Alessandra Graziottin

Centro di Ginecologia e Sessuologia Medica

H. San Raffaele Resnati, Milano

Presidente, Fondazione Graziottin

per la cura del dolore ONLUS

www.alessandragraziottin.it

ENDOMETRIOSI E SESSUALITA’

DISCLOSURE 2013-2014

• Speakers’ bureau:

Bayer, Deakos, Jenapharm, Lolipharm, Menarini, Pfizer, Sanofi

• Advisory Boards: Bayer, Menarini

• Consultant:

Bayer, Deakos, Epitech, Loli-pharm, Menarini, Palatini, Pfizer, Zambon

Prossimo convegno

Dolore in gravidanza, sessualità, pavimento pelvico

Milano, 6 giugno 2014 Hotel Gran Visconti Palace

www.fondazionegraziottin.org @ProfAGraziottin

Parte 1.

Lo scenario del dolore

A.Graziottin, 2014

Domanda 1.

Qual è il significato del dolore?

Pericolo!!! Graziottin et AL, J.Depression & Anxiety, 3; 1: 142-151, dec 2013

Domanda 2.

Quale pericolo?

Danno tissutale, perdita dell’ integrità fisica, riduzione funzionale,

malattia e morte

A.Graziottin, 2014

Domanda 3.

Quali è la nuova evidenza sui correlati biologici del dolore?

L’infiammazione! Periferica e centrale

Graziottin et AL, J.Depression & Anxiety, 3; 1: 142-151, dec 2013

INFLAMMATION= TO SET ON FIRE

a biochemical fire, involving mastcells, tissues,

cytokines, nerves and neurons, microglia

Graziottin et AL, J.Depression & Anxiety, 3; 1: 142-151, dec 2013

Domanda 4.

Che cosa correla l’infiammazione al dolore?

I mastociti legano

l’infiammazione al dolore, alla neuro-infiammazione, alla depressione e

ai sintomi sessuali

Graziottin et AL, J.Depression & Anxiety, 3; 1: 142-151, dec 2013

Picture: Courtesy of R. Della Valle

The mast-cell is the powerful protagonist behind the clinical scenario of inflammation and pain

More than 38.000 papers (!) credit the mastcell to be the director of the chronic inflammation orchestra

A.Graziottin, 2001, 2007, 2013

THE UP-REGULATED MASTCELL

Menstrual blood in the tissue

Neurogenic stimulus & neurotrophic changes x 52-58% enlargement of peripheral neurons x 10 Proliferation of pain fibers Bornstein, 2001, 2004, 2008; Bohme-starke, 1998, 201Omoigui 2009; Costigan 2010, Graziottin, 2013

Mechanical trauma Intercourse!!!

FLUCTUATING Estrogens

Vasoactive factors

Hystamine

Bradychinine

Serotonine

NERVE GROWTH FACTOR (x 50!) Dupont et Al, 2001

Chemical & Physical insults

Infections

Agonist stimuli

Cytokines

Inflammation: the triad

•Significant increase in tissue mastcells •Significant increase of degranulated mastcells •Significant increase of mastcells in close proximity of pain fibers

Graziottin et Al, J. Depress Anxiety, 3; 142-151, dic.2013

Domanda 5.

Infiammazione DOVE?

1.Negli organi pelvici coivolti 2.Nel midollo spinale 3.Nel cervello= neuroinfiammazione Graziottin et AL, J.Depression & Anxiety, 3; 1: 142-151, dec 2013

A.Graziottin, 2014

Anaf et al; Fertil Steril 2006

Objective: To detect and quantify mast cells in peritoneal, ovarian, and deep infiltrating

endometriosis and to study the relationship between mast cells and nerves in

endometriosis.

Tryptase-Positive Mast Cells Count

Anaf et al; Fertil Steril 2006

Number of degranulating Mast Cells/mm2

Anaf et al; Fertil Steril 2006

Anaf et al; Fertil Steril 2006

Mast Cells Located < 25 µm from Nerve Structures

Domanda 6.

Che cosa succede se la diagnosi è tardiva?

