{{ANAT2341Project2015header}}

='''Oncofertility'''=

[[File:Summary of Oncofertility.jpg|center|400px]]

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 is an adverse side affect of cancer and cancer treatment. Previously, this has been tolerated since the main concern was treating patients with the main goal being their survival. However, over the past decade more people have been surviving cancer, and concern for fertility has garnered greater attention as reproductive ability is considered an imperative for many. Thus came about the notion of Oncofertility as an attempt to spare or restore fertility function in men and women suffering from cancer. <ref name=consortium><pubmed>20498666</pubmed></ref>

='''Oncofertility timeline'''=

{| class="wikitable mw-collapsible mw-collapsed"
|- bgcolor="CEDFF2"
| '''Date'''
|| '''Event'''
|-
| 1838
|| Blastema Theory – Muller demonstrates that cancer contain cells. His student found the cells were derived from other cells.
|-
| 1846
|| Anesthesia invented, allowing doctors to remove entire tumors during surgery along with the lymph nodes. Later Paget (surgeon) reported cancers spread through metastasis
|-
| 1856
|| J. Marian Sims incised the cervix through surgery to make the opening larger to address infertility
|-
| 1878
|| Thomas Beatson finds by removing a rabbits ovaries, their breast stop producing milk. This lead to new hormonal drugs to treat prostate and breast cancer.
|-
| 1896
|| X-ray discovered by Roentgen. 3 years later, radiation used to diagnose and treat cancer.
|-
| Late 1800s to early 1900s
|| More doctors were using surgery to treat infertility and more women sought medical advice due to their inability to conceive. Success rates are unknown. Options available included unblocking fallopian tubes through surgery, artificial insemination (husband or donor sperm) or ovarian transplantation (grafting portion of fertile woman’s ovary into infertile woman).
|-
| 1915
|| Cancer induced in rabbits by applying coal tar to its skin. Now more than 100 carcinogens have been discovered.
|-
| 1940s
|| John Rock and Miriam Menkin fertilized four human eggs In Vitro
|-
| Mid 1900s
|| Scientists find cancer can be due to carcinogens, radiation, viruses or inherited. These can damage DNA.
|-
| 1960s
|| Mammograms develop to help detect breast cancer
|-
| 1970s
|| Scientists discover Oncogenes (cause uncontrolled cell growth) and Tumour Suppressor Genes (normally cause growth inhibition, when mutated lead to uncontrolled cell growth)
Medical imaging replaces explorative surgery.
|-
| 1978
|| First baby, Louise Brown is born through In Vitro fertilization
Alex Lopata in Australia stimulates ovarian cycles by using clomiphene citrate
|-
| 1980s
|| IVF is no longer experimental, and is now an accepted reproductive technique. First Australian IVF baby delivered, Candice Elizabeth Reed.
|-
| 1982
|| The first baby is born via Intrauterine Insemination. Media came into use for culturing embryos.
|-
| 1983
|| Pregnancies achieved by using donor oocyte, donor embryo, and frozen embryo. In-vitro maturation is introduced. Oocytes retrieved through vaginal route. Robert Casper and team use hCG to aid the luteal phase during assisted ovarian cycles.
|-
| 1984
|| First birth from a frozen embryo. First baby born through surrogacy.
|-
| 1986
|| First pregnancy from sperm surgically retrieved.
First pregnancy via Zygote intrafallopian transfer (ZIFT)
|-
| Late 1900s
|| Surgery, chemotherapy and radiation combined as appropriate approaches to treat cancer. More targeted cancer treatments came about such as growth signal inhibitors, apoptosis inducing drugs and endogenous angioinhibitors (first one not approved til 2004).
|-
| 1992
|| First pregnancy after Intracytoplasmic sperm injection (ICSI)
|-
| 1996
|| Successful pregnancy after the use of ICSI from cryopreserved sperm
|-
| 2000s
|| Antiangiogenic Chemotherapy – combines angioinhibitors and chemotherapy (in clinical trials). Targeted treatments continue to advance for example with the use of nanotechnology and RNA profiling.
Success of human ovarian tissue transplant after frozen storage in 2000
|-
| 2004
|| First birth after orthotopic transplantation of crupreserved ovarian tissue. First single blastocyst transfer.
|-
| 2006
|| The term “Oncofertility” is coined
|-
| 2010
|| First pregnancy from vitrified blastocysts.
|-
| 2015
|| Online registry launched in Australia to provide a patient history of their cancer treatment and reproductive journey to help survivors plan a family.
|} <ref><pubmed>20740081</pubmed></ref> <ref><pubmed>24163793</pubmed></ref> <ref><pubmed>20811828</pubmed></ref>

='''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.

