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

Introduction

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. 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. 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.


Surgery

Surgery on certain parts of the reproductive system can cause infertility. For some cancers, a hysterectomy is part of the treatment. A hysterectomy is surgery to remove the uterus (womb) either through the vagina or through a cut made in the abdomen (belly). Once the uterus is removed, a woman cannot carry a child.The ovaries might be removed (called an 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. In some women with early stage ovarian or cervical cancer, the surgeon will 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. 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.

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.

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.

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.

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.


Fertility Drugs

Clomiphene

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 [4] .


Fertibella

This drug 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 [5].

Follistim

This drug 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 [5] .

Gonadotrophins

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 [5] .

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 [5] .


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 [6] .

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 [6] .

OHSS – Ovarian Hyperstimulation Syndromeis 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 [6] . 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 [7] .

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 [6] .


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. [8]

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. [9]


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. [10]

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. [11]

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. [12]

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. [13]

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.


How Does Chemotherapy Work?

Types of Chemotherapy Drugs

How Does it Effect the Cancer Cells?

Side Effects of Chemotherapy

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.

Fertility preservation in women

Fertility preservation in men

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.[14]

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 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. BabyCenter Australia Medical Advisory Board, [ http://www.babycenter.com.au/a6186/fertility-drug-clomiphene-citrate-clomifene-clomid ], 'Fertility drug: clomiphene citrate (clomifene, clomid)'
  5. 5.0 5.1 5.2 5.3 BabyCenter Australia Medical Advisory Board, [ http://www.babycenter.com.au/a4090/fertility-drugs-for-women ], 'Fertility drugs for women'
  6. 6.0 6.1 6.2 6.3 Human Fertilisation and Embryology Authority,[ http://www.hfea.gov.uk/fertility-treatment-risks.html#wrapper ], 'Risks of fertility treatment'
  7. about health, [1], 'Clomid (Clomiphene) Side Effects and Risks'
  8. Cancer Council Australia, 'Chemotherapy', 'Cancer Council of Australia - About Cancer', Friday June 5, 2015
  9. Cancer Research UK, ‘How Chemotherapy Kills Cancer Cells, ‘About Cancer’
  10. Science Museum, 'How Do Healthy Cells Become Cancerous?', 'Who am I?'
  11. Science Museum, 'How Do Healthy Cells Become Cancerous? - Missing Checkpoints', 'Who am I?'
  12. Scitable by Nature Education 'Cell Division and Cancer'
  13. Scitable by Nature Education 'Cell Division and Cancer'
  14. <pubmed>26010087</pubmed>