they become their own functioning and active indestructible cell. [20]

Normal cells, in their functioning and division processes, respond to many signals and cellular checkpoints controlled by hundred of genes. These control mechanisms are in place to regulate the cells division, life span and growth – as well as preventing mutated or damaged cells from dividing and thus furthering damaged cells. When these checkpoints are not met, the result is chaos. Chromosomes may be lost, rearranged, or copied too many times, often giving the cell further ability to develop mutations. [21]

Cancer cells develop mutations in the genes that regulate the control checkpoints, according to findings from the Cancer Genome Project, most cancer cells possess over 60 mutations to their genome. Normal cells do, however often have multiple mutations and are still able to function normally – almost as if the mutation did not exist. It is thus the challenge for researchers to discover which mutations are the cause of the uncontrollable dividing. Often related to searching for a needle in a hay stack. [22]

Some mutations researches have discovered as common in developed cancer cells are the gene for the signaling protein Ras, as well as the tumor suppressor genes – the genes that suppress cell proliferation, such as the p53 gene.

Cancer cells originate in tissues and as they continue to grow and divide, they diverge further and further away from cell regulations and thus normal cell functioning. As they grow, these cells become increasingly resistant to the controls that maintain normal tissue, and as such, they divide increasingly more rapidly than their progenitors and become less dependent on signals from other cells. Allowing these cells to divide uncontrollably.

This uncontrolled cell division is problematic for the body because destructive and dangerous mutations cannot be prevented from spreading throughout the body like they would be in healthy cells.

Cancer cells, through their lack of functioning regulation and control genes, thus have the ability to evade programmed cell death – which normally would occur if a cell became abnormal or mutated. Making cancer cells ultimately immortal. They have the ability to escape destruction from the body’s defences and go on to develop their own blood supply and invade into other regions of the body – further spreading their cancerous capabilities. [23]

Cancer is uncontrolled cell growth – with the body being incapable of destroying these cells on its own accord. It is thus necessary to introduce external mechanisms, often vicious and aggressive, such as chemotherapy and radiation to kill these cells.

<html5media height="384" width="352">File:How Cancer Cells Divide.mp4</html5media> Click Here to play on mobile device

How Does Chemotherapy Work?

Chemotherapy used to treat cancer mainly uses drugs known as cytostatic, which aim to stop the uncontrollable dividing of cancer cells. There are a few different types of chemotherapy – all used aiming to achieve different outcomes in the treatment of cancer.


Curative Chemotherapy → The most popular type of chemotherapy used, and often tried first in many cases. This model of chemotherapy aims to eliminate all cancer cells and removes the cancer completely and permanently.
Adjuvant Chemotherapy → Is predominantly aimed at cancer cells that may be left in the body after surgery to remove a cancerous tumor has occurred, but the cells cannot be detected.
Neoadjuvant Chemotherapy →This type of chemotherapy typically is done before surgery. Some cancerous tumors are too big and complex to operate on, so patients with these types of tumors will undergo neoadjuvant chemotherapy to shrink the tumor as much as possible before surgery.
Palliative Chemotherapy → When it is no longer possible to remove all of the cancer cells from an individual, chemotherapy may still be used to reduce the extent of the symptoms, slow down the growth of the cancer and to avoid further complications. The use of palliative chemotherapy is often debated due to the side effects of chemotherapy being weighted against the benefit received from palliative chemotherapy, which in some cases can be almost none.


Methods of Administration

The most common method of administering chemotherapy is intravenously. Cytostatics can however be taken in a variety of forms, and often a combination of a range of different applications will be utilized for patients. Venous administration is useful, as the drug is in the bloodstream it is able to reach all parts of the body quicker - reaching cancer cells that may not have been detected in any examinations or tests.

Vein Administered Chemotherapy

Local chemotherapy is directed chemotherapy - where a drug may be administered directly to the affected region - for example the spinal canal, or skin cancers. This may be used if it is known that the cancer is isolated in one area (such as the skin) and can be managed with a direct application of the drug. Preventing unnecessary and extensive side effects on the body.

People who are receiving chemotherapy treatment over a long extended time period, may have a device known as a port set up. The port is a small device/container inserted under the skin and is connected to a major vein. The port then administers the drugs by easily connecting the drugs to the port - which saves the hassle and pain of finding a vein every time the administration of chemotherapy is required. It also prevents extensive damage to the veins.