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 <ref><pubmed>26217165</pubmed></ref>. 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 the direct effects of radiation fibrosis or scar tissue which causes pain with sexual activity. <ref><pubmed>16304430</pubmed></ref>

Beside '''Chemotherapy''', other treatments can also affect the ability to have a child such as targeted and biologic (immune) therapies, Radiation therapy and surgery.

==Infertility Causes==

===Targeted drugs===

These drugs attack cancer cells differently from standard chemotherapy 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), an angiogenesis inhibitor 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. <ref> American
Cancer Society, [ http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/targetedtherapy/targeted-therapy-toc ], 'Targeted Cancer Therapy', Retrieved on 8 September 2015</ref>

===Radiation===

[[File:Radiation.jpeg|400px|thumb|right| Action of Radiation on Cancer Cells<ref name="How does radiation work to treat cancer"><pubmed>22408567</pubmed></ref> ]]

Radiation treatments use high-energy rays to kill cancer cells. Radiation works by damaging the DNA and ultimately the genes in cells. As depicted in the flow diagram, radiation can interact directly with DNA causing damage or indirectly by forming free radicals through ionisation of the water components within the cell which then damage the DNA causing double stranded or single stranded breaks. DNA controls how cells grow, divide and develop. When radiation damages the DNA of cells, the cells are no longer able to grow, divide or perform their ordinary function and over time, the cells die. Therefore, radiation can be used as a treatment for cancer. <ref name="How does radiation work to treat cancer" />

However, radiation can also compromise fertility such as in the following scenarios:
*Causing damage to a woman’s ovaries, especially when treating cancers in the abdominal or pelvic region. For a woman in this scenario 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 directed right at the ovaries, the rays can bounce around inside the body and still cause damage the ovaries.
*When radiation is directed inside the vagina, the ovaries also 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.
*In both men and women, when radiation is directed at the brain it can affect the pituitary gland thus affecting fertility. The pituitary gland normally signals the ovaries and testis to make hormones, so interfering with these signals can affect ovulation (the release of eggs from the ovaries) and sperm production respectively. This may or may not affect fertility depending on the focus and dose of the radiation.
*Women who are still fertile when they start getting radiation treatments should avoid becoming pregnant until treatment is completed because radiation can also harm the foetus. <ref name="Effect of radiation on the human reproductive system."><pubmed>8243379</pubmed></ref>
*Men undergoing radiation treatment directed at their testis can also have their fertility compromised. Radiation at high doses kill spermatogonia i.e. undifferentiated male germ cells that produce sperm. Radiation is aimed directly at the testicles to treat some types of testicular cancer e.g,. seminoma, which is a type of cancer of the testicle, which involves radiation to the groin area, in close proximity to the remaining testicle.
*Radiation to treat a tumour in a males abdomen or pelvis can also affect the testis. <ref name="Effect of radiation on the human reproductive system." /> <ref> 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', Retrieved on 8 September 2015</ref>

===Surgery===

Surgery on certain parts of the reproductive system as a cancer treatment causes infertility.

====Surgery in women====

'''Hysterectomy:''' Removal of the uterus either through the vagina or through an incision made in the abdomen, such as in the case of endometrial cancer. When the uterus is removed the woman is no longer able to carry a child.

'''Oophorectomy:''' Refers to the surgical removal of the ovaries. This may occur in conjunction with a hysterectomy or alone such in the case of ovarian cancer. Without ovaries, a woman can’t get pregnant because she no longer has oocytes to mature and release at ovulation. <ref name="Ovarian cancer risk associated with varying causes of infertility"><pubmed>15302291</pubmed></ref>.In some women with early stage ovarian or cervical cancer, surgeons try to save one ovary, if possible, to preserve oocytes, which might still allow a woman to conceive through artificial means. Keeping at least one ovary also preserves the hormones that prevent menopause symptoms like hot flashes and vaginal dryness <ref name="Ovarian cancer risk associated with varying causes of infertility" />.

'''Trachelectomy:''' Performed on women with small cervical cancers. In this technique the cervix is removed but the uterus is spared, allow a women to bear a child.

In some scenarios, surgery can cause scarring in the fallopian tubes. These scars may block the tubes and prevent oocytes from traveling through the fallopian tubes to be fertilised by the sperm and implant into the uterus.

