Fertility Perservation

Question 1

Why do we need to preserve fertility?

Answer 1

1. Cancer, radiotherapy and chemotherapy can cause premature gonadal failure.
2. 20% of patients with premature ovarian failure have autoimmune associated disease such as diabetes, thyroid dysfunction, addition syndrome, Cohen’s disease
3. Surgery endometriosis, infection, family history of premature ovarian failure and idiopathic causes.

Question 2

How does cancer link to fertility?

Answer 2

Half the people diagnosed with cancer now survive and almost 75% of children are now cured.
Cancer therapy can result in infertility or premature gonadal failure leading to a significant quality of life issues for young survivors

Question 3

What are some surgeries that can preserve fertility in females?

Answer 3

1. Hysterectomy or oophorectomy may be performed
2. Ovarian or cervical cancers may undergo trachelectomy, which removes the cervix but leaves the uterus in situ

Question 4

What are limitations to the surgery?

Answer 4

• surgery can cause scarring in the uterine tubes which may obstruct them

Question 5

What are surgeries to perserve fertility in males?

Answer 5

• unilateral orchidectomy reduces sperm conc, 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 prostectomy may lead to erectile dysfunction, retrograde ejaculation and poor semen quality
• Rectal cancer surgery may lead to erectile dysfunction

Question 6

Radiotherapy causes damage to males reproductive system:

Answer 6

Irradiation in the G2 phase of the cycle induces chromatid defect.
Analyse dose/response of peripheral blood cells, enabling restriction of dose.

As you increase dose of radiation the damage becomes more reversable :

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.
Total body irradiation (TBI) with high-dose chemotherapy will sterilise men.

Question 7

Radiotherapy causes reproductive damage to females

Answer 7

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.

The damage is dose dependent:
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.

Question 8

chemotherapy on males

Answer 8

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.

!Not all chemotherapy regimens affect male fertility,
preservation is only offered where a high risk of
azoospermia or DNA damage is expected.

Question 9

chemotherapy on females

Answer 9

Several mechanisms including follicular depletion,
vascular damage, cortical fibrosis.

Alkylating agents such as cyclophosphamide 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.

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.

Question 10

The effect of chemotherapy on the ovary

Answer 10

• no. of surviving primordial follicles following exposure correlates inversely to dose of chemotherapy
• if a women is younger and has more primordial follicle you need to try preserve it from damage so use lower doses.
• likely to get early menopause : the age of a women and dose-dependent

Question 11

Patient psychological concerns & reactions

Answer 11

• Digesting the ‘double blow’. Bewildered and overwhelmed.
• 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 opportunity to fulfil one’s dreams
• Anger toward the medical community for failing to provide adequate information regarding fertility risks.

Question 12

Fertility preservation options

Answer 12

Question 13

What is cryopreservation?

Answer 13

egg freezing
a process in which women’s oocytes are extracted and frozen.

Question 14

Oocyte cryopreservation

Answer 14

-Controlled ovarian stimulation using gonadotrophins for 8-12 days given to women before oocyte retrieval.

-The entire process takes minimum of 2-3 weeks depending upon patients menstrual cycle

-Exposure to high levels of estradiol is contraindicated.
There are controversy on this issue - arguments that a short term increse is not harmful.

-ovarian stimulation protocaols including aromatase inhibitors have been described in order to avoid excessive high estradiol levels

Question 15

What are advantages of cryopreservation?

Answer 15

-Suitable strategy for patients who can
postpone oncologic treatment and where
controlled ovarian stimulation 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.

Question 16

What are limitations of cryopresevervation?

Answer 16

-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.

Question 17

What is vitrification?

Answer 17

alternative to cryopreservation, enables hydrated living cells to be cooled to cryogenic temperatures in the absence of ice so avoids the ice crystallisation issue

Question 18

Embryo Cryopreservation issues

Answer 18

Most standardized procedure
High embryo survival and cumulative pregnancy rates of 60%.
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.