Port Administered Chemotherapy

The port automatically closes when treatment is removed, and is easily re-opened when needed.


Chemotherapy usually operates in cycles.The patient is treated with the cytostatics at different intervals - based upon a variety of factors which influence the number and length of cycles, and the length of the interval between each cycle. These factors include;

- how long the effect of the drug will last
- how much time the body and its cells will need to recover
- the overall length of the treatment

These factors also largely will be influenced by the wishes and more general health of the patient, and the direction and guidance that the doctor thinks is best for the individual circumstance. The response of the tumor also is taken into consideration when administering and regulating the chemotherapy treatment. Blood tests and constant monitoring of the tumor allows medical professionals to see if or how much effect the treatment is having on the cancerous cells.

Types of Chemotherapy Drugs

There are various types of chemotherapy drugs, all used for different purposes and often specific to a certain type of cancer or certain type of patient. They are often divided into several groups based on how they work, their chemical structure, and their relationship to another drug. Cancer drugs are not however limited to one type of group, and often work in various ways and as such will belong to many groups. [24]

Groups of Chemotherapy Drugs

Alklyating Agents

Alkylating agents work on cancer cells by directly damaging the DNA to prevent the cell from reproducing and dividing. The drugs work in all phases of the cell cycle and can be used to treat a wide variety of cancers, including leukemia, lymphoma, Hodgkin disease, multiple myeloma, and sarcoma, as well as cancers of the lung, breast, and ovary. Alkylating agents are the first class of chemotherapy drugs to be used and have been used to treat cancer since as early as the 1940s. [25]

Alkylating agents have 3 different mechansims of operation, however all function to achieve the same result - the disruption of the cell's DNA, preventing replication and thus causing cell death.

- In the first mechanism, an alkylating agent will attach an alkyl group - a small carbon compound - to the bases of the DNA. This attachment results in a fragmentation of the DNA as repair enzymes attempt to remove/replace the alkylated bases. The alkylated bases prevent DNA synthesis and RNA transcription in the affected area - thus limiting the cell's ability to divide.
- The second mechanism in which the drug can operate causes DNA damage through the formation of cross bridges - bonds formed between atoms in the DNA. 2 bases are linked together by an alkylating agent which has 2 DNA binding sites. These bridges prevent the DNA from separating for synthesis or transcription thus preventing its life.
- The third mechanism of function sees alkylating agents induce the mis-pairing of nucleotides in the DNA, leading to mutations. Normal DNA helix’s have permanent base pairings; A pairs with T, G pairs with C. An alkylated DNA strand can have G bases erroneously pair with T bases. This altered pairing can lead to permanent mutations and the cells death. [26]

The different classes of drugs that alkylating agents are divided into include; [27]

- Nitrogen mustards: such as mechlorethamine (nitrogen mustard), chlorambucil, cyclophosphamide (Cytoxan®), ifosfamide, and melphalan
- Nitrosoureas: such as streptozocin, carmustine (BCNU), and lomustine
- Alkyl sulfonates: busulfan
- Triazines: dacarbazine (DTIC) and temozolomide (Temodar®)
- Ethylenimines: thiotepa and altretamine (hexamethylmelamine)


Antimetabolites

Antimetabolites function by interfering or disrupting the DNA and RNA growth by substituting out the normal building blocks of the DNA. Metabolite is a general term used for the organic compounds that are synthesised, broken down in cells or recycled during metabolism. Examples of metabolites can include vitamins and amino acids, as well as urea - waste which is excreted (as urine).

Antimetabolites are similar in structure to metabolites but they cannot be used in the body in a productive way. Antimetabolites in a cell are mistaken for metabolites, and as such are processed in a manner analogous to the metabolite they resemble. The presence of the antimetabolite however, instead of a metabolite, prevents the cell from carrying out vital functions that allow the cell to grow and survive. The antimetabolites interfere with the production of the nucleic acids in the RNA and DNA - and as new DNA cannot be made, the cell will be unable to divide.

Antimetabolites operate in the S phase of the cell cycle, when the cell's chromosomes are being copied. Antimetabolites are mainly used to treat cancers such as leukemias, cancers of the breast, ovary and the intestinal tract.