====Surgery in men====

'''Orchiectomy:''' Involves the removal of a testicle and is performed on males as a treatment for testicular cancer. As long as a man has one healthy testicle, he can continue to produce sperm after surgery. (Less than 5% of men develop cancer in both testicles.) However, some men with testicular cancer have poor fertility because the remaining testicle may carry some abnormalities. <ref> American Cancer Society,[ http://www.cancer.org/cancer/testicularcancer/detailedguide/testicular-cancer-treating-surgery ], 'Surgery for testicular cancer', Retrieved on 8 September 2015 </ref> .

In metatstatic prostate cancer, orchiectomy may be performed on both testicles as a form of castration. This stops testosterone production in order to reduce the rate of growth of prostate cancer cells. This is referred to as a bilateral orchiectomy. These men cannot father children unless they have banked sperm before surgery. <ref><pubmed>9761805<pubmed> </ref>

'''Radical prostatectomy:''' Removal of the prostate gland and seminal vesicles for men who have prostate cancer that has not spread beyond the gland. The prostate is removed through a cut in the abdomen or in the perineum (the area behind the testicles and in front of the anus), as a result the male can no longer produce semen. Surgery to remove the prostate also can damage the nerves that control erection, causing erectile dysfunction (ED). The patient can not conceive a child through sex as a result of both outcomes mentioned. <ref> American Cancer Society,[ http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-surgery ], 'Surgery for prostate cancer', Retrieved on 8 September 2015 </ref> .

'''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 in an invasive surgery the vas deferens may also be cut. Therefore, there is no ejaculate with sperm at sexual intercourse. <ref> Cancer Council NSW ,[ http://www.cancercouncil.com.au/58014/b1000/bladder-cancer-10/surgery-for-invasive-bladder-cancer/ ], 'Surgery for invasive bladder cancer', Retrieved on 8 September 2015 </ref> .

'''Surgery that interferes with erection and ejaculation:''' Some surgical treatments can also damage nerves that are required for an erection and to ejaculate sperm. They include removing lymph nodes in the pelvis during surgery for testicular cancer and some colon cancers which may damage nerves in the process. 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. 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. <ref><pubmed>4068047</pubmed></ref> ,<ref> 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', Retrieved on 8 September 2015 </ref> .

='''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. <ref>Cancer Council Australia, [http://www.cancer.org.au/about-cancer/treatment/chemotherapy.html 'Chemotherapy'], 'Cancer Council of Australia - About Cancer', Friday June 5, 2015 </ref>

[[File:Chemotherapy Treatment.jpeg|thumb|left|Patient undergoing chemotherapy]]

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. <ref>Cancer Research UK, [http://www.cancerresearchuk.org/about-cancer/cancers-in-general/treatment/chemotherapy/about/how-chemotherapy-works, ‘How Chemotherapy Kills Cancer Cells], ‘About Cancer’</ref>

==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 cells become their own functioning and active indestructible cell. <ref> Science Museum, [http://www.sciencemuseum.org.uk/WhoAmI/FindOutMore/Yourbody/Whatiscancer/Whathappensincancer/Howdohealthycellsbecomecancerous.aspx, 'How Do Healthy Cells Become Cancerous?'], 'Who am I?'</ref>

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 chromosomes may be lost, rearranged, or copied too many times, often giving the cell further ability to develop mutations. <ref> Science Museum, [http://www.sciencemuseum.org.uk/WhoAmI/FindOutMore/Yourbody/Whatiscancer/Whathappensincancer/Howdohealthycellsbecomecancerous.aspx, 'How Do Healthy Cells Become Cancerous? - Missing Checkpoints'], 'Who am I?'</ref>

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. <ref>Scitable by Nature Education [http://www.nature.com/scitable/topicpage/cell-division-and-cancer-14046590, 'Cell Division and Cancer'] </ref>
::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.

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

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. <ref>Scitable by Nature Education [http://www.nature.com/scitable/topicpage/cell-division-and-cancer-14046590, 'Cell Division and Cancer'] </ref>

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 which can also cause infertility.

==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.