Question 19

In- Vitro maturation of oocytes

Answer 19

Retrieval of immature oocytes followed by in-vitro maturation.
One of the strategies in cases where ovarian stimulation is not possible, can’t give the women gonadotrophins for some reason or the oocyte is not naturally entering ovulation state.
immature oocytes can be recovered during both follicular and luteal phases.

Limitations :
Vitrification of IVM oocytes has resulted in live birth rates <20%.
Survival and fertilisation rates lower than for oocytes matured in-vivo.

Question 20

In- vitro follicle culture

Answer 20

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

Question 21

Ovarian tissue cryopreservation

Answer 21

Removal of an ovary and cryopreservation of cortical fragments.
Fragments may be autotransplanted after recovery.
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.
Because of the lack of a worldwide registry the
effectiveness of the technique has not been quantified.
However, the leading groups report encouraging success rates.

Question 22

what is the only option for pre-pubescent girls and women who cannot delay cancer treatment or undergo controlled ovarian stimulation?

Answer 22

• ovarian tissue cryopreservation because no sperm to do embryo cryopreservation

Question 23

Transplants of cortical fragments can be done

Answer 23

• orthotopically: contralateral ovary = in the right place = ovary
• heterotopically : peritoneal cavity = different place = need IVF to impant it in the right place

Question 24

What is the limiting factor of ovarian tissue cryopreservation?

Answer 24

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

Question 25

Laparoscopic oophorectomy - removing ovary

Answer 25

- cut the belly -put camera in one hole and plastic bag to collect ovary - ovary removed -cut it into small equal piecese and freeze it

Question 26

Freezing ovarian tissue - cryoprotectant

Answer 26

- incubation 30 min @ 1 degree - 0.1 mM sucrose - 1.5 mM ethylene glycol - phosphate buffered saline

Question 27

Freezing ovarian tissue - freezing cycle

Answer 27

1. 2 degree/min to -9 degree 2. 5 min of soaking 3. Manual seeding for ice crystal nucleation. induction 2-3 seconds 4.0.3 degree /min to -40 degree 5. 10 degree/ min to -140 degree 6. plunge into liquid nitrogen at -196 degree

Question 28

Thawing frozen ovarian tissue

Answer 28

1. 0.75M ethylene glycerol , 0.2 M sucrose in PBS 10 min 2. 0.1M sucrose in PBS 10 min 3. PBS 10min

Question 29

Ovarian tissue autotransplantation site - where do we implant the ovarian tissue back?

Answer 29

orthotopic - colateral ovary = right place = you get a cycle = they get pregnant spontaneously no need for IVF because ovarian tissue is in the right place peritoneal wall = insert the ovary tissue and stitch = cycle = IVF needed to get the ovarian tissue in the right place

Question 30

Ovarian Cryopreservation advantages

Answer 30

- available at short notice - preserves functional unity of the ovary - the follicle - preserves potentially a large number of follicles - only option available for pre-pubertal girls

Question 31

Ovarian cryopreservation limitations

Answer 31

efficacy is unknown... not enough data Risk of transplanting the original disease /malingnant cell Functional duration of the transplants.

Question 32

Pregnancy after cancer

Answer 32

Cancer survivors often desire, yet fear, pregnancy after cancer therapy...particularly that for hormone-responsive malignancies like breast cancer. Multiple studies have show that pregnancy after cancer does not appear to adversely affect recurrence or survival. 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.

Question 33

Some ethical issues in oncofertility

Answer 33

* Is fertility preservation successful? * What are the risks of delaying treatment? * What is the hormonal impact of treatment or pregnancy on the tumour? * Are there long term risks to fertility preservation strategies? * Are some patients too ill to consider fertility preservation? If so who decides? Should patients freeze eggs, embryo’s or ovarian tissue? What happens to these if the patient dies? * What is ethically responsible fertility preservation for children with cancer? * At what age should fertility preservation be discussed? * Who should pay for fertility preservation?

Question 34

summary

Answer 34

The diagnosis of cancer can be overwhelming, healthcare professionals need to be informed about fertility preservation. Rapid referral to a reproductive specialism is essential because some fertility preservation strategies require 2-3 weeks to complete. Many technical, logistic and ethical questions surround this field and more will emerge as the technology continues to develop.