Some common antimetabolites include;

- 5-fluorouracil (5-FU)
- 6-mercaptopurine (6-MP)
- Capecitabine (Xeloda®)
- Cytarabine (Ara-C®)
- Floxuridine
- Fludarabine
- Gemcitabine (Gemzar®)
- Hydroxyurea
- Methotrexate
- Pemetrexed (Alimta®)5-fluorouracil (5-FU)
- 6-mercaptopurine (6-MP)
- Capecitabine (Xeloda®)
- Cytarabine (Ara-C®)
- Floxuridine
- Fludarabine
- Gemcitabine (Gemzar®)
- Hydroxyurea
- Methotrexate
- Pemetrexed (Alimta®)


Anti-tumor antibiotics

These drugs, although named antibiotics, do not function like regular antibiotics used to treat infections. Anti-tumor antibiotics also function by altering and disrupting the DNA of cells to stop it dividing and surviving. The main group of anti-tumor antibiotics are anthracyclines, however other used anti-tumor antibiotics include;

- Actinomycin-D
- Bleomycin
- Mitomycin-C
- Mitoxantrone (also acts as a topoisomerase II inhibitor)


Anthracyclines
Anthracyclines are anti-tumor antibiotics that interfere with the enzymes involved in DNA replication. The drugs work in all phases of the cell cycle and can be used for a wide variety of cancer types.
Anthracyclines operate similiary to other replication inhibiting drugs by intercollating base pairs of the DNA. Anthracycline also largely functions by interfering with the enzyme topoisomerase II which relax's supercoiled DNA for replication.
Anthracycline is one of the most effective chemotherapy drugs used, however it has severe adverse effects, including major cardiotoxicity, which greatly limits its usefulness.


Examples of Anthracyclines include;
- Daunorubicin
- Doxorubicin (Adriamycin®)
- Epirubicin
- Idarubicin


Topoisomerase inhibitors These type of drugs inhibit the function of the enzyme topoisomerase (I and II). Some Anthracyclines will also belong to this category. Topoisomerase are enzymes that regulate the unwinding and rewinding of DNA during replication and synthesis.


Topoisomerase I

Most, if not all topoisomerase I inhibitors are derived from the plant extract camptothecin (http://theoncologist.alphamedpress.org/content/2/6/359.full)


Mitotic inhibitors

Mitotic inhibitors are derived from natural products and often are plant alkaloids and other products. The drugs prevent mitosis in the M phase of the cell cycle, but also have the ability to damage the cell in all cycles by hindering enzyme's production of proteins needed for cell replication. Mitotic inhibitors disrupt mitotic spindle assembly as the include microtubule toxins such as taxol, taxanes and vinca alkaloids (all of which prevent spindle formation). These drugs prevent the cell from carrying out replication and thus cause the cell to die.

These drugs can be used for a variety of cancers, including breast, lung, myelomas, lymphomas, and leukemias, however the drugs have been known to cause nerve damage - which often limits the amount of usage, and hence the effectiveness of the drug.

Some examples of Mitotic Inhibitors include;

- Taxanes: paclitaxel (Taxol®) and docetaxel (Taxotere®)
- Epothilones: ixabepilone (Ixempra®)
- Vinca alkaloids: vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®)
- Estramustine (Emcyt®)


Corticosteroids

Cortisol is a natural compound formed in the body by the adrenal gland and is essential for life. Cortisol helps maintain Blood Pressure, control the body's inflammatory processes and the immunes response. The release of cortisol from the adrenal glands is regulated by the pituitary gland. Corticosteroids are synthetic cortisol-like compounds that can be used to manage and treat a variety of different issues in the body. When used to treat cancer patients they are considered to be a chemotherapy drug. Corticosteroids help to control and regulate;

- how the body uses food to produce energy
- the balance of salt and water
- regulating blood pressure
- reducing inflammation and allergies
- controlling mood and behaviour

The corticosteroid used in cancer treatment is beneficial as it can reduce inflammation as well as the immune response (in reaction to the aggressive cancer drugs), it helps to relieve sickness and boosts the appetite of patients.

Some common corticosteroids used during cancer treatment include;

- Prednisone
- Methylprednisolone (Solumedrol®)
- Dexamethasone (Decadron®).

Unique Chemotherapy Drugs

How Does it Effect the Cancer Cells?