<html5media height="384" width="352"|center|>File:Angiogenesis.mov</html5media>

===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. [[File:Chemotherapy via Vein Infusion.jpg|thumb||300px|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. [[File:Port Administered Chemotherapy.jpg|thumb|300px|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. <ref>[http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/chemotherapy/chemotherapyprinciplesanin-depthdiscussionofthetechniquesanditsroleintreatment/chemotherapy-principles-types-of-chemo-drugs "Types of Chemotherapy Drugs"], "[[American Cancer Society]]", 2, June 2015, Retrieved on 4 October 2015. </ref>

===Groups of Chemotherapy Drugs===

{| width="75%"
|-bgcolor="CEDFF2"
| width="25%" |
''' Type'''
| width="25%" |
'''Description'''
| width="25%" |
'''Examples'''

|-

|'''Alklyating Agents'''
| Alkylating agents directly damage 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. <ref>[http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/chemotherapy/chemotherapyprinciplesanin-depthdiscussionofthetechniquesanditsroleintreatment/chemotherapy-principles-types-of-chemo-drugs "Types of Chemotherapy Drugs"], "[[American Cancer Society]]", 2, June 2015, Retrieved on 4 October 2015. </ref>

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. <ref> [http://www.cancerquest.org/genotoxic-chemotherapy-drugs.html "A Closer Look at Mechanisms of Alkylating Agents"], "[[CancerQuest - Emory University]]", 6 May 2013, retrieved on 4 October 2015. </ref>
| The different classes of drugs that alkylating agents are divided into include; <ref>[http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/chemotherapy/chemotherapyprinciplesanin-depthdiscussionofthetechniquesanditsroleintreatment/chemotherapy-principles-types-of-chemo-drugs "Types of Chemotherapy Drugs"], "[[American Cancer Society]]", 2, June 2015, Retrieved on 4 October 2015. </ref>

* 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)

|-bgcolor="F5FAFF"

| '''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®)

|-

|'''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

|-bgcolor="F5FAFF"

| '''Topoisomerase inhibitors'''
|These type of drugs inhibit the function of the enzyme topoisomerase (I and II). Some Anthracyclines will also belong to this category. Most, if not all Topoisomerase inhibitors are derivatives of the plant extract camptothecin.

Topoisomerase are DNA enzymes that control the topology of coiled DNA during transcription and replication of genetic material. The two major types are Topo I and II.
Topo I initiates the cleavage of one strand of a DNA molecule, while Topo II cleaves both DNA strands. The actions of these enzymes guarantee that replication of the DNA can occur.

By inhibiting this enzyme from completing its function, the drug functions by the result of accumulation and stability of cleavable complexes and thus subsequent death of the cell, and is the main mechanism by which these drugs produce their anti-tumor effect.
There has been some evidence however to suggest that the drugs work through the accumulation or prolongation of Topo I cleavable complexes, resulting in irreversible DNA replication defects, thus producing subsequent cell cycle arrest and death.
The cytotoxic effect of the drugs is largely determined by the length of exposure (as compared to the concentration of the drug), thus the schedule of administration for the drug is a very important determinant in tumor response. <ref>Reginald B. Ewesuedoa and Mark J. Ratainb, 'Topoisomerase I Inhibitors', "The Oncologist", December 1997 vol. 2 no. 6 359-364.</ref>
|Currently there are only 2 approved Topoisomerase inhibitor drugs, namely ''topotecan'' and ''irinotecan'', however there are many more currently undergoing clinical trials.

|-

| '''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®)

|- bgcolor="F5FAFF"

| '''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. 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.

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
| Some common corticosteroids used during cancer treatment include;
* Prednisone
* Methylprednisolone (Solumedrol®)
* Dexamethasone (Decadron®).

|-

| '''Unique Chemotherapy Drugs'''
|
|

|}

==Side Effects of Chemotherapy==
[[File:Chemotherapy Side Effects.jpg|thumb|left|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 – and it is this killing of healthy cells that cause often severe side effects.

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 include hair cells, blood producing cells in bone marrow, cells lining mucous membranes including areas of the pharyngeal region and the digestive system.<ref>[http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/chemotherapy/understandingchemotherapyaguideforpatientsandfamilies/understanding-chemotherapy-chemo-side-effects, “Chemo Side Effects”], “[[American Cancer Society]]”, 6 September 2015.</ref>

[[File:Side effects of Chemotherapy.png|thumb|400px|right|"Side Effects of Chemotherapy"]]

Some common side effects experienced can include; <ref>[http://www.cancer.net/navigating-cancer-care/how-cancer-treated/chemotherapy/side-effects-chemotherapy, “Side Effects of Chemotherapy”], “[[Cancer.Net]]”. </ref>
::* Fatigue
::* Pain
::* Mouth and throat sores
::* Diarrhea
::* Nausea and vomiting
::* Constipiation
::* Blood disorders
::* Nervous system effects
:::- Tingling
:::- Burning
:::- Weakness/numbeness of hands/feet/limbs
:::- Weak/achy muscles
:::- Loss of balance
:::- Trembling
::* Changes in thinking/memory
::* Appetite loss
::* Hair loss

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. It is a tough balance using drugs and therapy to kill cancer cells and tumors, while preserving the health of the patient, and retaining vital factors for the future, including fertility. Oncofertility largely focuses and addresses these issues.

