module 6- health and fertility Flashcards
Oncofertility
is a specialty field bridging the gap between oncology and reproductive medicine
- emerged as an interdisciplinary field focused on understanding and expanding the methods of fertility
preservation in cancer survivors
Cancer
umbrella term for the abnormal and malignant growth of any of the body’s own cells
- generally due to a loss of the normal regulatory mechanisms that maintain cellular homeostatic control.
most therapeutic methods
used to eliminate cancer cells
will also affect normal cells, tissues and organs, which is why cancer
treatments have such strong side effects in patients, such as anemia, hair loss, and loss
of fertility because, the abnormalities that make a cell cancerous are not easy to pinpoint,
what is the leading cuase of death in canada
Cancer; the Canadian Cancer Society (CCS) estimates it is
responsible for ~30% of deaths.
cancer and children
- less than 1% of all new cancer cases in Canada are children
- top 3 types of cancer at leukemia (32%), brain and CNS (19%) and lymphomas (11%)
what is the leading cause of disease-related death among canadian children
childhood cancer
impact of cancer on children
- future physical development and fertility prospects is more serve
- challenges balancing the benefits of a particular treatment with the future well-being of the survivor
how are cancer treatments selected
- depending on factors such as cancer type and individual characteristics of the condition
- most go under combination therapy
the degree to which cancer treatment affects fertility depends on what
the type and severity of the cancer, method of treatment, and individual health status
different cancer treatments.
SURGERY
CHEMOTHERAPY
RADIATION
HORMONE THERAPY
IMMUNOTHERAPY
TARGETED THERAPY
SURGERY and effects on fertility
Reproductive organ surgeries may damage innervation and sexual function, thus impairing fertility.
CHEMOTHERAPY and effects on fertility
Fertility can be affected by DNA damaging drugs. The damage can be temporary or permanent.
RADIATION and effects on fertility
X-ray energy damages DNA, leading to cell necrosis.
HORMONE THERAPY and effects on fertility
Blocking the production of reproductive hormones causes temporary fertility loss.
IMMUNOTHERAPY and effects on fertility
Long term fertility effects are unknown, since this is a new form of therapy which enhances the
immune response to cancer cells.
TARGETED THERAPY and effects on fertility
Long term fertility effects are unknown, since this is a new form of therapy being introduced to target
specific molecules in cancer cells.
what is one of the most common chronic medical problem reported by cancer survivors
infertility
what are the 2 main ways cancer treatment impair fertility
- damage to the organs
- damage to the organs involved in hormone production
what are some factors that need to be considered what choosing treatment on fertility
the risk of spreading
the risk of delaying cancer
chances of success in fertility
the risk of spreading
if there’s a high risk of the cancer spreading to the reproduction organs, fertility preservation may no longer be possible
the risk of delaying cancer treatment
some patietns may choose to delay cancer treatment in order to undergo fertility preserving methods. however, the risk of delaying cancer treatment may be too high in cases where the cancer is too adavanced or invasive
chances of success in fertility
in older women, the success rate of fertility procedures is much lower, so the benefits of getting the cancer treated may outweigh the benefits of preserving fertility
why would patients sometimes choose less effective cancer treatments
in an effort to decrease the risk of infertility
what are current preservation methods involve?
- gonadal shielding
- cryopreservation
what is gonadal shielding?
is a procedure used to help keep a person fertile by preventing damage to reproductive organs during radiation therapy
- available to men and women but it is limited to cases of radiation treatment
how does gonadal shielding work?
a protective shield is placed on the outside of the body to cover the area of the gonads’ and other parts of the reproductive system during radiation therapy
what is cryopreservation?
involves the freezing of gametes or embryos, for use in the future with the aid of assisted reproductive technologies
- availability and effectiveness of such methods differs significantly between males and females because each presents unique challenges
how can cryopreservation preserve live cells?
- holds tissue at temperatures between -140 and -200 at which no biological activity can occur, producing a state of suspended animation of tissues that can be maintained indefinitely.
- the process of cooling and warming causes damage to the cells
types of damage that can occur during cryopreservation.
