Fertility Preservation Flashcards
Why is fertility preservation important?
There are some things that can cause premature failure and infertility and if we know this is going to happen then we take steps to preserve the infertility:
Cancer, radiotherapy & chemotherapy can cause premature gonadal failure. Associated somatic disorders such as fever, malnutrition, anxiety or depression may affect fertility.
20% of patients with premature ovarian failure have an autoimmune associated disease such as diabetes, thyroid dysfunction, Addison syndrome, Crohn’s disease etc.
Surgery, endometriosis, infection, family history of premature ovarian failure & idiopathic causes.
Women delaying child bearing due to social factors.
What is the main reason for preserving fertility?
Cancer is the main reason for preserving fertility.
Half of people diagnosed with cancer now survive their disease for at least five years - cancer survival rates in the UK have doubled in the last 40 years.
Almost three-quarters of children are now cured of their disease, compared with around a quarter in the late 1960s.
Cancer therapy can result in infertility or premature gonadal failure leading to a significant quality of life issue for young survivors.
Approximately 75% of patients under 35 who are childless at the time of cancer diagnosis desire children in the future.
Surgery
Males
Unilateral orchidectomy (removal of the testis) reduces sperm concentration. Reduced spermatogenesis is reversible within the first year after surgery.
Retroperitoneal lymph node dissection can cause serious disruption of ejaculation (testicular or renal cell carcinoma).
Radical prostatectomy may lead to erectile dysfunction (nervous supply damaged), retrograde ejaculation (ejaculation back down the urethra into the bladder) and poor semen quality.
Rectal cancer surgery may lead to erectile dysfunction (nervous supply).
Females
Hysterectomy (removal of the uterus) or oophorectomy (removal of the ovaries) may be performed.
In some women with early stage ovarian or cervical cancer it is appropriate to attempt to retain one ovary, both for future fertility and hormone production.
Patients with small cervical cancers may undergo trachelectomy, which removes the cervix but leaves the uterus in-situ.
Sometimes surgery can cause scarring in the uterine tubes which may obstruct them.
Radiotherapy (Males)
Irradiation in the G2 phase of the cycle induces chromatid aberrations. Analyse dose/response of peripheral blood cells, enabling restriction of dose.
There are varying amounts of infertility with increasing dose
0.5 Gy Transient suppression with subsequent recovery of spermatogenesis.
2–3 Gy Period of azoospermia after which full recovery is expected within three years.
4–6 Gy Recovery is not universal and may take up to five years.
6 Gy High risk of permanent sterility.
With radiotherapy some of the radio waves might bounce off bones and are reflected around.
Total body irradiation (TBI) with high-dose chemotherapy will sterilise men.
With tumours in the head and neck you risk damage to the HPG axis.
Radiotherapy (Females)
Ovarian damage depends on patients age, dose & field of irradiation. Radiation to the pelvis can have a direct negative impact on ovarian function and the uterus by altering vascularisation.
Doses of 4-6 Gy can produce a loss of 50% of the follicle population.
Total body irradiation (typically 10-12 Gy) causes infertility, recovery of ovarian function occurs in 10-15% of cases.
Non-pelvic radiation, especially head and neck may disrupt the hypothalamic-pituitary axis.
Chemotherapy- what is it?
Is the main one as it is systemic. It attacks mainly dividing cells (tumours) BUT any other rapidly diving cell will also be targeted, therefore hair follicles are damaged. Some of the therapy is toxic to the sperm and oocytes.
Chemotherapy (Males)
Males
Most chemotherapeutic agents are gonadotoxic. Alkylating agents pose the greatest risk to spermatogenesis.
DNA of spermatozoa can also be damaged by low doses of chemotherapeutic agents – DNA integrity may be recovered after treatment.
BUT if you damage the primordial germ cells, then you have irradicated the fertility.
Not all chemotherapy regimens affect male fertility, preservation is only offered where a high risk of azoospermia or DNA damage is expected.
Chemotherapy (Females)
Is determined by their ovarian reserve before you start, the type of chemotherapy and the dose.