L’infiammazione si estende agli organi vicini e al cervello =neuroinfiammazione

Graziottin et AL, J.Depression & Anxiety, 3; 1: 142-151, dec 2013

A.Graziottin, 2014

PELVIC PAIN SYNDROMES Mastcells & cytokines

Post-coital cystitis

Bladder pain syndrome/ IC

Vaginismus

Dyspareunia

Vulvar Vestibulitis Vulvodynìa, VP A.Graziottin, 2014

DYSMENORRHEA ENDOMETRIOSIS

IRRITABLE BOWEL SYNDROME

PELVIC INFLAMMATORY DISEASE

NEUROINFLAMMATION, DEPRESSION, SEXUAL SYMPTOMS & SICKNESS BEHAVIOUR

Domanda 7. Quali cellule sono coinvolte nella neuroinfiammazione?

1.mastociti 2.microglia 3.astroglia 4.oligodendroglia

Neuroinfiammazione causa depressione biologicamente mediata

A.Graziottin, 2014

Inflammatory disorders of the peripheral nervous system and central nervous system are common, and contribute to the physical and emotional disability of affected individuals.

Stüve &Zettl 2014; 175(3):333–335

The term ‘neuroinflammation’, in its broadest sense, of course encompasses any inflammatory process, whether acute or chronic, involving the nervous system.

Boche &Nicoll

Neuronal activity triggers neurogenic inflammation in peripheral tissues.

Xanthos & Sandkühler Nature Reviews 15(1):43-53, 2014

Neuronal activity triggers neurogenic neuroinflammation in the CNS.

Xanthos & Sandkühler Nature Reviews 15(1):43-53, 2014 .

A.Graziottin, 2013

SYSTEMIC & BRAIN HEALTH CONSEQUENCES

due to inflammation

PELVIC AND SEXUAL PAIN

Parte 2.

ENDOMETRIOSI E SESSUALITA°

A.Graziottin, 2014

DISPAREUNIA

• Persistente o ricorrente dolore genitale durante i tentativi di penetrazione o durante la penetrazione vaginale completa nel rapporto sessuale.

–Superficiale/introitale

–Profonda

Basson R, et al. J Urol. 2000 Graziottin, 2004; 2007; 2010 Graziottin & Murina, 2011

DISPAREUNIA •La localizzazione del dolore e il suo

modo di insorgenza: sono i fattori predittivi più importanti

della presenza e del tipo di causa biologica

Meana M. Binik YM. et Al; J.Neural Mental Diseases 1997

Bergeron S. Binik YM. et Al. Clin. J.Pain 1997

•Variabili psicosociali: non hanno valore predittivo!

Meana M. Binik YM et Al; Obstet Gynecol 1997

Dolore ai rapporti (Dispareunia): tre domande di base

• DOVE fa male? • QUANDO fa male?

• QUALI sono i sintomi associati? descrivere la mappa del dolore! A. Graziottin, 2004

DOVE fa male?

Dolore introitale

Nell’età fertile

Dolore profondo

Nel post-menopausa

www.alessandragraziottin.it

Dispareunia introitale:

A) Nell’età fertile

• Vulvodinia /VVS/VP

•Vulvovaginite

•Pavimento pelvico iperatt. • Episiorrafia

• Sindrome del nervo pudendo?

• Dermatosi

• Mutilazioni genitali

B) Nella postmenopausa

• deficit ormoni sessuali

• distrofia

• Lichen sclerosus

• Sjogren S.

• Iatrogenica

“DOVE fa male?” Cause biologiche più importanti

A. Graziottin, 2014

Dispareunia profonda:

a)Nell’età fertile

•Endometriosi •PID

•Dolore pelvico cronico • Mialgia

• IBS/ rettocolite ulcerante

• Iatrogenica: parti operativi

• Varicocele (?)

• ACNES (?)

b)Nella post menopausa

• Atrofia vaginale

• Iatrogenica: RT

chirurgia radicale

A. Graziottin, 2014

“DOVE fa male?” Cause biologiche più importanti

DOLORE

NEUROINFIAMMAZIONE E DEPRESSIONE

IL DOLORE FISICO ED EMOTIVO E’ UN FATTORE DI RISCHIO PER LA DEPRESSIONE

LA DEPRESSIONE PEGGIORA LA PERCEZIONE DEL DOLORE

anche SESSUALE

A. Graziottin, 2014

FSD: Dispareunia DESIDERIO

SESSUALE

E AROUSAL

CENTRALE

ECCITAZIONE GENITALE

E LUBRIFICZIONE

ORGASMO

RISOLUZIONE &

SODDISFAZIONE

DISPAREUNIA

VAGINISMO

A. Graziottin 2006

UMORE Ormoni sessuali

Endometriosis

and related

comorbidity!