Side Effects of Chemotherapy

Chemotherapy Side Effects

The common downside or obstacle of treating cancer cells effectively is current chemotherapy treatments operate with severe side effects. Cytostatic's function not only by killing the cancer cells, but healthy cells that may divide quickly. It is very common for healthy, and often extremely necessary cells to become killed and attacked in the process. Some cells commonly destroyed while a patient undergoes chemotherapy treatment includes hair cells, blood producing cells, cells lining mucous membranes including areas of the pharyngeal region and the digestive system.

This can lead to short term effects including hair loss, anemia, nausea, vomiting, diarrhea and infections in the mouth. Chemotherapy largely does leave a patient exposed to a wide region of adverse effects and complications that may arise as a result of the compromised system. Patients have to undergo careful and systematic monitoring of their health, limiting any further issues as best as possible.

The severity of chemotherapy side effects varies considerably from person to person, and depending on the type of drug used. Every case must be dealt with individually.

Chemotherapy's long term side effects often will not be seen until slightly after treatment has commenced, including effected oocytes or spermatozoa.

Fertility preservation

As discussed previously, cancer and cancer treatments are a cause of lost fertility. Fertility is important among many men and women and as a result there are various fertility preservation techniques being study and implemented to help patients. The most common fertility preservation techniques involve the use of artificial reproductive technologies.

Fertility preservation in women

Fertility preservation options available for females include:

Before Treatment

During Treatment

After Treatment

oocyte freezing
Fertility-sparing surgical

procedure for certain women

with ovarian cancer
Adoption
Embryo freezing
GnRH treatment
Donor eggs
GnRH treatment
Oral contraceptive (birth control pill) treatment
Donor embryos
Oral contraceptive (birth control pill) treatment
Ovarian shielding
Natural pregnancy
Ovarian tissue freezing
Radical trachelectomy (for

certain women with cervical

cancer)
Surrogacy
Ovarian transposition
-
Using own frozen eggs
-
-
Using own frozen embryos
-
-
Using own frozen ovarian tissue

Laparoscopic Ovarian Suspension Before Irradiation: In many patients the use of radiotherapy is an essential part of treatment. The effect of radiotherapy on fertility depends on the location and extent of the disease as well as the dose of radiation being administered. It is especially detrimental to fertility in women with genitourinary or low intestinal tumours. To preserve fertility doctors may perform ovarian transposition by laparotomy to an extrapelvic site where radiation can be avoided. [28]

Ovarian Suppressor agents: This is also called " GnRH agonist treatment". As mentioned previously, chemotherapy treatment in cancer patients is involved in decreased fertility in women. In an analysis by Clowse et al. (2009) is was found that patients on GnRH agonists during chemotherapy had improved ovarian function and therefore an increased ability to get pregnant after chemotherapy. Therefore, the aim of this treatment is to shut down the ovaries during cancer treatment to help protect them from the damaging effects of treatment. The reduces the activity in the ovaries during treatment and will reduce the number of eggs that are damaged, so women will have normal menstrual cycles after treatment. [29] . Gonadotropin-releasing hormone (GnRH) agonist is a long acting hormone drug that can be used to make a woman go into menopause for a short period of time. GnRH treatment is given each month the whole time a woman is getting the cancer treatment. Studies explain that this method of treatment would help prolong fertility in some women, especially those with 35 years old and younger, but results are not clear and more research is needed to prove it works. If this treatment is used, it’s best done with a back-up method of preserving fertility like embryo freezing [30] .

Oocyte Freezing: This recommended for teenagers or adults without a stable partner. As in the previous case, the ovaries are stimulated and oocytes harvested and then frozen for future use where ICSI can be used again.


Embryo Freezing: or embryo cryopreservation, is the most common and successful method for preserving women's fertility. This is considered the better option for women who are married or in stable relationships. In this process the ovaries are stimulated to form mature oocytes with gonadotropins. The oocytes are aspirated and fertilized with their partner’s sperm through ICSI or can be fertilized in the lab through IVF (vitro fertilization) [31]. The process of collecting eggs for embryo freezing is similar to egg freezing where under light anesthetic, eggs are collected during surgery. With the use of ultrasound mature eggs in the fluid follicles can be seen. Therefore a needle is placed in the upper vagina and guided into each follicle to collect the eggs. The eggs are fertilized, then frozen and stored. As each egg produces a single embryo at best, thus women will have a better chance of a successful pregnancy if several embryos are stored. Hormones play an important role in maturation of several eggs at once. This means, in most women starting a cycle of hormone shots within 3 days of starting their menstrual cycle and continuing them for 2 to 3 weeks until many eggs are mature. However, in women with fast-growing cancers is not possible to wait 2 to 3 weeks to begin treatment. In this case, women with breast cancer may increase the growth of their tumors during IVF cycles due of the high levels of estrogen caused by the hormone shots. Therefore, one of the best option is "natural cycle IVF" with having ultrasounds to follow the progress of normal ovulation, and one or sometimes two eggs can be collected. Second option for group of women with breast cancer is to use drugs such as aromatase inhibitors or tamoxifen during the hormone stimulation to keep the estrogen from helping cancer cells to grow. Although more research is needed in this field but results show that this does not have any harmful effects on women’s breast cancer treatment or survival [32] , [33] .


