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ENDOMETRIOSI E
SESSUALITA’
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
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
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
Picture: Courtesy of R. Della Valle
THE UP-REGULATED MASTCELL
Mechanical trauma
Menstrual blood Intercourse!!!
in the tissue
Neurogenic stimulus
& neurotrophic changes
FLUCTUATING
Estrogens
Bornstein, 2001, 2004, 2008;
Bohme-starke, 1998, 201Omoigui 2009;
Costigan 2010, Graziottin, 2013
Chemical &
Physical insults
x 52-58% enlargement
of peripheral neurons
x 10 Proliferation of pain fibers
Agonist
stimuli
Infections
Cytokines
Bradychinine
Vasoactive
factors
Hystamine
Serotonine
NERVE GROWTH
FACTOR (x 50!)
Dupont et Al, 2001
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
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
Vaginismus
Dyspareunia
DYSMENORRHEA
ENDOMETRIOSIS
PELVIC
INFLAMMATORY
DISEASE
IRRITABLE
BOWEL
SYNDROME
Vulvar Vestibulitis
Vulvodynìa, VP
Bladder pain
syndrome/
IC
Post-coital
cystitis
A.Graziottin, 2014
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
Boche &Nicoll
The term ‘neuroinflammation’, in its broadest
sense, of course encompasses any inflammatory
process, whether acute or chronic, involving the
nervous system.
Stüve &Zettl 2014; 175(3):333–335
Inflammatory disorders of the peripheral nervous
system and central nervous system are common, and
contribute to the physical and emotional disability of
affected individuals.
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
PELVIC AND SEXUAL PAIN
SYSTEMIC & BRAIN
HEALTH CONSEQUENCES
due to inflammation
A.Grazio
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 postmenopausa
www.alessandragraziottin.it
“DOVE fa male?”
Cause biologiche più importanti
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
A. Graziottin, 2014
“DOVE fa male?”
Cause biologiche più importanti
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
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
UMORE
Ormoni
sessuali
DESIDERIO
SESSUALE
E AROUSAL
CENTRALE
RISOLUZIONE &
SODDISFAZIONE
DISPAREUNIA
VAGINISMO
ECCITAZIONE GENITALE
E LUBRIFICZIONE
ORGASMO
A. Graziottin 2006
Deep dyspareunia
in the fertile age
Endometriosis
and related
comorbidity!
SYMPTOMS AND DIAGNOSES RECORDED IN THE 3 YEARS BEFORE THE INDEX
(DIAGNOSIS) DATE AMONG CASES AND CONTROLS, WITH UNADJUSTED ODDS
RATIOS FOR ENDOMETRIOSIS
Controls
%
(n = 21239)
Cases
%
(n = 5540)
OR (95% Cl)
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)
2895
13.6
1197
21.6
1.8 (1.6–1.9)
Symptoms associated
366
with sexual intercourse**
1.7
638
11.5
7.4 (6.5–8.5)
Depression*
* 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
ENDOMETRIOSIS AND PELVIC PAIN
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)
Stage was not correlated with frequency and severity of
pain symptoms
Vercellini et al., Fertil Steril 1996
Colposcopic appearance of
the posterior fornix with
reddish vegetations and a
bluish nodule
courtesy of: P. Vercellini
Clinica Ostetrica e Ginecologica “Luigi Mangiagalli”, University of Milan, Italy.
ENDOMETRIOSIS AND DEEP DYSPAREUNIA
LOGISTIC REGRESSION ANALYSIS OF 1054 PATIENTS
Variable
Age at surgery
Douglas pouch lesion
P
O.R.
95% C.I.
8.15
0.004
0.95
0.92 – 0.98
17.00
0.0001
2.64
1.68 – 4.24
Wald 
2
From Vercellini et al., Hum Reprod 2006
OVULATION
SEXUAL
SYMPTOMS
& PAIN
Estrogen synthesis
Menstruation
Tubal reflux
Endometrial cell implantation
SICKNESS
BEHAVIOUR
INFLAMMATION
1
2
NGF;
NGFRp75;
DEPRESSION
Trk-A
Ingrowth of nerve fibers in endometriotic
lesions (neurotrophism)
Degranulation of mast cells;
PGs; ILs; TNF ; TGF1; H; 5HT
Sensitization/activation of sensory
nerve fibers
NEURO
INFLAMMATION
HYPERALGESIA
Modified from
Vercellini 2012
MAIN RESULTS OF INDIVIDUAL STUDIES IN SYSTEMATIC REVIEW OF
MEDICAL TREATMENTS FOR RECTOVAGINAL ENDOMETRIOSIS. EFFECT
ON DEEP DYSPAREUNIA
Author
Year
Treatment
Pain at
baseline *
Pain during
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
NETA
46 (22) ‡
51 (25)
11 (23)
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
Transdermal patch
71 (12) ‡
71 (22)
30 (19)
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.
Modified from Vercellini et al., Hum Reprod 2009
PAIN SYMPTOMS VARIATIONS
NONMENSTRUAL PAIN
nonmenstrual pain score
100
80
60
40
20
EE+CA
100
80
60
40
20
0
ba
se
lin
e
3
m
on
th
s
6
m
on
th
s
9
m
on
th
s
12
m
on
th
s
m
on
th
s
6
m
on
th
s
9
m
on
th
s
12
m
on
th
s
3
se
lin
e
0
ba
dysmenorrhea score
DYSMENORRHEA
NETA
Vercellini et Al. Clinica Ostetrica e Ginecologica “Luigi Mangiagalli”, University of Milan, Italy.
PAIN SYMPTOMS VARIATIONS
DYSCHEZIA
100
dyschezia score
100
80
60
40
20
0
80
60
40
20
Vercellini et Al.
m
on
t
hs
s
12
m
on
th
s
9
m
on
th
s
6
m
on
th
e
3
se
lin
ba
m
on
th
s
s
12
m
on
th
s
EE+CA
9
on
th
m
6
3
m
lin
on
th
s
e
0
ba
se
deep dyspareunia score
DEEP DYSPAREUNIA
NETA
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 PRESACRAL NEURECTOMY WITH CONSERVATIVE SURGERY ONLY FOR DEEP
DYSPAREUNIA ASSOCIATED WITH ENDOMETRIOSIS
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., 2000
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.
From Vercellini et al., Hum reprod 2009
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