Deep dyspareunia in the fertile age

* Not including postnatal depression, diagnoses/treatments prescribed during pregnancy or within 2 years of

delivery. ** Postcoital bleeding, dyspareunia.

Modified from Ballard et al.,BJOG 2008

SYMPTOMS AND DIAGNOSES RECORDED IN THE 3 YEARS BEFORE THE INDEX (DIAGNOSIS) DATE AMONG CASES AND CONTROLS, WITH UNADJUSTED ODDS RATIOS FOR ENDOMETRIOSIS

Controls % Cases % OR (95% Cl)

(n = 21239) (n = 5540)

Dysmenorrhoea 725 3.4 1364 24.6 9.8 (8.8–10.9)

Pelvic pain 312 1.5 862 15.6 13.5 (11.7–15.7)

Dyspareunia 219 1.0 509 9.2 9.4 (8.0–11.1)

Infertility/subfertility 377 1.8 533 9.6 6.2 (5.4–7.1)

Depression* 2895 13.6 1197 21.6 1.8 (1.6–1.9)

Symptoms associated 366 1.7 638 11.5 7.4 (6.5–8.5) with sexual intercourse**

ENDOMETRIOSIS AND PELVIC PAIN

Stage was not correlated with frequency and severity of pain symptoms

Vercellini et al., Fertil Steril 1996

Patients with vaginal endometriosis had a significantly increased risk of deep dyspareunia compared with those whose lesions were at other sites (OR, 2.55; 95% C.I., 1.21-5.39)

Colposcopic appearance of the posterior fornix with reddish vegetations and a bluish nodule

Clinica Ostetrica e Ginecologica “Luigi Mangiagalli”, University of Milan, Italy.

courtesy of: P. Vercellini

ENDOMETRIOSIS AND DEEP DYSPAREUNIA LOGISTIC REGRESSION ANALYSIS OF 1054 PATIENTS

Variable

Wald 2

P

O.R.

95% C.I.

Age at surgery

8.15

0.004

0.95

0.92 – 0.98

Douglas pouch lesion

17.00

0.0001

2.64

1.68 – 4.24

From Vercellini et al., Hum Reprod 2006

OVULATION

Estrogen synthesis

Menstruation

Tubal reflux

Endometrial cell implantation

INFLAMMATION

Degranulation of mast cells; PGs; ILs; TNF ; TGF1; H; 5HT

Ingrowth of nerve fibers in endometriotic lesions (neurotrophism)

HYPERALGESIA

Sensitization/activation of sensory nerve fibers

NGF;

NGFRp75;

Trk-A

2 1

Modified from Vercellini 2012

NEURO INFLAMMATION

DEPRESSION

SICKNESS BEHAVIOUR

SEXUAL SYMPTOMS

& PAIN

Modified from Vercellini et al., Hum Reprod 2009

MAIN RESULTS OF INDIVIDUAL STUDIES IN SYSTEMATIC REVIEW OF MEDICAL TREATMENTS FOR RECTOVAGINAL ENDOMETRIOSIS. EFFECT ON DEEP DYSPAREUNIA

Author Year Treatment Pain at Pain during baseline * treatment*

Fedele et al. 2000 GnRHa 2.0 (0.7)† 1.2 (0.4)

Fedele et al. 2001 Lng-IUD 1.9 (0.9) † 0.5 (0.5)

Vercellini et al. 2005

EE + CPA 46 (22) ‡ 11 (23)

NETA 51 (25) 14 (23)

Razzi et al. 2007 Vaginal danazol 1.9 (0.8) † 0.1 (0.3)

Remorgida et al. 2007 Letrozole + NETA 7.6 (1.5) ‡ 2.2 (2.0)

Vercellini et al. 2009§

Vaginal ring 71 (12) ‡ 30 (19)

Transdermal patch 71 (22) 42 (26) EE + CPA = ethinylestradiol + cyproterone acetate; NETA = norethindrone acetate.

* Values are mean (SD); † verbal rating scale scores; ‡ visual analog scale scores; § only subjects with rectovaginal endometriotic

lesions are considered.