Ovarian tissue storage: In this technique, laparoscopy is used to take a biopsy of the ovary or to completely remove the ovary for preservation. The most follicles are found in the cortical tissue which is made into strips and cryopreserved. Once the patient is free from cancer, the thawed strips can be transplanted back into the patient’s ovary via grafting, or in the case of autotransplantation, the tissue is reimplanted into a different pelvic site, or extrapelvic site e.g. the forearm or abdominal wall. In the later case, pregnancy is only achieved via oocyte harvesting followed by IVF. Whole ovary transplantation is more difficult and requires immediate revascularisation. [28]

Fertility-sparing surgery

Fertility sparing surgery is used for young women with with ovarian cancer in only one ovary. It also can be used for females with genital cancer and breast cancer [34] . This type of the cancer must be slow growing type of cancer and less likely to spread all over the body such as borderline, low malignant potential, germ cell tumors, or stromal cell tumors. Thins typically includes grades 1 and some grade 2 epithelial ovarian cancers .In this situation, surgeons remove just the ovary with cancer and leaving the healthy ovary and the uterus in place. Studies have shown that this does not affect long-term survival, and allows future fertility. The remaining ovary should be removed later if there is a risk of recurring cancer. This can be done after the woman has finished having children [35] .

Natural pregnancy

Women's body may recover naturally to produce mature eggs that can be fertilized after different cancer treatment. Doctors recommend women to wait anywhere from 6 months to 5 years getting pregnant. This is due to the risk of the cancer recurring in the first 2 to 5 years after treatment. It is important to consider that this length of time depends on the type and treatment of the cancer. Group of women with chemo or radiation to the pelvis are also at risk for sudden and early menopause even after they start having menstrual cycles again. Menopause can start 5 to 20 years earlier than expected.

Fertility preservation in men

Depending on the sexual maturity of a male, different fertility preservation options may be prescribed:

Before Treatment

During Treatment

After Treatment

Sperm banking
Radiation shielding
Adoption
Testicular sperm extraction

(TESE) or epididymal sperm

aspiration
-
Collecting sperm from urine
Testicular tissue freezing
-
Donor sperm
-
-
Natural pregnancy
-
-
Electro-ejaculation
-
-
Using banked sperm
-
-
Testicular sperm extraction

(TESE) or epididymal sperm

aspiration


Sperm Banking - This is usually the first choice for males who are still capable of producing semen. However, this strategy isn't suitable for all patients as most males will not produce sperm suitable for cryopreservation until the age of about 12-13 [28]. This technique is a well-established method, easy and successful way for those who have gone through puberty to store sperm. This method is usually used for men before cancer treatment,but it can be an option for many men if they have reduced sperm quality or quantity. Once the sperm bank obtains the sample, they test it to see how many sperm cells it contains (sperm count), what percentage of them are able to swim (motility), and how many have a normal shape (morphology). The sperm cells are then frozen and stored. Sperm Banking is a suitable option for men interested to have children after completing cancer treatment and they can decide later to use it ,discard it or donate it for research [36] . There are some limitations for Sperm Banking such as Fast-growing cancers, Infectious diseases associated with sperm banking and Costs. For the fast-growing cancer like acute leukemia (AML or ALL), the patient may be too ill or may not have time to store semen samples before starting cancer treatment.

Electro-ejaculation is still an experimental procedure and used when a male still makes semen, but it doesn't come out of the penis at orgasm (climax), due to some of the cancer treatments. In this technique a prob is placed into the rectum and a low electrical voltage stimulates ejaculation. Semen collected from Electro-ejaculation can be used for intrauterine insemination or IVF [37] .

