Hananel Holzer, MD Medical Director, MUHC Reproductive Center McGill University Health Center

Hananel Holzer, MDMedical Director, MUHC Reproductive Center

McGill University Health CenterDirector, REI Division, Dept. of Obstetrics & Gynecology

McGill University

McGill University

McGill University Health Centre

McGill University Health Centre

Fertility preservationFertility preservation

Fertility preservation

Indications:

• Cancer patients before gonadotoxic treatment

• Other diseases before gonadotoxic treatment

• Young patients with Turner syndrome, Fragile X premutation (FMR 1), Galactosemia

• Women in mid-thirties without partner ?

Options for fertility preservation Options for fertility preservation

Should be tailored according to:Should be tailored according to:

• Patient’s age Patient’s age

• Type of disease Type of disease

• Spread of the diseaseSpread of the disease

• Planned treatmentPlanned treatment

• Time available Time available

• Whether she has a partnerWhether she has a partner(Holzer Tan 2005)

Options for fertility preservation

Ovarian protection:• Ovarian shielding• Ovarian transposition prior to local

radiotherapy:– reduces dose to 5-15%– patients <40– Laparoscopy– Location depends on the planned radiation.– Does not protect against chemotherapy.

(Tulandi 2004)


• GnRH agonist acts to protect gonads during chemotherapy by preferentially steering cells into less active cell cycle stage with decline in response to chemotherapeutic agents• Simulating pre-puberty.• Direct effect?• Decreased perfusion?

• Young patients.(Blumenfeld 2007 ,Huser 2008)


• 3 meta-analyses were published:3 meta-analyses were published:• GnRHa are effective in preserving ovarian GnRHa are effective in preserving ovarian

function and in reducing amenorrhoea function and in reducing amenorrhoea (Clowse 2009, Ben Aharon 2010)(Clowse 2009, Ben Aharon 2010)

• only prospective randomized studies:only prospective randomized studies:

• odds ratio of 3.5 favouring the use of odds ratio of 3.5 favouring the use of GnRHaGnRHa..

• Higher rates of resumption of menses and Higher rates of resumption of menses and ovulationovulation

• No improvement of pregnancy rates No improvement of pregnancy rates (Bedaiwy (Bedaiwy 2010)2010)


• Some evidence that GnRHa has a protective Some evidence that GnRHa has a protective effect. effect.

• the final conformation is still awaited.the final conformation is still awaited.

• GnRH antagnist – faster desensitization.GnRH antagnist – faster desensitization.• Flare up effect; combined treatment? Flare up effect; combined treatment? (Mardesik (Mardesik

2004 von Wolff 2011)2004 von Wolff 2011)

• The GnRHa could be used to induce ovulation The GnRHa could be used to induce ovulation in a stimulated cycle. in a stimulated cycle.

• Reduced tumour cell sensitivity to chemo in E+ Reduced tumour cell sensitivity to chemo in E+ cases ?cases ?


Apoptosis inhibition:

• Ceramide – 2nd messenger signals apoptosis

• Sphingosine 1 phosphate (S1P) ceramid antagonist

• Interesting and promising; still far from clinical implementation

(Morita, Paris, Perez, Tilly et al 1999,2000, 2002)

Cryopreservation for fertility preservation

• Transplantation of whole intact ovary by vascular anastomosis Wang et al Nature 2002;Imhof et al 2006; Bedaiwy et al 2007

• Huge technical challenge, perfusion of the cryoprotectant

• In theory, risk of cancer cell transmission

Options for fertility preservation: Cryopreservation of ovarian tissue

• Available for pre- and post-puberty patients

• Hundreds to thousands of primordial follicles may be preserved.

• No medical delay.

• No ovarian stimulation.

• Does not require a male partner

• At least 2 surgical procedures (+ IVF)

• Anesthesia- risks

• Theoretic risk of neoplastic cells in transplanted tissue – recurrence?

Risk of presence of neoplastic cells in the transplanted tissue

• Subclinical involvement of Hodgkin’s Lymphoma has not Subclinical involvement of Hodgkin’s Lymphoma has not been identified in ovarian tissuebeen identified in ovarian tissue (Seshadri Gook et al 2006)(Seshadri Gook et al 2006)

• detection of Hodgkin lymphoma within ovarian tissue detection of Hodgkin lymphoma within ovarian tissue taken at the time of harvest for cryopreservationtaken at the time of harvest for cryopreservation. . (Bittinger (Bittinger 2011)2011)

• 58 patients with hematological malignancies underwent 58 patients with hematological malignancies underwent ovarian tissue cryopreservationovarian tissue cryopreservation− after thawing, markers to detect minimal residual after thawing, markers to detect minimal residual

disease useddisease used− real-time RT-PCR positive in one patient with CML.real-time RT-PCR positive in one patient with CML.

− this alarming result avoided tissue transplantationthis alarming result avoided tissue transplantation (Meirow et al 2008)(Meirow et al 2008)

• Positive markers of CML and AML in cryopresrved Positive markers of CML and AML in cryopresrved harvested ovarian tissue harvested ovarian tissue (Dolmans 2010)(Dolmans 2010)

Risk of presence of neoplastic cells in the transplanted tissue

• Other organ transplants: donor derived Other organ transplants: donor derived malignancy malignancy ( Kauffman 2002, Ison 2011 AM J ( Kauffman 2002, Ison 2011 AM J Transplant)Transplant)

• Extreme caution is warranted before we assume Extreme caution is warranted before we assume that we understand tumour biology well enough that we understand tumour biology well enough to estimate the risk of transmission of to estimate the risk of transmission of malignant cells in autotransplanted ovarian malignant cells in autotransplanted ovarian cortex.cortex.

• BRCA 1&2 carriers - potential of developing BRCA 1&2 carriers - potential of developing ovarian cancer ovarian cancer (Colgan 2001)(Colgan 2001)

• Prophylactic BSO, transplant ovarian Prophylactic BSO, transplant ovarian fragments?fragments?


• Loss of follicles during transplantation and initial ischemia. Absence of inhibitory mechanism? Longevity of the graft?

• 14 pregnancies and live births reported :− Donnez, Meirow*− Rosendahl* (6 pregnancies,3 live births, 2

women)/12 cases.− Demeestere (OTx2)

*IVF• Bias due to selective reporting?


• Culture and IVM of primordial follicles: 2 step culture system: culture of tissue followed by isolation of follicles and culture. Or using 3D supportive matrix. Culturing to MII is the next chalange (Abir et al. Histol. Histopatho 2006 Picton et al. Reproduction 2008, Tefler et al. Hum Rep. 2008, Woodruff 2009)

• Suspension of isolated primordial follicles (Dolmans et al 2008)

• Xenotransplantation: human ovarian tissue to SCID mice. Aberrant microtubule and chromatin patern. Transmission of pathogens, short life span ethical issues, and … ( Lucifero 2002, Kim 2001)

Embryo cryopreservation

• Integral part of IVF programs >25 years

• Success rates 30-50% per embryo transfer, depending on the age at the time of oocytes retrieval.

• Only well-established option of fertility preservation

• Post pubertal patients.

• Partner required

• Donor sperm?

Hananel Holzer, MD Medical Director, MUHC Reproductive Center McGill University Health Center

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