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. Most side effects disappear when treatment stops, however some side effects can have a long term significance. Fertility of a woman, if compromised during chemotherapy can have serious long term effects.

'''Late Side Effects'''

Damage done any major organs, including the heart, kidneys, lungs or liver can also cause complications in the future for chemotherapy patients. Brain and neurological damage received can also open a pathway to many complications in the future for the patient. Nervous system changes can continue to develop after treatment, and have the ability of causing further problems many years down the track – these are known as late effects, and are often extremely complicated and problematic for cancer survivors. This can often be the case with fertility viability also. <ref>[http://www.cancer.net/navigating-cancer-care/how-cancer-treated/chemotherapy/side-effects-chemotherapy, “Side Effects of Chemotherapy”], “[[Cancer.Net]]”. </ref>

='''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.

[[File:Fertility Timeline.jpg|thumb|center|800px|Fertility Timeline]]

=='''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 <ref>BabyCenter Australia Medical Advisory Board, [ http://www.babycenter.com.au/a6186/fertility-drug-clomiphene-citrate-clomifene-clomid ], 'Fertility drug: clomiphene citrate (clomifene, clomid)', Retrieved on 9 September 2015</ref> .

'''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 <ref name="Fertility Drugs"> BabyCenter Australia Medical Advisory Board, [ http://www.babycenter.com.au/a4090/fertility-drugs-for-women ], 'Fertility drugs for women', Retrieved on 9 September 2015</ref>.

'''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 <ref name="Fertility Drugs" /> .

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 <ref name="Fertility Drugs" /> . 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 <ref name="Fertility Drugs" /> .

===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 <ref name="Risks of fertility treatment"> Human Fertilisation and Embryology Authority,[ http://www.hfea.gov.uk/fertility-treatment-risks.html#wrapper ], 'Risks of fertility treatment',Retrieved on 9 September 2015</ref> .

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 <ref name="Risks of fertility treatment" /> .

'''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 <ref name="Risks of fertility treatment" /> . 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 <ref> about health, [http://infertility.about.com/od/clomid/tp/clomid_side_effects.htm], 'Clomid (Clomiphene) Side Effects and Risks',Retrieved on 9 September 2015</ref> .

'''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 <ref name="Risks of fertility treatment" /> .

==Fertility preservation in women==

Fertility preservation options available for females include:

{| width="75%"
|-bgcolor="CEDFF2"
| width="25%" |
''' Before Treatment'''
| width="25%" |
'''During Treatment'''
| width="25%" |
'''After Treatment'''
|-
|
<center>oocyte freezing</center>
|
<center>Fertility-sparing surgical
procedure for certain women
with ovarian cancer</center>
|
<center>Adoption</center>
|-bgcolor="F5FAFF"
|
<center>Embryo freezing</center>
|
<center>GnRH treatment</center>
|
<center>Donor eggs</center>
|-
|
<center>GnRH treatment</center>
|
<center>Oral contraceptive (birth
control pill) treatment</center>
|
<center>Donor embryos</center>
|-bgcolor="F5FAFF"
|
<center>Oral contraceptive (birth
control pill) treatment</center>
|
<center>Ovarian shielding</center>
|
<center>Natural pregnancy</center>
|-
|
<center>Ovarian tissue freezing</center>
|
<center>Radical trachelectomy (for
certain women with cervical
cancer)</center>
|
<center>Surrogacy</center>
|-bgcolor="F5FAFF"
|
<center>Ovarian transposition</center>
|
<center>-</center>
|
<center>Using own frozen eggs</center>
|-
|
<center>-</center>
|
<center>-</center>
|
<center>Using own frozen
embryos</center>
|-bgcolor="F5FAFF"
|
<center>-</center>
|
<center>-</center>
|
<center>Using own frozen ovarian tissue</center>
|}

'''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. <ref name="fertility strategies"><pubmed>24669162</pubmed></ref>

'''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. <ref><pubmed>19281314</pubmed></ref> . 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 <ref><pubmed>17462639</pubmed></ref> .