Dehydration/Osmotic Damage
Mechanical Changes
p H Changes
Rehydration Damage
Oxidative Stress
Temperature Stress
Dehydration/Osmotic Damage
- Increased solute concentration
- Interruption of ion exchange
Mechanical Changes
Excessive folding of membrane as cell volume is reduced
p H Changes
Changes in electrochemical gradients
Alterations to enzyme activity
Rehydration Damage
Lysis of damaged cells
Loss of electrolytes
Oxidative Stress
Free radical damage
Lipid peroxidation
Temperature Stress
Denaturation of proteins
Breached membranes due to formation of ice crystals
cryopreservation in females
depending on sexual maturity, stage of cancer, and the availability of donor sperm, women can choose to preserve ovarian tissue, oocytes, or embryos
Ovarian tissue cryopreservation
method in which individual follicles or strips of ovarian cortical tissue can be cryopreserved directly for future use in either tissue transplantation or in vitro follicle maturation
transplantation of ovarian tissue risk
reintroducing cancer cells from
the transplanted tissue and is thus considered a last option for the preservation of fertility in patients
with cancer
what is a safer option for transplantation of ovarian tissue
In vitro follicle maturation
when is Ovarian tissue cryopreservation used
in pre-pubertal girls who are not candidates for hormonal stimulation due to their stage of development. It is also used in post-pubertal women who may not be able or willing to
undergo ovarian stimulation
Hormonal stimulation
The process by which ovaries are induced by using medications for follicular development and oocyte maturation. Ovarian stimulation occurs for approximately 10-14 days,
beginning at the start of the menstrual cycle
Cryopreservation of oocytes
women undergo hormonal stimulation prior to the retrieval of oocytes.
who is Cryopreservation of oocytes ideal for?
for women who do not have a male partner or sperm donor at
the time of ovarian stimulation
what does Cryopreservation of oocytes avoid
ethical issues surrounding the preservation and long-term storage of embryos.
bad things about Cryopreservation of oocytes
- more complicated than cryopreservation of embryos
- Only 50- 65% of oocytes survive slow-rate freezing, and they are usually damaged from intracellular ice
formation due to their large cytoplasmic volume
steps involved in oocyte cryopreservation; how many
5
step 1 oocyte cryopreservation.
Hormonal stimulation is used to induce superovulation.
step 2 oocyte cryopreservation.
Oocytes are collected via transvaginal oocyte retrieval.
step 3 oocyte cryopreservation.
Harvested oocytes are cryopreserved.
step 4 oocyte cryopreservation.
Cyropreserved oocytes can be thawed and fertilized by in vitro fertilization.
step 5 oocyte cryopreservation.
Resulting embryos are transferred into patient during disease remission.
Superovulation
This is the process of inducing a woman to ovulate more than one follicle per month.
Transvaginal Oocyte Retrieval:
In this procedure, a needle is inserted through the vaginal wall into the
ovary. Gentle suction is applied to aspirate follicular fluid, tissue, and oocytes.
embryo freezing
- In post-pubertal women g is the most successful method of fertility preservation.
- a woman will undergo hormonal stimulation, usually in the form of oral
administration of ovarian stimulating drugs, for about two weeks. Then, her oocytes are collected and
fertilized by in vitro fertilization (I V F) - The resulting embryos are
frozen until later.
steps involved in oocyte cryopreservation.
5
step 1 embryo cryopreservation.
Superovulation occurs due to hormonal stimulation.
step 2 embryo cryopreservation.
Oocytes are collected via transvaginal oocyte retrieval.
step 3 embryo cryopreservation.
Harvested oocytes are fertilized in vitro.
step 4 embryo cryopreservation.
Embryos are cryopreserved.
step 5 embryo cryopreservation.
Cryopreserved embryos will be thawed and transferred into patient at remission.
Cryopreservation in males
Cryopreservation of sperm before therapy is the best method of preserving fertility in male cancer
patients
- Fertility challenges in men with cancer are less complex than those in women because of the
relatively lower sensitivity of sperm to the damaging effects of cryopreservation.
testicular tissue preservation
- In prepubertal boys who do not yet produce mature sperm, testicular tissue freezing is used
- testicular tissue containing immature sperm is removed and frozen before cancer therapy starts, and can be used in the future to be
implanted back into the testicles or elsewhere
is the frozen testiuclar tissue is implanted back elsewhere
the sperm that it produces can be collected with a needle and used in IVF procedures.
what does testicular tissue preservation involve?
testicular biopsy, which is a procedure to remove a small sample of tissue from one or both testicles
mature sperm preservation
- can be collected from post-pubertal men for cryopreservation.
- spermatozoa seem to be less sensitive to cryopreservation damage
because of the high fluidity of the membrane and the low water content. However, there are some
negative effects.
Cryopreservation and sperm effects
- widely known to increase the rate of impaired sperm motility and decrease
fertilization rate through detrimental effects on the spermatozoa membrane, acrosomal structure, and
acrosin activity. - freezing-thawing procedure of human spermatozoa may also be detrimental to
the chromatin structure of D N A.
barrier to mature sperm preservation
is variability of the quantity and quality of sperm collected. In men who are unable to ejaculate or produce low amounts of semen with ejaculation, a
surgical extraction, such as testicular sperm aspiration, may be needed.
guidelines for oncologists
- in 2016 the American society of clinical oncology published recommendation for fertility preservation in cancer patients
- were created as a resource to advise oncologists on best practises for addressing inferility as a possible risk of cancer treatment and available methods for fertility preservation
report not receiving adequate fertility information
- females prior to treatment or not understanding the information provided
- males only 18% to 26% of at-risk adolescent males cryopreserve their sperm prior to treatment in the united states and canada
- problems reported in post-treatment as survivors care plans often do not include comprehensive sexual and reproductive health counseling
The oncogertility consortium
is a major advancement in advocacy for the devastating effects that cancer can have on the possibility of having children
Assisted reproductive technologies (A R T)
provide individuals with fertility issues with several methods
to conceive biologically-related children.
embryo Selection
techniques focus on the evaluation and pre-selection of embryos that are most viable for conception.
