Endometriosi e criopreservazione degli

ovociti

Bergamo 27/01/2017

Prof.ssa Maria Elisabetta Coccia

Prof.Associato di Ginecologia e Ostetricia

Direttore SODc PMA – AOUCareggi

In Italy

Endometriosis.org

Fertil Steril

LEA

E’ una patologia CRONICA, PROGRESSIVA che necessita di un controllo CONTINUO da parte dello specialista per tutta la durata dell’età fertile.

Quadro normale Endometriosi anteriore

Endometriosi Posterioreendometrioma

3D CORONAL PLANE

1. endometrioma

2. Deep endometriosisPre Post

3. Infertility

4. Chronic Pelvic Pain

ENDOMETRIOSIS

DIE

ADENOMYOSIS

5. Menorragia

REDUCTION OVARIAN RESERVEPOF

Endometriosis Treatment

Medical

Surgical

IVF

Alternative medicine

Why – When –Who-

Endometriosis

&

OoocytesCriopreservation

Ovarian Damage?

Effect of the disease?

• Generally, the decline in ovarian follicles that happens throughout life does not hamper greatly the chance of conception before 37 years of age

this deterioration can take place at an earlier age in cases of ovarian endometriosis

DECLINE IN FOLLICULAR NUMBER

INCREASE IN POOR QUALITY

?

Endometrioma

– space-compression effects,

– Local reactions

– - Adverse changes in blood flow

– Both

Can reduce the amount offunctional ovarian tissue available

Surgery

- Healthy ovarian tissue excised

-Reduced ovarian volumes

- Adverse changes in blood flow

- Spontaneous ovulation < frequent -

Responsiveness to hyperstimulation <

Risks of surgical treatment of endometrioma before ART

Risks of intact endometrioma during ART

Hamdan 2015

endometrioma-related damage to ovarian reserve clinically evident in

surgically treated bilateral endometriomas

2011

2006

Mean age at menopause after surgery forbilateral endometriomas

Coccia et al. 2011

Bilateral Monolateral

Significant relationship preoperative ovarian endometriomas total diameter /age at menopauseLarger size of ovarian endometriomas

younger age at menopause onset.

not confirmed in case of unilateral ovarian endometrioma:the contralateral intact ovary might adequately compensate

The endometrioma-related damage to ovarian reserve become clinically evident in women surgically treated for

bilateral endometriomas

Coccia et al. 2011

Coccia et al 2008

Timing surgery/pregnancySurgery

• the immediate post-operative period favourable for conception (6 months)

• time-dependent diminution of fecundity for– a detrimental effect of the disease on fertility

– Patients’ age

• patients should be advised to start trying to conceive immediately after surgery

oocyte quality?

• fertilization rates, IVF cycles– Peritoneal Fluid from patients with Endometriosis may attenuate the

potential of fertilization and embryo development by altering embryo-derived EGF and IGF-I and signal transduction (Ding 2010)

– Increased fertilization rate in more advanced stages (Barnhart 2002)

• oocytes donors– Embryos derived from the ovaries of women

with endometriosis display a

reduced ability to implant (Pellicer 1994)

Endometriosis IVF-ICSI patients: 2016 SOD PMA

• 156 infertile patients with endometriosis• Mean age 33.9 yrs (22-44) (2 patients <25 years)• 120 underwent surgery for endometriosis• 10/120, 8.3%, first surgery for endometriosis younger than

23 years• Women who had their first surgery earlier showed:

– Lower ovarian reserve▪ basal FSH 20.2±15.6 vs 10.9 ±8.4, P= 0.038;▪ AMH 0,6 ±0,4 vs 2.2 ng/ml ,P=0.198)– Younger at their first visit in a ART centre

(31±7.4 vs 35.4 ±4.2 yrs , P= 0.032)

So….. real endometriosis problem exist nedded precociusdiagnosis

**Coccia et al. Unpublished

Endometriosis IVF-ICSI patients: 2016 SOD PMA

On this results nedded to preserve fertility with tissue and or oocytes vitriifcation!!!

Endometriosisand adolescence/young woman

Adolescent endometriosis is different from adult endometriosis:shorter cycles, larger ovarian endometrioma, higher dysmenorrhoea

bilateral? Patients with larger ovarian endometrioma higher probability to be re-operated and

they will develop deep endometriosis.

This should led to- follow up in adolescent (also with AMH)

-suggest OC- Counselling on future fertility

- Ovarian freezing?