[[File:Ovarian tissue extracted after ovarian stimulation.jpeg|300px|thumb|right|Ovarian tissue extracted after ovarian stimulation<ref><pubmed>23510640><pubmed></ref>]]

'''Oocyte Freezing:'''

This recommended for teenagers or adults without a stable partner. As in the previous case, the ovaries are stimulated through the use of hCG, then the oocytes harvested through transvaginal retrieval and then frozen for future use where ICSI can be used again. The histological image to the right shows how the ovarian tissue extracted laprascopically (the same technique used in the case of ovarian tissue preservation) looks after stimulation for oocyte retrieval, demonstrating the increased number of follicles.

Less is known about egg freezing than embryo freezing, but the methods and success rates have greatly improved in the past several years and it’s being done more often in the US. Some fertility centers have reported success rates much the same as using unfrozen eggs, especially in younger women.It is important to note that if you have frozen eggs, it’s important to stay in contact with the cryopreservation facility to be sure that any yearly storage fees are paid and your address is updated. Once a couple is ready to have a child, the frozen eggs are sent to their fertility specialist.

'''Donor Oocytes:'''

Donated oocytes are used for fertilisation by a couple when the female is unable to use her own oocytes and does not have any cryopreserved ones. Women who wish to donate their oocytes can apply to egg donation programs where they undergo screening and interviews to ensure the woman is an appropriate donor. Once a donor is selected, they are matched to a recipient and then begins administering injections to suppress her menstrual cycle in order to synchronise it with the recipient. Next, the donor injects gonadotropins to stimulate her ovaries which encourages many oocytes to maturity for retrieval. Meanwhile the recipient receives oestrogen and progesterone to prepare her endometrial lining for implantation. The donor receives hCG to trigger ovulation when ready and the oocytes are aspired through a needle. The oocytes can be fertilised with the partners sperm (or donor sperm) and the embryo transferred at day 3. <ref>Centre for Human Reproduction, 2015, Egg Donation, [https://www.centerforhumanreprod.com/egg-donation/how-it-works/], retrieved 9 October, 2015</ref>

'''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) <ref> IVF Australia , [ http://ivf.com.au/fertility-treatment/ivf-treatment/frozen-embryo-transfer#success-rates-with-frozen-embryos ],Freezing Embryos, Retrieved on 7 October 2015</ref>. 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 <ref> GENETICS and IVF institute, [ http://www.givf.com/fertility/embryofreezing.shtml ],Embryo Freezing (Cryopreservation),Retrieved on 7 October 2015</ref> , <ref> Advanced Fertility Center of Chicago,[ http://www.advancedfertility.com/cryo.htm ],Embryo freezing after IVF: Human blastocyst and embryo cryopreservation and vitrification,Retrieved on 7 October 2015 </ref> .

'''Embryo Donation:'''

When couples undergo fertility treatment such as IVF normally multiple embryos are created. Not all the embryo's are utilised and therefore a decision needs to be made on what happens to the remaining embryos once the couple has completed their family. In this case couples have the option of donating the remaining embryo's to infertile couples who are unable to start a family. The couple undergoes screening and can then match with a recipient. Embryos can be thawed when they are ready for use and implanted into the recipient. <ref>IVF Australia, 2013, Embryo Donation, [http://ivf.com.au/fertility-treatment/donor-program/embryo-donation], retrieved 9 October, 2015.</ref>

[[File:The morphology of follicles after ovarian tissue vitrification.jpg|450px|thumb|right|Representation of morphology of follicles after ovarian tissue vitrification <ref><pubmed>25250122</pubmed></ref>]]

[[File:Electron micrographs of granulosa cells (GC).jpg|500px|thumb|right|Representation of Electron micrographs of granulosa cells (GC).<ref><pubmed>20459796</pubmed></ref>]]

'''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) <ref> Resolve, The National Infertility Association ,[ http://www.resolve.org/family-building-options/adoption/?referrer=https://www.google.com.au/ ],FAMILY BUILDING OPTIONS/Adoption ,Retrieved on 9 October 2015 </ref> .

'''Ovarian transposition'''

This involves moving the ovaries away from the target zone of radiation treatment such as pelvic radiation. Ovarian transposition can be performed as outpatient surgery and therefore, does not require staying in the hospital. Surgeons move the ovaries above and to the side of the central pelvic area. The rate of success for this procedure is measured by the percentage of women who regain their menstrual periods, not by being able to have a live birth. Typically, 50 % of the women start menstruation cycle again <ref><pubmed>16369371</pubmed></ref> , <ref> Togas Tulandi, MD, MHCM,[ http://www.uptodate.com/contents/ovarian-transposition-before-pelvic-radiation ],Ovarian transposition before pelvic radiation,Retrieved on 6 October 2015 </ref> .