Collecting sperm from urine is used when the the nerves that are necessary to ejaculate semen or close the valve at the bottom of the bladder are damaged during cancer surgery. In this case, a male still makes sperm but it does not come out of the penis at orgasm and it goes backward into the bladder which is know as "retrograde ejaculation". Therefore, fertility specialists collect sperm from the urine of these men and use them to fertilize their female partner’s eggs in the lab through IVF (vitro fertilization) [38] .

Testicular biopsy - This process is suitable for boys who have not yet undergone puberty and therefore spermatogenesis. Spermatogonia are then preserved through cryopreservation.

Through cryopreservation sperm may be stored indefinitely within liquid nitrogen at a fee. After each of these methods, the spermatozoa which has been collected can be used when the patient is ready to conceive for Intracytoplasmic Sperm Injection (ICSI), Artificial insemination or in the use of IVF. [28]

Adoption is an option to approach the issue of parenting a child. Adoption takes place through public agencies or by a private arrangement or even internationally by these public agencies. Most of these organisations do not exclude cancer survivors as potential parents but they need a letter from their doctor stating their healthy lifespan. Some agencies require a period of being off treatment and cancer-free before a cancer survivor can apply for adoption. Costs of adopting vary greatly from $4,000 (for a public agency) up to $50,000 ( some international adoptions).

Sperm donors or Donor insemination (DI) is the process of conceiving a baby using donated sperm. Donated sperm can be used in intrauterine insemination (IUI) or IVF. This is similar to donated eggs which can be used in either in vitro fertilisation (IVF) or intra-cytoplasmic sperm injection (ICSI) [39] . Donor insemination is very simple and least expensive way for those men who are infertile after cancer treatment to become a father. Most of organisations only collect sperm from young men with standard physical health, family health history, educational and emotional history, and even some genetic testing. These sperm donors are also examined for sexually transmitted diseases, including HIV (the virus that causes AIDS) and the hepatitis B and C viruses. Sperm donors might remain anonymous or can be in contact with the child later in life . The cost of donor sperm varies. The averages is between $200 to $700 a sample, which this does not include the cost of the insemination or hormones for the woman.

intrauterine insemination is a laboratory procedure for separating fast-moving sperm from more sluggish or non-moving sperm. IUI can only begin if it has been confirmed that fallopian tubes are open and healthy [39] . In this process, the purified sperm sample is put right into the woman’s uterus through a tiny, flexible tube. Several hormones can be prescribed by doctors to mature more than one egg, which will increase the chance of a pregnancy.

Radiation shielding Fertility can be protected in men and women who are getting radiation treatments that focus harmful rays on areas of the body. A lead barrier, or shield, can be placed over the patient's body to keep harmful radiations from affecting the pelvis, testicles and ovaries. Therefore, ovarian shielding preserves ovarian function and does not appear to increase the risk of damage. Risk of harming the sperm for those men getting radiation to the areas near testicles is uncertain, thus doctors suggest men to avoid getting a woman pregnant during and for some weeks after radiation treatment. [5]

Testicular sperm extraction and epididymal sperm aspiration

Epididymal sperm aspiration and testicular sperm extraction (TESE) are experimental fertility options for collecting sperm in men who do not have mature sperm cells in their semen, after cancer treatments. In epididymal sperm aspiration, a tiny opening is made in the epididymis and sperm are taken out with a needle. In TESE, tiny pieces of tissue are removed from the testicles and checked for sperm cells. With either technique, if mature sperm are found, they can be used for IVF-ICSI or frozen for future use [40] .

Testicular tissue freezing

This is also an experimental procedure for young boys who have not reached puberty. This is the only options for young boys as there are no proven fertility preserving methods for them yet. In this method, sample tissue from the testicles is collected with a thin needle by a surgery procedure. The tissue removed will contain stem cells that will later produce mature sperm. The tissue is frozen in order to use in future to treat infertility. The thawed tissue can be implanted to the young men's testicles or stem cells might be taken out and injected into their testicles, which might allow them to make their own sperm. The only concern with this procedure is that the tissue removed from a boy with cancer before treatment could re-introduce cancer cells and cause a disease again [41] , [42] .

Natural impregnation

A man can make a woman pregnant both during and after cancer treatment. But during and for some time after treatment, a man’s sperm may have a higher risk of genetic damage. Doctors recommends to wait anywhere from 1 to 5 years before trying to have a child.The exact length of time is not known and depends on the type and treatment of the cancer [43] .