Several mechanisms including follicular depletion, vascular damage, cortical fibrosis.
The most damaging types of chemotherapy are Alkylating agents such as cyclophosphamide they are most gonadotoxic since they are not cell cycle specific and also affect other cells in the ovary. All patients exposed to chemotherapy might have a diminished ovarian reserve, this could lead to premature menopause.
Younger patients 20% - 90% affected .
Probability of early menopause is at least 25% at age 30 years. Infertility at 35 years >40%.
Women over 40 years have a 90% chance of amenorrhoea subsequent to multi-agent chemotherapy.
Effect of chemotherapy on the ovary?
As dose increases the number of primordial follicles reduces.
Patient psychological concerns & reactions
Digesting the ‘double blow’. Bewildered and overwhelmed. Cancer and infertility
Feelings of being ‘out of control’ and struggling to regain a sense of personal stability.
Sense of being robbed of one’s manhood or womanhood.
Grief over the possible loss of the opportunity to fulfill one’s dreams.
Anger toward the medical community for failing to provide adequate information regarding fertility risks.
Fertility preservation options- for males
In adults: Before treatment freeze their sperm
Testicular tissue cryopreservation – Surgical removal of testicular tissue and maturation in-vitro/autotransplantation. (eg seminiferous tubules)
Fertility preservation options- for females
For pre-pubescent: Ovarian tissue cryopreservation- Surgical removal of ovarian tissue and later autotransplantation
In-vitro maturation of oocytes/follicles Collection of immature oocytes (at any stage) and maturation in-vitro in lab
Ooctye / Embryo cryopreservation – Freeze eggs, Controlled ovarian stimulation / oocyte retrieval followed by IVF
Oophoropexy - Surgical relocation of ovaries outside radiation field
Ovarian suppression (with GnRH) – whilst treatment is happening, idea is that: if the ovary is more quiescent then there is less damage.
Oocyte cryopreservation- background
Have an IVF cycle and then collect the eggs
Controlled ovarian stimulation using gonadotrophins for 8-12 days followed by oocyte retrieval.
There was difficulties with slow freezing – ice crystal formation, low survival and poor embryo quality. Now becoming routine practice in IVF centres with the development of oocyte vitrification - quicker so there is no ice crystal formation
Suitable strategy for patients who can postpone oncologic treatment and where COS is not contraindicated.
Valid option for post pubertal women without a male partner or those who do not want donor sperm or object to embryo cryopreservation.
Could alternatively freeze embryos – more reliable
Issues with oocye cryopreservation
The entire process takes a minimum of 2-3 weeks depending upon the patients menstrual cycle. So time is an issue if the patient has a verry aggressive tumour
Exposure to high levels of estradiol is contraindicated. There is controversy on this issue with some authors arguing that a short-term increase is not harmful.
Some tumour cells contain estrogen receptors (common in breast cancer). So by allowing multiple follicles to grow, we will produce mass amounts of estrogen and stimulate the growth of the tumour.
Ovarian stimulation protocols including aromatase inhibitors have been described in order to avoid excessive high estradiol levels.
Embryo cryopreservation- background
Most standardised procedure
High embryo survival and cumulative pregnancy rates of 60%
BUT there is Requirement for male partner or sperm donor.
Ethical implications of increasing numbers of embryos stored in IVF clinics make oocyte vitrification a preferred option in many cases.
In-vivo maturation of oocytes
Less invasive
Retrieval of immature oocytes followed by in-vitro maturation.
Will culture and grow the oocytes so that they are ready for ovulation
One of the strategies in cases where ovarian stimulation is not possible.
Oocyte retrieval usually performed prior to ovulation, but immature oocytes can be recovered during both follicular and luteal phases.
Vitrification of IVM oocytes has resulted in live birth rates <20%. Survival and fertilisation rates lower than for oocytes matured in-vivo.
In-vitro follicle culture
Here a whole follicle is removed as opposed to just the oocyte
Proposed as an alternative to IVM, the aim being to develop an in-vitro system that allows growth of primordial follicles to antral stages in order to obtain mature oocytes.