SURGERY : our Results in young women

• endometriosis Clinic number of patients: 1153 (686+14deep+453amb endom (210 operated))

• endometriosis Clinic number of patientsundergoing surgery: 898

• Patients ≤24 years old: 88 (9.7%)

– Mean age 21.5±2.5 (range 12-24), median 22 years

What types of endometriosis

n. %

Ovarian endometrioma 66 75

- MonolateralRight Left

421626

- bilateral 24 27.3

Minimal mild endometriosis 8 9.1

Deep endometriosis 37 42

higher incidence of severe endometriosis Ultrasound diagnosis in young patients

>22 yrs ≤ 22 yrs P

Menarche 12.4±1.5 11.9±1.4 0.042

BMI 22.1±3.5 20.5±2.6 0.020

Period length(before surgery)

28.4±2.9 26.5±4 0.022

Flow length(before surgery)

5.1±1.8 5.4±1.7 0.322

Mean diameter ovarianendometrioma

37.1±17.9 50.3±20.1 0.027

Are younger women different from adults?

Are younger women different? Mean diameter ovarian endometrioma

• Pearson correlation -0.176, Sig (2-tailed), 0.031

L’esperienza di un centro IstituzionalePMA ETEROLOGA

• N cartelle aperte PMAe : n. 1986

• 1^ visite febbraio 2018

• 2^ visite luglio 2017

POF 18%

Età avanzata14%

Ridotta RO dopo fallimenti

26%

Donne con difetti genetici

2%

Ovociti e/o embrioni di

scarsa qualità11%

Fattoreiatrogeno

femminile 4%

Fattoremaschile severo

11%

Disfunzioneeiaculatoria

incurabile 0%

Uomini con difetti genetici

3%Infezione sess.

Trasmissibile 0%

Uomini con fattoreiatrogeno 0 %

Indicazioni cliniche

PMA Omologa – indicazione endometriosi( 01/14 – 11/16 )

• 165/1959 (8.4%)

PMA Eterologa – indicazione endometriosi(09/14 – 07/16)

• 166/1304 (12.7%)

P value 0.0001

• 153/1042 (14.7%) solo fattore femminile

P value 0.0001

Prevalenza di pazienti con endometriosi

PMAOmologan=155* PMAEterologan=153

Media±DS Media±DS Pvalue

Età(anni) 35,9±4,3 40,9±3,9 <0,001

BMI(kg/m2) 22,2±4,0 22.9±4,2 ns

AMH(ng/mL) 1,2±1,2 0,5±0,8 <0,001

FSHbasale(mUI/mL) 11,11±8,4 31,4±35,8 <0,001

Estradiolobasale

(pg/ml)

90,5±115,2 85,0±109,6 ns

TSH(mUI/mL) 1,95±1,17 1,8±0,8 ns

Ciclimestruali N=139 N=152

Regolari 86,3%(120) 63,8%(97) <0,001

Irregolari 13,7%(19) 17,8%(27) ns

Menopausa 0% 18,4%(28) <0,001

*datimancanti

Pazienti infertili con endometriosiomologa vs eterologa

Caratteristiche delle pazienti

Cicli Omologa vs Eterologa

Pazienti con endometriosi PMAOmologa

N=66

PMAEterologa

N=29

Pvalue

n(%) n(%)

Ciclisospesi 13(19,7) 1(3,5) 0,039

EmbryoTransfer(ET) 45(68,1) 28(96,5) 0,002

Beta-hCGpositive(β+) 7(10,6) 9(31) 0,014

Gravidanzebiochimiche 2(3) 1(3,4) ns

PerET 2(4,4) 1(3,6) ns

Perβ+ 2(28,6) 1(11,1) ns

Gravidanzecliniche 5(7,5) 8(27,6) 0,008

Pregnancyratepercicloiniziato 8,3% 27,6 0,008

PregnancyrateET 11,1% 28,5% 0,057

Aborti 1(1,5) 0(0) ns

GravidanzeOngoingperET 1(2,2) 4(14,3) 0,047

Parti 3(6,6) 4(14,3) ns

Bambininati

4

1p.gemellare

4

Outcome Riproduttivo: Discussione

Endometriosi Eterologa12,7 %

• Cicli Omologa vs. Eterologa

• Cicli Eterologa: Endometriosi vs. Non Endometriosi

Necessità di informazione e gestione della paziente con endometriosi sotto il profilo riproduttivo:

CONCLUSIONI:

▸ ↓ Ovociti

▸ ↓ Embryo Transfer

▸ ↓ Gravidanze

+ Favorevole

Endometriosi Omologa 8,4 %

VS.(P<0,001)

Stesso Outcome

▸ Orientare a gravidanza precoce?▸ Preservazione? ▸ Ovodonazione come possibilità