Artificial Insemination

Artificial insemination, also known as Intra-Uterine Insemination (IUI) involves the placing of sperm within the uterus with the use of a plastic catheter. A patient is usually monitored for ovulation onset through hormone levels and ultrasound of the ovaries for the crucial time of sperm deposition. By increasing the number of sperm in the uterine cavity, and bypassing poor ejaculation the chance of pregnancy is increased by 2 to 3 fold. Furthermore, the chance for pregnancy is further enhanced by combining IUI with controlled ovarian hyper-stimulation. [44]

In-Vitro Fertilisation

In-Vitro Fertilisation (IVF) refers to the fertilisation of an oocyte outside of the body within glass tubes. Other IVF related procedures include Intracytoplasmic Sperm Injection (ICSI), In Gamete Intra-Fallopian Transfer (GIFT), Zygote Intra-Fallopian Transfer (ZIFT).

The flow chart below lists the main steps involved in the IVF process:

IVF flow chart.png

IVF Procedure[44]

Intracytoplasmic Sperm Injection

In Intracytoplasmic Sperm Injection (ICSI) a single sperm is chosen, and then inserted into an oocyte to fertilise it through the use of a needle as depicted in the image A below. Once the oocyte is fertilised it is cultured and the blastocyst as in image B is transferred into the woman's uterus as in the case of IVF.[44]

ICSI of marmoset oocytes.jpeg

ICSI of marmoset oocytes[45]

PMID 24751978

In Gamete Intra-Fallopian Transfer

In Gamete Intra-Fallopian Transfer (GIFT) involves placing mature oocytes and sperm in the fallopian tube unfertilised where they can undergo natural fertilisation in the natural location.[44]

Zygote Intra-Fallopian Transfer

Zygote Intra-Fallopian Transfer (ZIFT) combines both the standard IVF procedure and GIFT technique by fertilising the oocyte In-Vitro and then placing the embryo in the fallopian tube to take it's natural course towards implantation. [44]

Fertility preservation counselling

While there are various fertility preservation options available, it does not indicate whether they are being regularly implemented in medical practice. In a study by Reynolds et al. (2015) endocrinologists were surveyed with a 36 item survey to determine fertility preservation practice for cancer patients.

They found that 98% of endocrinologists who responded were counseling women diagnosed with cancer about the fertility options available. Cryopreservation of oocytes and embryos was the most common, offered by all providers, however managed differently. For example, in women with breast cancer, 86% of respondents used letrozole in the women positive for estrogen receptor breast cancer, when undergoing controlled ovarian stimulation (COS). This is essential in minimizing exposure to estrogen. Men were also managed differently among practioners, 86% were informed about sperm banking, and 22% were advised against it if they had already undergone rounds of chemotherapy.[46]

Through this study, it is evident that awareness in fertility preservation is increasing and improving. However, it is clear not all patients are advised in a universal manner.


