Fertility preservation

FERTILITY PRESERVATIONFERTILITY PRESERVATION

Hesham Al-Inany, M.D, PhDHesham Al-Inany, M.D, PhD

WHY THIS TALK

Increase incidence of cancer during the

reproductive age. Survival and cure rates of cancer are improving. One in 1000 adults is a survivor of childhood cancer.

BREAST CANCER

The commonest malignancy in women during reproductive age.

One out of every 228 women will develop breast cancer befor 40 years of age.

15% of all breast cancer occur at <40 years.

AUTOIMMUNE DISEASES TREATED WITH CHEMOTHERAPY.

SLE; systemic lupus erythematosus (incidence 3 per 1000 people )

Behcet’s disease. Autoimmune glomerulonephritis. Crhon’s disease. Ulcerative colitis Using cyclophosphamide , methotrexate , 5

fluoro-uracil.

HAEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT)

Pre-existing bone marrow ablation using cytotoxic chemotherapy is a pre-requisit before HSCT. (for example: treatment of leukaemia )

CONSEQUENCES OF MULTI-AGENT CHEMOTHERAPY AND RADIOTHERAPY

Premature ovarian failure (POF). Early pregnancy loss.

FACTORS AFFECTING THE EXTENT OF CHEMOTHERAPY INDUCED

GONADOTOXICITY.

Type, duration, dose. Gonatotoxicity induced by chemotherapy

is almost irreversible.

FACTORS AFFECTING THE EXTENT OF RADIOTHERAPY INDUCED

GONADOTOXICITY

1. Patient’s age. 2. Dose of radiation (Breaking point 300cGy). 3. Extent. 4. Type of radiation (abdominal, pelvic external beam,

brachytherapy).

AMENORRHEA

Temporary amenorrhea or permanent. Older women have a shorter duration of

onset of amenorrhea<40years 6-16 months.>40years 2-4 months.

Agents Effect on sperm

• Radiation to the testes, Chlorambucil, Cyclophosphamide, Procarbazine, Melphalan, Cisplatin

Prolonged azoospermia

• BCNU, CCNU Azoospermia in adulthood after treatment before puberty

• Busulfan, Ifosfamide, BCNU, Nitrogen Mustard, Actinomycin D

Azoospermia likely, but always given with other highly sterilizing agents

• Carboplatin Prolonged azoospermia not often observed at indicated dose

• Doxorubicin, Thiotepe, Cytosine arabinoside, Vinblastine, Vincristine

Can be additive with above agents in causing prolonged azoospermia, but cause only temporary reductions in counts when used alone

• Amacrine, Bleomycine, Dacarbazine, Daunorubicin, Epirubicin, Etoposide, Fludarabine, 5-Fluorouracil, 6-Mercaptopurine, Methotrexate, Mitoxantrone, Thioguanine

Only temporary reductions in counts at doses used in conventional regimens, but additive effects are possible

• Newer agents?

Lee et al. JCO, 2006

SO WHAT TO DO??

ASAP

The decision for fertility preservation should be considered as soon as possible to maximize the likelihood of success.

FERTILITY PRESERVATION STRATEGIES

Pharamacolgical protection. IVF and cryopreservaion of embryos. Oocyte cryopreservation. Ovarian transposition. Cyropreservation and transplantation of

ovarian tissue.

PHARMACOLGIC PROTECTION A) GnRH agonists.

Premenarchal gonads appear to be least sensitive to cytotoxic drugs.

By suppressing gonadotrophin. No protection effect of radiation therapy. No protetive effect on male gonads.

B) GnRH Antagonists.

Potentially relevant RCTs identified

and screened for retrieval (n= 1439)RCTs excluded,

Duplicate publication (n=78)

RCTs retrieved for more detailed

evaluation (n=1361)RCTs excluded

Does not fulfill the inclusion criteria

(n= 1336)

Potentially appropriate RCTs to be

included in the meta-analysis (n=25) RCTs excluded from meta-analysis:

- GNRH agonist was begun after chemotherapy; no concomitant treatment of GnRH agonist and chemotherapy (n= 6)

- Majority of patients had oophorectomy prior to treatment

(n= 1)

- Ovarian suppression performed reversibly (GnRH agonist for 3 years) or irreversibly (oophorectomy or radiotherapy). Data not provided separately (n= 1)

RCTs included in meta-analysis (n=17)

RCTs withdrawn, by outcome:

- No data available for inclusion

(n= 13)

RCTs with usable information,

by outcome (n= 4)