[[File:Woman's Uterus.gif|thumb|left|400px|Female Uterus]]

'''Radical trachelectomy'''

Radial trachelectomy is considered as an option for women with cervical cancer who have very small and localised tumors. In this procedure, the cervix is removed but the uterus and the ovaries keep in place with uterus connecting to the upper part of the vagina. A special band or stitch is wrapped around the bottom of the uterus to act as the cervix and a small opening allows blood from female’s period to flow out and sperm to enter the uterus to fertilize an egg. Overall, Trachelectomy is a successful option in treating cervical cancer in women as radical hysterectomy, removal of the uterus and cervix. It is important to note that women can become pregnant after the surgery, but they are at risk of miscarriage and premature birth because the opening to the uterus may not close as strongly or tightly as before <ref><pubmed>26095894</pubmed></ref> , <ref><pubmed>26026821</pubmed></ref> .

'''Surrogacy''':

Surrogacy is a good option for women who cannot carry a pregnancy, either because they no longer have a health uterus, or would be at high risk for a health problem if they got pregnant. There are 2 types of surrogate mothers:

A "gestational carrier" is a healthy female who receives the embryos as a result of fusion of the egg and sperm of the intended parents. The gestational carrier does not contribute her own egg to the embryo and has no genetic relationship to the baby <ref name="Surrogacy" > IVF Australia,[ http://ivf.com.au/fertility-treatment/donor-program/surrogacy ], 'Surrogacy',Retrieved on 8 October 2015</ref> .

A "traditional surrogate" is usually a woman who becomes pregnant through artificial
insemination with the sperm of the man in the couple who will raise the child. Thus, woman’s egg is fertilized with man’s sperm in the lab and carries the pregnancy. The woman now is the genetic mother of the baby <ref name="Surrogacy" /> .

'''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 histological image above demonstrates the ovarian tissue retrieved through this technique. 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. <ref name="fertility strategies"><pubmed>24669162</pubmed></ref>

'''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 <ref><pubmed>26255458</pubmed></ref> . 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 <ref><pubmed>25628110</pubmed></ref> .

'''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 <ref>Leukaemia Foundation,Leukaemia, Lymphoma, Myeloma & Related Blood Disorders,[http://www.leukaemia.org.au/treatments/stem-cell-transplants/stem-cell-transplants ],Stem Cell Transplants ,Retrieved on 9 October 2015 </ref> .

==Fertility preservation in men==

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

{| width="75%"
|-bgcolor="CEDFF2"
| width="25%" |
''' Before Treatment'''
| width="25%" |
'''During Treatment'''
| width="25%" |
'''After Treatment'''
|-
|
<center>Sperm banking</center>
|
<center>Radiation shielding</center>
|
<center>Adoption</center>
|-bgcolor="F5FAFF"
|
<center>Testicular sperm extraction
(TESE) or epididymal sperm
aspiration</center>
|
<center>-</center>
|
<center>Collecting sperm from urine</center>
|-
|
<center>Testicular tissue freezing</center>
|
<center>-</center>
|
<center>Donor sperm</center>
|-bgcolor="F5FAFF"
|
<center>-</center>
|
<center>-</center>
|
<center>Natural pregnancy</center>
|-
|
<center>-</center>
|
<center>-</center>
|
<center>Electro-ejaculation</center>
|-bgcolor="F5FAFF"
|
<center>-</center>
|
<center>-</center>
|
<center>Using banked sperm</center>
|-
|
<center>-</center>
|
<center>-</center>
|
<center>Testicular sperm extraction
(TESE) or epididymal sperm
aspiration</center>
|}

'''Adoption'''

See above in 'Fertility preservation in women'

'''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 <ref name="fertility strategies" />. 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. 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 <ref name="sperm banking" > 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), Retrieved on 25 September 2015</ref> .

'''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 <ref name="Electroejaculation: its technique, neurological implications and uses"><pubmed>6451670 </pubmed></ref> .

'''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) <ref> Memorial Sloan Kettering, cancer center, [ https://www.mskcc.org/cancer-care/patient-education/cancer-and-fertility-information-men ], Cancer and Fertility: Information for Men,Retrieved on 24 September 2015 </ref> .

