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Fertility preservation is a means for preserving an individual's ability to reproduce at will or at a chosen time.

The reasons why preserving fertility can be offered as a safe option in current times are:

1. The post-thaw embryo or gamete survival rate is 90% and implantation rate is 50%.
2. There is a marked increase in the incidence of cancer worldwide, and increasing childhood cancer survivors.
3. The trend of men and women delaying childbearing.

ESHRE (2020) indications for fertility preservation in women

1. Post pubertal woman with cancer undergoing gonadotoxic therapy.
2. Post pubertal women with benign diseases undergoing gonadotoxic therapy.
3. Women with genetic conditions predisposing to premature ovarian insufficiency. (POI)
4. Transgender men previously assigned as women at birth.
5. Women considering oocyte cryopreservation for age related fertility loss.

Post pubertal women undergoing chemo or radiotherapy for cancer.

Cyclophosphamide, chlorambucil, busulfan, Mechlorethamine cause breakage of double strand or single search strand DNA in the ovarian cells. They cause cortical fibrosis and blood vessel damage in the ovarian tissue resulting in premature ovarian insufficiency. Radiotherapy damages the ovaries and uterus by reducing the vascularity, causing myometrial fibrosis and endometrial damage and also reducing uterine volume.

Post pubertal women undergoing chemotherapy or radiotherapy for non-cancerous conditions

Stem cell transplantation, bone marrow transplantation, non-oncological conditions like thalassemia major, aplastic anaemia, sickle cell anaemia, myeloproliferative and myelodysplastic disorders are some situations where ovarian cryopreservation may be sought for.

Alkylating agents are also used in autoimmune diseases like SLE, Behcet’s syndrome, Sjogren’s syndrome, steroid resistant glomerulonephritis, irritable bowel disease, Scleroderma etc.

Genetic conditions that predispose to TOI.

Turner's syndrome fragile X syndrome galactosemia

Endometriosis

Fertility preservation must be offered in endometriosis if:

There is an alteration in ovarian reserve because of repetitive surgeries.

Recurrent endometriosis bilateral endometrioma.

Large, more than five centimetre emdometrioma.

Patient selection for fertility preservation

A detailed evaluation of the patient, ovarian reserves (age, AMH and AFC), underlying disease, surgical/anesthetic risk, assessment of health status constitute the initial evaluation.

The patient is counselled about the time available for the procedure, the possibility of malignancy contaminating the tissues, the expertise available and whether the treatment is of high, medium, low or uncertain risk. A fully informed consent is obtained.

Model of care for patients seeking fertility preservation

1. The clinical care team comprehends the impact of the disease or treatment on infertility and hence refers the patient to the fertility preservation team.
2. The fertility preservation team does the patient assessment, provides information and decides about the method of fertility preservation and intervention.
3. After treatment reproduction involves assessment of fitness for pregnancy, timing and follow up of pregnancy and detailed discussion about the options.

Fertility preservation methods in women

This includes embryo cryopreservation, oocyte cryopreservation, ovarian tissue cryopreservation, transposition of ovaries and hormonal suppression.

Embryo cryopreservation

Current cryopreservation techniques offer 90% survival post-thaw and pregnancy rates of upto 45 to 50% At least 2 weeks are needed for ovarian stimulation and oocyte retrieval. This can be a limitation if women need immediate therapy, and also in case of pre pubertal girls and single women.

Oocyte cryopreservation

This is ideal for women without partners. MII, MI and GV oocytes can be cryopreserved. MI and GV oocytes can later be subjected to In Vitro Maturation (IVM) and frozen. In IVM, immature oocytes are retrieved with minimal or no stimulation and then they are allowed to mature in vitro over 24 to 48 hours, and cryopreserved as oocytes or even embryos (if fertilised with the partner semen). It is of relevance if the woman has to start treatment immediately

Ovarian tissue cryopreservation

The indications for this include:

1. Situation where oocyte or embryo cryopreservation is not feasible, or patient refuses other forms of treatment.
2. Patients with primary ovarian insufficiency associated with genetic or chromosomal disorders.
3. Pre pubertal girls
   The contraindication to ovarian tissue cryopreservation are patients with low ovarian reserve ( AMH < 0.5 ng/ml or AFC less than 5 or age more than 36.)
   The preservation can be ovary as a whole or only ovarian cortical tissue. Slow freezing and not vitrification is the method used.
   The tissue thus preserved can be utilised in two ways. It could be implanted back after cancer therapy, or the follicles can be made to undergo in vitro maturation and eggs harvested. Ovarian tissue transplant (OTT) OTT is orthotopic when the Ovary is implanted back into the ovarian fossa, or as heterotopic when it is implanted into the other places.
   

Transposition of ovaries ( Oophoropexy.)

This is a method of moving ovaries out from the field of radiation and can be used for women undergoing radiotherapy. The contraindications are women with high risk of variant metastasis and low ovarian reserve.

Harmonic suppression with GnRH agonist pretreatment during and for 2 weeks post chemotherapy can help protect the ovaries by reducing amenorrhoea and also insufficiency. This is offered to pre-menopausal women with cancer breast receiving cancer chemotherapy and those with autoimmune diseases receiving cyclophosphamide.

Emerging technologies in cryopreservation for women:

1. Ovarian follicle culture in vitro
   In order to avoid risks of reintroducing cancer cells with OTC and OTT. Oocytes are developed from in vitro cultures. But this is still experimental.
2. Ovarian follicle transplantation (Artificial Ovary)
   This involves cryo preserving ovarian tissue grown on biodegradable 3D matrix scaffold. This can restore fertility and hormonal functions once transplanted in patient.
3. Using Stem cells to develop into oocytes
   Oogonial stem cells (OSC), Embryonic stem cells (ESC), Induced pluripotent stem cells (IPS) are being used to develop into oocytes.
4. In vitro activation of ovarian follicle.
   Inducing activation of primordial follicles by ovarian fragmentation, drilling or laser are used to disrupt the hippo signalling pathways and activate the primordial follicle. Activated follicles are then treated with AKT stimulators, P13K activators and P-10 inhibitors that proote growth of the follicle. This is later auto-transplanted.
5. Using drug delivery systems for particular target tissues.
   Use of nanoparticles to delivery chemotherapeutic agents to specific target cells, use of ferti-protective reagents ( drugs which kill the cancer cells but protect oocytes against chemoradiation) are being tried.

To conclude

Women can now be offered the autonomy to bear the child according to their will and time of their preference. Robust cryopreservation, with good post-thaw and successful fertilisation rates, increasing trend of starting a family at an older age are some contributors that are favouring fertility preservation.