Embryo Modification
Embryo modification involves the direct genetic editing of the D N A sequence of an embryo.
what are the 2 techniques that are currently being used to select embryos for IVF + what do they both involve
preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS)
- both involve embryo biopsy
Prenatal genetic screening (P G S)
is an adjunct to I V F and is used to aid embryo selection for certain groups of patients, such as those with advanced maternal age, repeated I V F failure, severe male factor infertility, or repeated miscarriage in parents with no known genetic abnormalities.
what does prenatal genetic screening test focuses on
screening for aneuploidy, to select euploid embryos that will result in higher implantation rates and lower risk of miscarriages
- based on the fact that even in
otherwise normal couples, the risk of trisomy disorders increases with advanced maternal age.
Preimplantation genetic diagnosis (P G D)
diagnostic test used to select genetically or chromosomally normal embryos for patients at high risk of transmitting a specific genetic abnormality to their children before proceeding with I V F.
why was Preimplantation genetic diagnosis (P G D) developed
as a method of reducing the risk of genetic disease in families with known X linked recessive disorders by determining the genetic sex of the embryo
- since creation the
technology has improved and expanded greatly to serve many other uses.
when is Preimplantation genetic diagnosis (P G D) used
in cases where both prospective parents are carriers of an autosomal recessive mutation.
- where one of the prospective
parents is heterozygous for an autosomal dominant mutation, which are responsible for the
occurrence of diseases such as Huntington’s disease and neurofibromatosis type 1.
how can Preimplantation genetic diagnosis (P G D) vary
in the method of biopsy and on which day of embryo development the biopsy is performed.
Monogenic diseases
Diseases caused by a mutation in a single gene
Huntington’s disease
A hereditary, neurodegenerative illness that causes the progressive
degeneration of nerve cells in the brain.
Neurofibromatosis
A group of conditions in which non-cancerous tumors grow in nerve tissue.
ethical aspects of PGS
- use of it during IVF has been debated due to reports of healthy babies being born after transferring aneuploid embryos diagnosed by PGS (may be because of mosaic embryos
- on a small fraction of embryo cells are tested and some embryos have been observed to “self correct” (abnormal cells under going apoptosis)
Mosaic Embryos
An embryo that contains cells with a normal chromosome number and cells with an abnormal number of chromosomes. Approximately 20% of all embryos created through IVF are
considered mosaic.
ethical aspects of PGD
- which of the inheritable conditions are severe and deblilitating enough to to be acceptable for treatment with PGD
Genome editing, or gene editing
concept that comprises all the technologies that allow scientists
to change the D N A of a cell or organism in a targeted manner.
applications of genome editing in each sector.
Crops and Livestock
Biomedicine
Industrial Technology
Reproduction
Crops and Livestock
Genetic editing is used in crops and livestock to increase yield, for example to introduce resistance to
disease and pests, and tolerance of different environmental conditions.
Biomedicine
genome editing is used in pharmaceutical development, xenotransplantation, gene
and cell-based therapies, control of insect-borne diseases).
Industrial Technology
has many applications in industrial biotechnology e.g. developing ‘third generation’ biofuels, producing chemicals, materials and pharmaceuticals.
Reproduction
genome editing is used for preventing the inheritance of a disease trait.
the 2 technologies used for embryo gene editing
mitochondrial
replacement and the CRISPR/Cas9 system
Mitochondrial modification
used to treat conditions caused by mutations of mitochondrial D N A (m t D N A)
Mitochondrial diseases
are the most common group of inherited metabolic disorders and are among the most common forms of inherited neurological disorders. Approximately 1 in every 5000 individuals has a mitochondrial disease, with 1 in 200 healthy individuals being a carrier of a pathogenic mitochondrial mutation that can affect the offspring of female carriers, because m t D N A is inherited
exclusively from the mother.
Mitochondria
key organelles present in the cytoplasm of most eukaryotic cells.