Vercellini et Al. Clinica Ostetrica e Ginecologica “Luigi Mangiagalli”, University of Milan, Italy.

PAIN SYMPTOMS VARIATIONS

DYSMENORRHEA NONMENSTRUAL PAIN

NETA EE+CA

basel

ine

3 month

s

6 month

s

9 month

s

12 m

onths

0

20

40

60

80

100

dys

men

orrh

ea s

core

basel

ine

3 month

s

6 month

s

9 month

s

12 m

onths

0

20

40

60

80

100

no

nm

enst

rual

pai

n s

core

PAIN SYMPTOMS VARIATIONS

DEEP DYSPAREUNIA DYSCHEZIA

PAIN SYMPTOMS VARIATIONS

NETA EE+CA

basel

ine

3 month

s

6 month

s

9 month

s

12 m

onths

0

20

40

60

80

100

dee

p d

ysp

areu

nia

sco

re

basel

ine

3 month

s

6 month

s

9 month

s

12 m

onths

0

20

40

60

80

100

dys

chez

ia s

core

Vercellini et Al. Clinica Ostetrica e Ginecologica “Luigi Mangiagalli”, University of Milan, Italy.

TWENTY-FOUR MONTH SYMPTOM-FREE SURVIVAL ANALYSIS IN 105 WOMEN WITH RECTOVAGINAL ENDOMETRIOSIS UNDERGOING CONSERVATIVE SURGERY AT LAPAROTOMY (n = 44; dashed line) OR EXPECTANT MANAGEMENT (n = 61; solid line)

From Vercellini et al., Am.J.Obstet.Gynecol. 2006

RESULTS OF STUDIES COMPARING CONSERVATIVE SURGERY PLUS PRE-SACRAL NEURECTOMY WITH CONSERVATIVE SURGERY ONLY FOR DEEP DYSPAREUNIA ASSOCIATED WITH ENDOMETRIOSIS

From Vercellini et al., 2000

Diamonds represent odds ratio of non-response and horizontal lines 95% confidence intervals. Breslow- Day

test for heterogeneity: 2 = 0.72, 2 df, P = 0.69.

From Vercellini et al., Hum reprod 2009

COST OF 12 MONTHS OF CONTINUOUS MEDICAL TREATMENT OF RECTOVAGINAL ENDOMETRIOSIS ; Italy, 2009

Medication Cost

€ £ $ Letrozole 2.5 mg/day* 2104 1868 2713

Anastrozole 1 mg/day* 2046 1817 2638

Depot GnRHagonist 1804–2160 1602–1918 2372–2784

Danazol 600 mg per os/day 821 729 1058

Danazol 200 mg per vaginam/day 274 243 353

Vaginal ring† 233 206 297

Transdermal patch‡ 220 195 280

Low-dose monophasic OC§ 80–260 71–230 101–331

Levonorgestrel-releasing IUD 38 34 49

Norethisterone acetate 2.5 mg/day** 18 16 22 * Cost probably higher owing to the need for combination with other standard regimens inhibiting ovulation.

** Partly reimbursed by the Italian National Health System with an overall yearly patient cost of €4 – £3.6 – $6. †,‡ Cost potentially higher owing to the need for system removal/replacement when breakthrough bleeding occurs.

§ The least expensive OCs contain 30 µg of EE and are partly reimbursed by the Italian National Health System with an overall yearly patient

cost of €18 – £16 – $28.

CONCLUSIONI 1.

Il dolore, anche sessuale, nell’endometriosi è segno di: • infiammazione periferica & • danno tessutale Se persiste, non diagnosticato e curato, causa: • neuro-infiammazione centrale • depressione & sickness behaviour • peggioramento dei sintomi sessuali fino

all’evitamento dei rapporti

CONCLUSIONI 2.

Diagnosi precoce e terapia appropriata, medica o chirurgica, migliorano significativamente: • Dolore ai rapporti (dispareunia profonda

e introitale) • Infiammazione e neuroinfiammazione • Depressione e sickness behaviour

A.Graziottin, 2014

Spegnere l’infiammazione,

pelvica e cerebrale, è essenziale anche per migliorare la vita sessuale delle

donne affette da endometriosi

Graziottin et AL, J.Depression & Anxiety, 3; 1: 142-151, dec 2013