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