FERTILITY PRESERVATION

Q.Who should be offered fertility preservation in the case of both males and females?

Ideally anyone at risk of loss of ovarian function in females and or loss of reproductive potential in case of males.

 Causes of loss of ovarian function:–

Oncogenic causes—

• All forms of cancer patients requiring   radiotherapy /chemotherapy.
• Mutation carrier for certain types of cancer.

Nononcogenic causes:-

• Autoimmune diseases
• Endometriosis
• Any surgery on the reproductive tract —ovarian cystectomy etc.
• Social /iatrogenic —wanting to postpone childbirth.
• Patients undergoing bone marrow or stem cell transplantation.
• MS patients receiving new generation treatments.
• Patients with genetic mutations leading to loss of fertility and early menopause.

Fertility preservation program requirements:-

• Rapid access
• Interdisciplinary medical team –oncologists,reproductiveendocrinologists,urologists,reproductive surgeons trained in FP techniques.
• Lab requirements—Experienced ART programs—embryo cryopreservation/oocyte cryopreservation/cryopreservation of ovarian and testicular tissues
• Counsellors –

Mental—to navigate them for a difficult decision making process.

Genetic —risk of transmission to offspring /genetic testing like PGT .

Financial—cost due to lack of insurance coverage.

Medical considerations to be discussed:-

• All methods of FP.
• Give alternative options of donor gametes,donor embryos and adoption.
• Given state of the patient capable of undergoing the procedure.
• Potential safety of future  pregnancy after cancer should be addressed especially after pelvic irradiation.
• Infectious disease testing for all patients banking.
• All those who elect  to cryopreserve —disposition in the event of death should be discussed and documented.

Chemotherapy –the impact is mostly on ovaries .Degree of damage is dependant on:

• Type of agent .
• Dose given.
• Age of patient
• Baseline ovarian reserve .

The prepubertal ovary is less susceptible to ovarian failure as contrast to older women.

Radiotherapy-affects ovaries and uterus.

Human oocyte is sensitive to radiation with estimated lethal dose of <2Gy.prepubertal uterus is more susceptible to irradiation.

FERTILITY PROTECTION -MEDICAL AND SURGICAL STRATEGIES

1)Fertility sparing surgery like ovarian transposition ,sparing surgery for cervical cancer etc.

2)Ferto protective adjuvant therapy is the administration of adjuvant therapy during or prior to chemotherapy with an agent which prevents loss of ovarian reserve.eg—the only drug used in clinical practice is GnRH agonist.

FERTILITY PRESERVATION TECHNIQUES IN FEMALES

1)Embryo cryopreservation-this requires the patient to go through IVF .

Limitations:-

• Controlled ovarian stimulation takes approx. 2weeks from the 2^nd day of period which may delay cancer treatment.
• High estradiol treatment during stimulation may have anegative effect on estrogen sensitive tumors .
• Partner”s or donor sperm required which limits reproductive autonomy in the future and increases stress levels.
• Ethical,legal and religious implications regarding disposal of embryos in case patient dies before she can use the embryos or there is a separation of partners
• Cannot be used in prepubertal patients.

2)Oocyte preservation—it is an option in an unmarried woman or those who do not have apartner.it is a better option for all those who want to maintain a reproductive autonomy.due to improved freezing thawing techniques pregnancy rates with oocytes have improved.

Both embryo and oocyte cryopreservation cannot be performed in prepubertal girls.Another disadvantage is that only a limited numberof oocytes/embryos can be collected/generated in one attempt which in turn restricts the number of attempts for pregnancy.Also both the above require ovarian stimulation.

CONTROLLED OVARIAN STIMULATION:-

Limitations:-

• Recommended only if the patient “s medical condition permits to carry out both COS and oocyte retrieval safely.
• Time is a constraint since IVF starts from day 2 of the period –so delay in cancer therapy. To avoid delay random start COS has been suggested.
• Oocyte recovery is not compromised prior to cancer therapy but ovarian reserve may be compromised.

Ovarian stimulation regimes:-

• GnRH antagonist protocols afford more flexibility and are favoured because of lower estradiol rise and lower gonadotrophin usage.
• Dose of gonadotrophins based on AMH,BMI,AFC and AGE.
• Luteal phase and random start stimulations have been proposed.
• Anti estrogens letrozole and tamoxifen  have been added to OS regimes to lower the peak estradiol levels in oestrogen sensitive tumors
• Complications—to avoid OHSS,delay in cancer therapy,stimulation of estrogen sensitive tumors,risk of thromboembolism.

3)In vitro maturation—involves aspiration of mature oocytes after minimal or no stimulation followed by IVM and cryopreservation of mature oocytes.These can also be collected in the luteal phase and from antral follicles in the ovarian tissue removed for cryopreservation.

4)Ovarian tissue cryopreservation—involves obtaining ovarian cortical tissue that is rich in primordial follicles prior to ovarian failure by laparoscopy or laparotomy. And preserved by slow cooling or vitrification.

Two types—a) Orthotropic, & b) Heterotopic                      

Advantages:-

a) Does not delay cancer therapy.

b) Avoids risk of Ovarian stimulation.

c) No need for donor or partner sperm.

d) Allows larger pool of follicles to be preserved.

e) Ovarian function generally resumes between 60 and 240 days post transplant and last upto 7 years.

f) Only technique available for prepubertal girls.

Disadvantage:-

a) Reseeding of tumor cells after ovarian transplant esp in leukemias.

b) Male fertility preservation :

Sperm cryopreservation

It is the most common technique utilized for fertility preservation in pubertal and post-pubertal males. The potential benefits of cryopreservation have significantly increased following advancements in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) techniques, as only one appropriately preserved sperm is required for oocyte fertilization and future paternity.

In the case of anatomic obstruction (absence of the vas, prostatectomy, prior vasectomy, epididymal obstruction, etc.), sperm can be obtained via multiple techniques, including microsurgical epididymal sperm aspiration (MESA), percutaneous epididymal sperm aspiration (PESA), testicular sperm extraction (TESE), or testicular sperm aspiration (TESA). Testicular microdissection (micro-TESE) may be utilized in the setting of poor sperm retrieval using the above techniques. Sperm obtained via these methods can be frozen for future use or can be utilized immediately.

Testicular Tissue Cryopreservation  For prepubertal patients who have not initiated spermatogenesis, investigators are examining cryopreservation of testicular tissue through either cell suspension or whole tissue as a possible option for fertility preservation. Tissue can be obtained through the techniques previously described, including TESE, MESA. Although prepubertal germ cells do not contain mature spermatozoa, they do demonstrate the presence of spermatogonial diploid stem cells, which maintain the capacity to differentiate into mature cells given the appropriate microenvironment. The hope is that one day technology will evolve to permit successful use of this immature, cryopreserved, testicular tissue in ART.