'''Testicular biopsy'''

This process is suitable for young boys who have not yet undergone puberty and therefore spermatogenesis. As a result they do not have sperm available for cryopreservation for future utilisation. In this case cryopreservation of immature testicular tissue which contains spermatogonial stem cells can be undertaken. Tissue is removed through biopsy prior to cancer treatment. It is then cryopreserved and then can be used in the future for autotransplantation or for In-Vitro maturation. Results in this technique have been promising shown through spermatogonia surviving for future use and through the initiation of spermatogenesis. <ref><pubmed>25593971<pubmed></ref>

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'''. <ref name="fertility strategies" />

[[File:Male Sex Organs.jpg|thumb|400px|Male Sex Organs]]

'''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). 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 <ref name="DI " > 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?',Retrieved on 25 September 2015</ref> .

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. 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 <ref name="DI" /> .

'''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. <ref name="Effect of radiation on the human reproductive system." />

'''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 <ref><pubmed>8671323</pubmed></ref> .

'''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 <ref><pubmed>21481372</pubmed></ref> , <ref> Fertility Center Mauritius,[ http://www.harleystreetfertility.com/en/testicular-tissue-freezing.html ], 'Testicular tissue freezing',Retrieved on 27 September 2015</ref> .

'''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 <ref> American Society for Reproductive Medicine,[ https://www.asrm.org/FACTSHEET_Optimizing_Natural_Fertility/ ], 'Optimizing Natural Fertility',Retrieved on 26 September 2015</ref> .

==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. <ref name="IVF"><pubmed>23074488</pubmed></ref>

==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:

[[File:IVF flow chart.png|700px|thumb|centre|IVF Procedure<ref name="IVF"><pubmed>23074488</pubmed></ref>]]

===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.<ref name="IVF"><pubmed>23074488</pubmed></ref>

[[File:ICSI of marmoset oocytes.jpeg|600px|thumb|centre|ICSI of marmoset oocytes<ref><pubmed>24751978</pubmed></ref>]]

===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.<ref name="IVF"><pubmed>23074488</pubmed></ref>

===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. <ref name="IVF"><pubmed>23074488</pubmed></ref>

==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.<ref><pubmed>26010087</pubmed></ref>

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'''=

With oncofertility comes a list of limitations and risks:

*The amount of time available in which to employ fertility preservation methods in between cancer detection and cancer treatment.
*Only a limited amount of embryos will be available for selection from in the case of embryo storage.
*Gonadotropins leads to high oestrogen levels which is concerning in cancers such as oestrogen positive breast cancer.
*Ovarian tissue storage is an invasive procedure requiring general anaesthetic and has a 1 in 12 000 mortality rate.
*Ovarian tissue re-implantation carries the risk of a second surgery and re-implanting micro deposits of cancer
*Ovarian transplantation is limited by the small ovarian artery, short vascular pedicle length and in the case of failure a compromised ovary with no second chance of transplantation. <ref name="fertility strategies"><pubmed>24669162</pubmed></ref>
*Multiple pregnancies as a result of IVF run the risk of maternal complications such as hypertension, diabetes, metal malpresentation and postpartum depression. The babies are at higher risk or prematurity, death and disabilities.
*IUI can not be used for tubal infertility as ovum can not reach uterine cavity. <ref><pubmed>23074488</pubmed></ref>
*Timely patient referral and coordination between specialists for patient care limits access to fertility options.
*Lack of knowledge especially in men to a fertility threat at the time of cancer diagnosis.
*Oocyte retrieval is difficult compared to sperm because it requires surgery, is limited in numbers and varies in maturity. <ref name=consortium><pubmed>20498666</pubmed></ref>
*Ethical and moral issues surrounding the use of fertility preservation methods.
*Sperm Banking has number of limitations such it is not useful for fast-growing cancers as well as some issues with costs and the fact that many sperm banks do not accept samples from men who have HIV or hepatitis B (risk of infectious disease)<ref name="sperm banking" /> .
*One problem with donor embryos is that the couple donating the embryo may not agree to have the same types of genetic testing as is usually done for egg or sperm donors, and they may not want to supply a detailed health history.

=Glossary=

'''FSH''' - Follicle stimulating hormone

'''GnRH''' - Gonadotropin releasing hormone

'''FSH''' - Follicle stimulating hormone

'''ICSI''' - Intracytoplasmic Sperm Injection

'''IUI''' - Intrauterine Insemination

'''IVF''' - In Vitro Fertilisation

'''LH''' - Luteinizing hormone

'''GIFT''' - In Gamete Intra-Fallopian Transfer

'''ZIFT''' - Zygote Intra-Fallopian Transfer

=References=
<references/>