- main function is the production of cellular energy, they also play an important role in other cell
processes, and are implicated in the pathogenesis of numerous diseases, in particular neurodegenerative disorders.
where do all organelles and cell machinery required for embryo development provided from
the ovum
mitochondrial D N A (m t D N A)
Mitochondria have their own DNA which is inherited exclusively from the mother due to the way sperm maturation and fertilization occurs.
what are techniques for mitochondrial modification aimed at
- eradicating the maternal mtDNA in the individual’s cells
- done by either replacing the abnormal mitochondria with healthy donor mitochondria or direct genetic editing of the mutation
mitochondrial transfer
- extracting the chromosomes in metaphase II from the mother’s egg (whose mtDNA has some mutation) to then transfer them to a healthy donor egg, in which the chromosomes have been removed
- the hybrid egg is fertilized in vitro and then transferred to the mother’s uterus
Mitochondrial Transfer - 3-parent embryo
because the resulting embryo contains genetic
material from 3 individuals. T
Mitochondrial Gene Editing
a gene editing technology is used to directly remove and replace the D N A section containing the mutation. This method provides a more targeted approach that may be more effective
than mitochondrial transfer.
steps of editing gene using the crispr/cas9 technique step 1
- creaate a genetic sequence called a “guide RNA” that matches the piece of DNA they want to modify
steps of editing gene using the crispr/cas9 technique step 2
this sequence is added to a cell along with a protein called Cas9 which acts like a pair of scissors that cut DNA
steps of editing gene using the crispr/cas9 technique step 3
the guide RNA homes in on the target DNA sequence and Cas9 cuts it out. once their job is complete the guide RNA and Cas9 leave the scene
steps of editing gene using the crispr/cas9 technique step 4
now another piece of DNA is swapped into the place of the old DNA, and enzymes repair the cuts
CRISPR/Cas9 system
- genome editing tool that is rapidly replacing earlier methods due to its
efficiency and precision - CRISPR (clustered regularly interspaced short palindromic repeats) and its associated enzyme Cas9 (CRISPR-associated 9) are capable of recognizing specific D N A sequences,
cutting them and even replacing them with a new sequence.
CRISPR/Cas9 system was derived
from bacteria where it helps bacteria defend from viruses by recognizing and cleaving viral D N A. This
tool has revolutionized the way scientists perform genome editing.
ethical issues with embryo manipulation
- issue of selection
- issue of modification
- issue of long-term health of unborn offspring
THE ISSUE OF SELECTION
Although parents’ ability to select preferred genes may be far in the future, there are vital ethical
concerns that should be thoroughly evaluated in order to prevent the misuse of these technologies.
- choosing undesired genes “height, weight etc..”
THE ISSUE OF MODIFICATION
the ability to perform
genome editing on embryos raises ethical, legal, and health concerns. These matters are highlighted
when considering making changes to germ line D N A, since such changes can be passed on to future
generations
THE ISSUE OF LONG-TERM HEALTH OF UNBORN OFFSPRING
the extent to which this medical
technology affects the development of human embryos produced in vitro
- numerous mechanisms in addition to the D N A sequence that control the expression of genes. As the oldest ‘I V F children’ are at present only about 35 years of age, and the oldest child
conceived using I V F and intracytoplasmic sperm injection is 20 years old, we do not yet have a full
understanding of the long-term consequences of even the most non-invasive A R Ts on the health of
the resulting offspring. The mechanisms involving the regulation of the genes in embryos produced by
A R T are being studied for their effect on the resulting offspring and subsequent generations
developmental Origins of
Health and Disease (D O HaD) theory.
This concept of the uterine
environment influencing the future health of a person
Barker’s hypothesis formation
One of the earliest reports of the uterine environment influencing the future health of a child, was
found in a famous study published in 1986 by Barker
- noted poorest areas of england were the same areas with the highest rates of heart disease
- predictive relationship between low birth weight and heart disease in adults
Barker’s hypothesis
understand how fetal programming can influence health and disease and adulthood.
Fetal Programming:
The idea that the environment can alter physiological parameters of the
development of the embryo or fetus
epigenome about it
- researchers have confirmed that extrinsic factors such as nutrition, disease, and toxin exposure can induce changes in our genome without changing the underlying DNA sequence
Epigenetic mechanisms
make these changes possible and elements including histones, the proteins that package the D N A strand, and proteins that control gene transcription
genome
refers to our D N A sequence
epigenome
refers to elements that regulate the gene expression without
altering the D N A sequence.
Alterations in the epigenome
can persist throughout life and can be heritable, meaning that stressors
experienced by a parent can result in epigenetic changes in their children.
ART’s and epigenetic markers
some studies show that ARTs may have some effect on the epigenetic markers of manipulated embryos
do current assisted reproductive technologies have an impact on the future health of the children conceived
- yes
- some technologies are designed to select specific embryos before implantation in an attempt to prevent certain genetic conditions which definitely affect the child in the future
- gene editing have a more targeted effect to eliminate specific problems in the embryo and they might be affecting the epigenome which could affect multiple generations