Oncofertility limitations

Oncofertility timeline

References

  1. MNT, [ http://www.medicalnewstoday.com/articles/165748.php ], 'What is infertility? What causes infertility? How is infertility treated?'
  2. <pubmed>26217165</pubmed>
  3. <pubmed>16304430</pubmed>
  4. 4.0 4.1 <pubmed>22408567</pubmed>
  5. 5.0 5.1 5.2 <pubmed>8243379</pubmed>
  6. Medical Research Council, Radiobiology Unit, Harwell, Didcot, Oxon, [ http://www.birpublications.org/doi/abs/10.1259/0007-1285-53-628-271 ], 'The influence of radiation on fertility in man'
  7. 7.0 7.1 <pubmed>15302291</pubmed>
  8. American Cancer Society,[ http://www.cancer.org/cancer/testicularcancer/detailedguide/testicular-cancer-treating-surgery ], 'Surgery for testicular cancer'
  9. WebMD,Prostate Cancer Health Center[ http://www.webmd.com/prostate-cancer/orchiectomy-surgery ], 'Orchiectomy for Prostate Cancer'
  10. American Cancer Society,[ http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-surgery ], 'Surgery for prostate cancer'
  11. Cancer Council NSW ,[ http://www.cancercouncil.com.au/58014/b1000/bladder-cancer-10/surgery-for-invasive-bladder-cancer/ ], 'Surgery for invasive bladder cancer'
  12. <pubmed>4068047</pubmed>
  13. American Cancer Society,[ http://www.cancer.org/treatment/treatmentsandsideeffects/physicalsideeffects/sexualsideeffectsinmen/sexualityfortheman/sexuality-for-men-with-cancer-ejaculation-and-treatment ], 'How cancer treatment can affect ejaculation'
  14. BabyCenter Australia Medical Advisory Board, [ http://www.babycenter.com.au/a6186/fertility-drug-clomiphene-citrate-clomifene-clomid ], 'Fertility drug: clomiphene citrate (clomifene, clomid)'
  15. 15.0 15.1 15.2 15.3 BabyCenter Australia Medical Advisory Board, [ http://www.babycenter.com.au/a4090/fertility-drugs-for-women ], 'Fertility drugs for women'
  16. 16.0 16.1 16.2 16.3 Human Fertilisation and Embryology Authority,[ http://www.hfea.gov.uk/fertility-treatment-risks.html#wrapper ], 'Risks of fertility treatment'
  17. about health, [1], 'Clomid (Clomiphene) Side Effects and Risks'
  18. Cancer Council Australia, 'Chemotherapy', 'Cancer Council of Australia - About Cancer', Friday June 5, 2015
  19. Cancer Research UK, ‘How Chemotherapy Kills Cancer Cells, ‘About Cancer’
  20. Science Museum, 'How Do Healthy Cells Become Cancerous?', 'Who am I?'
  21. Science Museum, 'How Do Healthy Cells Become Cancerous? - Missing Checkpoints', 'Who am I?'
  22. Scitable by Nature Education 'Cell Division and Cancer'
  23. Scitable by Nature Education 'Cell Division and Cancer'
  24. "Types of Chemotherapy Drugs", "American Cancer Society", 2, June 2015, Retrieved on 4 October 2015.
  25. "Types of Chemotherapy Drugs", "American Cancer Society", 2, June 2015, Retrieved on 4 October 2015.
  26. "A Closer Look at Mechanisms of Alkylating Agents", "CancerQuest - Emory University", 6 May 2013, retrieved on 4 October 2015.
  27. "Types of Chemotherapy Drugs", "American Cancer Society", 2, June 2015, Retrieved on 4 October 2015.
  28. 28.0 28.1 28.2 28.3 <pubmed>24669162</pubmed>
  29. <pubmed>19281314</pubmed>
  30. <pubmed>17462639</pubmed>
  31. IVF Australia , [ http://ivf.com.au/fertility-treatment/ivf-treatment/frozen-embryo-transfer#success-rates-with-frozen-embryos ],Freezing Embryos
  32. GENETICS and IVF institute, [ http://www.givf.com/fertility/embryofreezing.shtml ],Embryo Freezing (Cryopreservation)
  33. Advanced Fertility Center of Chicago,[ http://www.advancedfertility.com/cryo.htm ],Embryo freezing after IVF: Human blastocyst and embryo cryopreservation and vitrification
  34. <pubmed>26255458</pubmed>
  35. <pubmed>25628110</pubmed>
  36. Cancer Research UK, [ http://www.cancerresearchuk.org/about-cancer/coping-with-cancer/coping-physically/sex-sexuality-and-cancer/Sperm-collection-and-storage ], Sperm collection and storage (sperm banking)
  37. <pubmed>6451670 </pubmed>
  38. Memorial Sloan Kettering, cancer center, [ https://www.mskcc.org/cancer-care/patient-education/cancer-and-fertility-information-men ], Cancer and Fertility: Information for Men
  39. 39.0 39.1 Human Fertilisation and Embryology Authority,[ http://www.hfea.gov.uk/fertility-treatment-options-donor-insemination.html ], 'What is donor insemination (DI) and how does it work?'
  40. <pubmed>8671323</pubmed>
  41. <pubmed>21481372</pubmed>
  42. Fertility Center Mauritius,[ http://www.harleystreetfertility.com/en/testicular-tissue-freezing.html ], 'Testicular tissue freezing'
  43. American Society for Reproductive Medicine,[ https://www.asrm.org/FACTSHEET_Optimizing_Natural_Fertility/ ], 'Optimizing Natural Fertility'
  44. 44.0 44.1 44.2 44.3 44.4 <pubmed>23074488</pubmed>
  45. <pubmed>24751978</pubmed>
  46. <pubmed>26010087</pubmed>