VALUE OF GNRH AGONIST IN REDUCING POF

Study or Subgroup

Badawy 2008Gilani 2007Guiseppe 2007Sverrisdottir 2009aSverrisdottir 2009bWaxman 1987ZORO 2009

Total (95% CI)

Total eventsHeterogeneity: Tau² = 1.38; Chi² = 17.68, df = 6 (P = 0.007); I² = 66%Test for overall effect: Z = 2.17 (P = 0.03)

Events

351514824

21

99

Total

40151429378

30

173

Events

13108236

17

59

Total

40151528291030

167

Weight

18.9%8.8%8.8%

15.6%14.3%14.2%19.5%

100.0%

M-H, Random, 95% CI

14.54 [4.62, 45.78]16.24 [0.81, 325.88]25.59 [1.29, 506.45]

4.95 [0.95, 25.86]0.50 [0.08, 3.18]0.67 [0.10, 4.35]1.78 [0.62, 5.17]

3.46 [1.13, 10.57]

GnRH Control Odds Ratio Odds RatioM-H, Random, 95% CI

0.01 0.1 1 10 100Favours Control Favours GnRH



ovarian tissue.

IVF

IVF before cancer treatment and cryopreservation of Embryos.

IVF after cancer treatment. (poorer responses)

CRYOPRESERVATION OF PREIMPLANTATION EMBRYOS

18.6% success rates. Survival rates of embryos between 35

and 90%. 8 – 30% implantation rates. Not acceptable to prepubertal,

adolescent and women without a partner.

LIMITATIONS

Some female treatments are dependent upon phase of the menstrual cycle and can be initiated only at monthly intervals

LIMITATIONS Requires 10–14 days of ovarian stimulation from the

beginning of menstrual cycle It is a surgical procedure Requires husband Cost: per cycle, storage fees



ovarian tissue.

OOCYTE CRYOPRESERVATION.

for single women, ethically accepted. Alternative strategy is to freeze

immature oocytes ( primordial follicle).

LIMITATIONS

Still experimental (3-4 times lower success rate than standard

IVF) Vetrification can be a good option

Vitrification

1min, 37℃ 　WS1,25min×23min

DSTS

LNLN22

Thawing

WS + ES1 + ES2

3min

ES3

9min

VS1 VS2 VS3 VS4

P1 2hrs

Cryotop

(20μl for each drop, at R.T.)

3min 15sec x 4

Before ICSI

(7.5%EG,7.5%DMSO in ES)(15%EG,15%DMSO,0.5M Suc in VS)

(1M Suc in TS, 0.5M Suc in DS)



ovarian tissue.

OVARIAN TRANSPOSITION

(The ovarian dose is reduced by transposition to 5–10%)A) Medial transposition Behind the uterus.

B) Lateral transposition up to the pelvic sidewall at least 3cm from the upper border of the radiation field.

techniques * by laparotomy during surgery. * by laparoscopy

- higher doses of radiation are more likely associated with vascular damage of transposed ovaries.

REPRODUCTIVE FUNCTION OF TRANSPOSED OVARIES.

89% spontaneous pregnancy with 75%

occurring without repositioning. 11% conceived with IVF.

REPRODUCTIVE FUNCTION OF TRANSPOSED OVARIES.

Controversies regarding pregnancy outcomes

after pelvic irradiation.

? Increase fetal wastage

? Birth defects

? Low birth weight

? Abnormal karyotype

? Cancer in the offspring ? Spontaneous abortions

advice: delay pregnancy for a year after completing radiation therapy.

COMPLICATIONS OF OOPHROPEXY

Fallopian tube infarction. Chronic ovarian pain. Ovarian cyst formation. Migration of ovaries back to their original position. Ovarian metastasis (No increased risk).

MALE: SPERM CRYOPRESERVATION

Outpatient procedure; Cost approximately 1,500 for three samples

stored for 3 years Most effective way

SAFETY

no detectable increased risk of disease recurrence associated with most fertility preservation methods and pregnancy, even in hormonally sensitive tumors.

OFFSPRING

no evidence that a history of cancer therapy, or fertility interventions increase the risk of cancer or congenital abnormalities in the offspring.



ovarian tissue.

Jeruss and Woodruff (2009) New England Journal of Medicine.

What Techniqu

e is Appropri

ate ?

CONCLUSION.

GnRH analogues are the only available medical protection for chemotherapy. Laparoscopic ovarian transposition is a

good option if radiotherapy is to be used.

THANK YOU!

Fertility preservation

Health & Medicine

Transcript of Fertility preservation