Impatto Psicologico: Discussione

Le pazienti infertili con endometriosi rispetto ai controlli:

▸ vivono la sfera emotiva e mente/corpo in modo peggiore,

attribuendo all’endometriosi un valore di possibile aggravante

▸ percepiscono il loro stato di salute più scadente

▸ sono più preoccupate per l’impatto della PMA sul proprio

corpo

L’endometriosi comporta un peggiore impatto emotivo nella donna infertile

Conclusioni:

History of cryopreservation technology

Mid-20° century cryopreservation of cellsand tissues

1953 The first human birth from frozensperm

1984 The first human birth from a frozenembryo

1986 The first human birth from oocyte

Slow freeze Vitrification ( since 1987)

The Revolution was ……

The Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology

Mature oocyte cryopreservation: a guideline

Society for Reproductive Medicine and Society for Assisted Reproductive Technology, Birmingham, AlabamaFertil Steril. 2013 Jan;99(1):37-43. doi: 10.1016/j.fertnstert.2012.09.028. Epub 2012 Oct 22

22, 2012

Oocyte cryopreservation should no longer be considered experimental

Criopreservazione di ovocitiPRO

•prelievo poco invasivo• efficacia provata

CONTRO•necessità di stimolazione ormonale

Shai E. Elizur Fertility and Sterility January 2009

oophorectomy

Ultrasound examination at our center revealed an absent right ovary and anormal-looking left ovary measuring 29 ! 19 ! 16 mm.We discussed the option of GnRH agonist (GnRHa) treatment or anothersurgery. Because of the concerns of possible further reduction in ovarianreserve related to surgery, we evaluated her ovarian reserve.Her basal serum levels of FSH, LH, and E2 on the third day of her menstrualcycle were 6.6 IU/L, 3.3 IU/L, and 122 pmol/L, respectively. However, the antralfollicle count (AFC) in the remaining ovary was only 3, suggesting diminishedovarian reserve. As she had no male partner, we counseled her on thepossibility of oocyte cryopreservation before further treatment. Oocytevitrification

Fertility preservation

PMA in AOUC 47

Regione che ascolta anche la sofferenza e da una opportunità anche nella “speranza” post cancro

Preservazione della fertilità

Toscana:Aree Prioritarie Intervento

Le aree prioritarie d’intervento possono essere individuate come segue:

• 1. Creazione di una rete multidisciplinare di specialisti per diffondere laconoscenza di questi temi ed agevolare percorsi appropriati alle pazienti,anche attraverso interventi di formazione specifica di ginecologi e oncologie dei soggetti che professionalmente sono coinvolti nella diagnostica e neltrattamento di tali patologie.

• 2. Definire percorsi appropriati di preservazione della fertilità cheincludano la raccolta e crioconservazione di cellule germinali e tessutoovarico.

• 3. Individuare opportuni centri di riferimento per macro-aree territorialiinterregionali per la raccolta e crioconservazione e stoccaggio di cellulegerminali e tessuto ovarico che costituiscano la rete di riferimento perdette pazienti

PRESERVAZIONE DELLA FERTILITA’

Affetti da neoplasie maligne

Affetti da patologie con previsione di chemio/radioterapia o immunosoppressori

Donne affette da endometriosi severa

RazionaleE’ facile evincere come la preservazione della fertilità nella giovane donna con endometriosi, spesso ancora single ( e quindi non in grado di accettare il suggerimento di cercare subito una gravidanza) possa tradursi in un risparmio per la spesa pubblica ottimizzando le possibilità di successo della PMA potendola eseguire con oociti in quantità maggiore e di quantità migliore in un periodo successivo

(A. Cobo et al. RBM online, 2012 – AMF Mohamed F&S Elsevier, 2011),

spesso caratterizzato da una riserva ovarica seriamente compromessa dalla malattia di per sé

(Marcoux et al, NEJM 1997 - Engl B and Brugger JG, Fertility 2011)

e dalla chirurgia ovarica (M. Kitajia, F&S 2011),

con importante riduzione del pregnancy rate in cicli di PMA

che in ogni caso – prima o poi - saranno garantiti dal SSN .

LOOKING FOR THE BEST ANALOGY(G. PENNINGS)

• Autodonazione di sangue per deposito preoperatorio- paziente sano al momento del prelievo- procedura ben testata ed accettata- vantaggio medico per il paziente: sicurezza- nessuna necessità di donatore- incerto utilizzo del materiale

Indicazione socialeIndicazione medica

Prelievo ovocitario per crioconservazione- paziente sano al momento del prelievo- procedura ben testata ed accettata- vantaggio medico per il paziente- nessuna necessità di donatore- incerto utilizzo del materiale

Tomei modified

Ma indispensabilità di informare

PRESERVAZIONE DELLA FERTILITÀ IN PAZIENTI DI SESSO MASCHILE

Criteri d’esclusione- uomo > 50 anni- malattie benigne/collaterali che possono interferire con le procedure collegate al prelievo degli spermatozoi/materiale testicolare.