Given the complexity of folliculogenesis, much research into culture conditions is still necessary in order to achieve results for clinical practice. STILL IN RESHEARCH
Ovarian tissue cryopreservation
Removal of some of the ovary and freeze it. Then when the patient has recovered, you transplant their ovarian tissue back to them.
Removal of an ovary and cryopreservation of cortical fragments. Fragments may be autotransplanted after recovery.
Becomes fertile and also causes resumption of menstrual cycle
Primordial follicles are relatively resistant to cryopreservation injury. Despite this a high loss of follicles may occur during the ischemic period until revascularisation is established.
The PF are not that active, there is no antrum, not much fluid so they are resistant to the freezing process.
Because of the lack of a world-wide registry the effectiveness of the technique has not been quantified. However, the leading groups report encouraging success rates.
One concern is the risk of re-seeding malignant cells – the technique is contraindicated in leukaemias.
It is the only option for pre-pubescent girls and women who cannot delay cancer treatment or undergo controlled ovarian stimulation.
As you cannot use IVF
Can be used to help with puberty later on
Transplants of cortical fragments can be done
orthotopically – contralateral ovary
heterotopically – eg. peritoneal cavity
Neoangiogenesis is still the limiting factor as it takes up to 5 days and leads to some loss of primordial follicles.
Pregnancies reported to date have been both spontaneous and after IVF.
Orthotopically
something that occurs in the normal or usual place in the body. It is often used to describe tissue or an organ that is transplanted into its normal place in the body.
- contralateral ovary
Heterotopically
Heterotopic: In the wrong place, in an abnormal place, misplaced. From the Greek roots “hetero-“ meaning “other” + “topos” meaning “place” = other place. For example, heterotopic bone formation is the formation of bone where it is not normally found, as in muscle.
Pregnancy after cancer
Cancer survivors often desire, yet fear, pregnancy after cancer therapy…particularly that for hormone-responsive malignancies like breast cancer (estrogen receptor positive).
Multiple studies have show that pregnancy after cancer does not appear to adversely affect recurrence or survival (relapse risk).
Generally patients are recommended to wait at least 2-5 years after therapy is concluded .
A final concern of many patients is whether offspring from gametes exposed to cytotoxic agents have an increased risk of birth defects.
Laparoscopic oophorectomy
You make 3 small holes in the abdomen.
One has camera with light
One has scalpel
One has plastic bag on a stick
So you drop the ovary into the bag and take it out the hole
Half a follice:
Get the ovary
Dissect off the cortex
Cut the cortex into small pieces
The pieces have to be the correct size and volume (then can freeze)
Freezing ovarian tissue
Start by incubating the ovarian pieces with cryoprotectant (antifreeze solution) to delay or stop the formation of ice crystals.
Then the machine does a slow freezing protocol to -196c
Cryoprotectant
Incubation 30min @ 1◦C
0.1 mM Sucrose
1.5 mM ethylene glycol
Phosphate buffered saline
Freezing cycle
2°C/min to -9°C
5 min of soaking
Manual seeding for ice crystal nucleation induction 2-3 seconds
0.3°C/min to -40°C
10°C/min to -140°C
Plunge into liquid nitrogen at -196°C
Ovarian tissue autotransplantation site
Can transplant the frozen ovarian tissue anywhere:
Can put it on the contralateral ovary (orthotopic)– if you remove one ovary and the other has been damaged. Then put the tissue fragment on the damaged ovary.
From this you can get natural conception or do it via IVF
BUT the contralateral ovary isn’t the best place to put it due to the tissue survival as once you defrost the ovarian tissue it is becomes ischaemic.
There will be time before angiogenesis occurs, and the contralateral ovary is not the best location for angiogenesis.
This is called orthotopic – where it is put on the other ovary
Can be heterotopic
Make a pocket in the peritoneal and place it in the pelvic wall.
In this location angiogenesis is quicker so there is better survival.
BUT you will not be able to get natural conception as the egg will be released into the pelvis.
So will have to use IVF