PRESERVAZIONE DELLA FERTILITÀ IN PAZIENTI DI SESSO FEMMINILE

Crioconservazione degli ovociti Crioconservazione tessuto ovarico o di ovaio in toto

Criteri d’esclusione- età > 40 anni;- malattie benigne/collaterali che possono interferire con le procedure collegate al prelievo degli ovociti o al prelievo del tessuto

Aggiornamento del nomenclatore regionale delle prestazioni di preservazione della fertilità

COUNCELING and check Ovarian Reserve

need for early counseling regarding fertility preservation: ovarian agingrelated to advancing age and the acute damage inflicted by surgery areboth factors that can be counteracted through FPT.

➢ Counseling patients with endometriosis should highlight the advantagesof early conception that will increase success rates and may attenuatedisease progression.

➢ women should be presented with the option of ovarian sparing surgeryand the most recent techniques of cryopreservation, already widelyadopted in oncological patients:➢ freezing oocytes, embryos, or➢ ovarian tissue at a younger age

• For women with laparoscopically and histologically confirmed stage III-IV endometriosis receiving their first ICSI cycle, – serum AMH levels were significantly low only in women with a previous history of

endometrioma surgery,

– AFC was significantly lower in both groups of endometriosis with and without a previous history of endometrioma surgery compared with the control group.

• Multivariate analysis confirmed that AFC represents the most useful ovarian response marker to COS in all studied groups, as the number of mature oocytes retrieved increased with increasing AFC but decreased with increasing age

– Patients affected with severe endometriosis are at significantrisk for ovarian tissue damage, which may lead to infertility,reduced response to ovarian stimulation, and occasionally,premature ovarian failure.

– The risk for a compromised ovarian reserve in young patientsis especially high following repeated surgical intervention and inthe presence of bilateral endometriomas.

– In light of recent advances in fertility preservation techniques(FPT), such as oocytes and ovarian tissue freezing, as well astheir increasing success rates

– Personalized counseling should be offered to all patients withendometriosis taking into account age, extent of ovarianinvolvement, current ovarian reserve, previous and impendingsurgeries for endometriosis, along with current success ratesand possible risks associated with FPT

Why : ovarian reserve damage

When follow-up suggests ovarian reserve damage coming

Who-mayor risk women had surgery for

bilateral cyst and or AMH low / AFC low before 35 yrs

Endometriosis

&

OoocytesCriopreservation

Ovarian tissue cryopreservation

Ovarian tissue cryopreservation represents a validstrategy to preserve reproductive function andsteroidogenic activity in patients with a high risk ofpremature ovarian failure.

During surgery a small tissue quantity for tissue preservation?

Ovarian tissue cryopreservation (OTCP)

Ovarian tissue cryopreservation (OTCP) is currently used worldwide to preserve fertility inyoung women facing chemotherapy or radiotherapy who are at high risk of losing ovarianfunctionOTCP is also practiced in some benign conditions associated with high risk of POF[Jadoul2010].

The technique usually involves one-sidedsurgical removal of ovarian cortical tissue orcomplete oophorectomy .The harvested cortical tissue is dissected intothin (1– 2 mm) strips measuring 0.5 × 1 cm2 ,which are frozen for future transplantation.Primordial follicles are located in a poorlyvascular environment and are relativelyresistant to ischemia.

• Early diagnosis

• US in adolescents suffering from pelvic-pain/dysmenorrhoea

• Research on endometriosis in adolescents

• Counsel patients (although still not looking for a

pregnancy) with medical therapy

• patients with bilateral endometriomas

– Avoid surgery when possible giving medicalwaiting for PMA

– Medical treatment and surgical treatment to have smaller endometrioma

– Avoid to check little nodules (?)

– experienced surgeons!

– ART

– PRESERVATION SELECTED CASES

fertility preservation

(oocytes, ovarian Tissue)

Grynberg M, Benard J. Gynecologie Obste´trique & Fertilite´ (2015),

Not the same treatment for all the womenBUT now

ELEMENT TO PRESERVE FERTILITY NEEDED TO BE USED

CHRONIC PELVIC PAIN

DIE

Thank you

OVARIAN RESERVE & POF

CouncelingBilateral cyst urgeryFollicle countAMH