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Endometriosis
– The Disease
• Definitions and Epidemiology
• Aetiology
• Symptomatology
– Diagnosis
• Laparoscopy
• Laparoscopic Images
• The Outlook
1
Endometriosis (continued)
– Treatment
•
•
•
•
•
•
•
•
– Summary
Current Treatment Options
Non-specific Therapies
Specific Therapies
Progestins
Danazol
GnRH Agonists
Surgery
Guidelines
2
Endometriosis: The Disease
Definitions and Epidemiology
Definitions
– ‘The presence of endometrial-like tissue outside the uterus… induces a
chronic, inflammatory reaction’1
• Endometriosis: derived from ancient Greek:
endo - ‘inside’ and metra - ‘womb’
– ‘…found predominantly in women of reproductive age, from all ethnic and
social groups’1
– ‘…associated symptoms can impact on general physical, mental and social
well-being’1
1. Kennedy S, Berggvist A, Chapron C et al. Hum Reprod 2005.
4
Epidemiology
•Endometriosis is a prevalent condition:
– 5–10% of the female population1,2
– ~5.5 million women in USA; ~16 million in Europe3
– Affects women during reproductive years
– Younger age at onset predicts more severe disease4
– ~50% in women with dysmenorrhea; 75% in women with pelvic pain;
25–40% in infertile/subfertile women5,6
1. Mounsey AL et al. Am Fam Phys 2006;
4. Ballweg ML et al. J Pediatr Adolesc Gynecol 2003;
2. Eskenazi B & Warner ML. Obstet Gynecol Clin North Am 1997; 5. Child TJ et al. Drugs 2001;
3. Taylor MM AORN 2003;
6. Cramer DW et al. Ann N Y Acad Sci 2002.
5
Endometriosis: The Disease
Aetiology
Sites Commonly Affected
– ‘Extent of disease varies from a few, small lesions on otherwise normal pelvic organs to large,
ovarian endometriotic cysts (endometriomas),
and/or extensive fibrosis and adhesion formation causing marked
distortion of pelvic anatomy’1
– Pelvic cavity:
•
Peritoneum, ovaries,
pouch of Douglas,
uterosacral ligaments
– Other sites:
•
Vagina, bowel, bladder, ureters
– Rare sites:
•
Lungs, brain
1. Kennedy S, Berggvist A, Chapron C et al. Hum Reprod 2005.
7
Critical Aspects of Pathogenesis
– Endometrial-like cells attach to peritoneal tissue/other sites
– Cellular infiltration/invasion, involving angiogenesis
– Cellular proliferation
– Inflammation which can cause
• Nerve irritation
• Adhesions
– Individual variation
Mahutte NG, Kayisli U, Arici A. Endometriosis in Clinical Practice. 2005;
Fraser IS. J Hum Reprod Sci 2008.
8
Risk Factors
– Pathophysiology unclear
– Certain characteristics lead to increased/decreased risk
Increased Risk
Decreased Risk
Increased exposure to endometrial material –
short menstrual cycles, heavy/longer bleeding,
early menarche, late menopause1,2
Increased number of live births1
Family history3
Longer duration of lactation1
Low exercise4-6
1. Mounsey AL et al. Am Fam Phys 2006;
2. Missmer SA et al. Obstet Gynecol 2004;
3. Bischoff F et al. Ann N Y Acad Sci 2004;
4. Eskenazi B et al. Obstet Gynecol Clin North Am 1997;
5. Cramer DW et al. Ann N Y Acad Sci 2002;
6. Hediger ML et al. Fertil Steril 2005.
9
Endometriosis: The Disease
Symptomatology
Symptomatology
– Typical symptoms:
•
•
•
•
Dysmenorrhea
Premenstrual pain
Dyspareunia
Diffuse/chronic pelvic pain
– Other symptoms:
• Perimenstrual symptoms
(e.g. bowel- or bladder-associated)
• Back pain
• Chronic fatigue
– Significant proportion of cases
asymptomatic
– Diagnosis based on symptoms
alone can be difficult
• Variable presentation
• Similar to other conditions –
irritable bowel syndrome,
pelvic inflammatory disease
Sinaii N, Plumb K, Cotton L et al. Fertil Steril 2008.
11
Prevalence and Overlap of Symptoms
Pelvic pain + dysmenorrhea
25.2%
Dysmenorrhea only
12.7%
Pelvic pain only 6.5%
Dyspareunia + pelvic pain +
dysmenorrhea 34.4%
Dysmenorrhea +
dyspareunia
6.5%
Pelvic pain +
dyspareunia
3.3%
Dyspareunia only 0.7%
Sinaii N, Plumb K, Cotton L et al. Fertil Steril 2008.
10.7% of women did not report any gynecologic pain symptoms.
12
Infertility
– Endometriosis is frequently associated with infertility
• 30–40% experience subfertility or infertility
– Lesions cause chronic inflammation/adhesions, impacting fertility
– Infertility may be the sole presenting symptom
• 25–40% of infertile women have endometriosis
– Endometriosis may be diagnosed by chance by an infertility specialist
Ozkan S, Murk W, Arici A. Ann NY Acad Sci 2008.
13
Natural History of Disease
– Highly variable and difficult to predict in individual
women
– Progressive course characterised by worsening of pain1
– Younger onset age predicts more severe disease course2
– Spontaneous regression is possible3
1. Koninckx PR, Meuleman C, Demeyere S et al. Fertil Steril 1991;
2. Ballweg J Pediatr Adolesc Gynecol 2003;
3. Mahmood TA, Templeton A. Hum Reprod 1990.
14
What is the Impact of Endometriosis?
Quality of life
Morbidity
Absenteeism
Socio-economic
cost
Educational
opportunities
Daily function
Self-esteem
Fertility
Mounsey AL, Wilgus A, Slawson DC. Am Fam Phys 2006;
Gao X, Yeh YC, Outley J et al. Curr Med Res Opin 2006.
15
Endometriosis: Diagnosis
Diagnosis
Diagnosis often delayed
(average 8.3 years1)
Suggestive
Laparoscopic
visualisation –
ideally with
confirmatory
histology1
Typical clinical
symptoms and signs
(e.g. uterosacral
nodularity)2,3
Magnetic resonance
imaging and
ultrasound4
Definitive
New
techniques
Laboratory tests
currently fail to show
predictive value5,6
New semi-quantitative
procedures being
assessed7
1. Kennedy S, Bergqvist A, Chapron C, et al. Hum Reprod 2005;
2. Mounsey AL, Wilgus A, Slawson DC. Am Fam Phys 2006;
3. Matorras R, Rodríguez F, Pijoan JI, et al. Am J Obstet Gynecol
1996;
4.
5.
6.
7.
Bazot et al. J Minim Invasive Gynecol 2005;
Bedawy et al. Clin Chem Acta 2004;
Matalliotakis et al. Arch Gynecol Obstet 2005;
Fraser et al. J Hum Reprod Sci 2008.
17
Diagnostic Pathway
Clinical presentation:
typical symptoms
Endometriosis
suspected
History
Examination
Investigations
Consider differential
diagnoses
Likely diagnosis of
endometriosis –
management
considerations
18
Typical Symptoms
– Dysmenorrhea
• Most commonly reported symptom
• Severe form highly suggestive of endometriosis1
– Dyspareunia
• Commonly found in peritoneal (88%) and rectovaginal (100%)
disease2
– No relationship between stage and site of disease
– Normal clinical examination cannot exclude
endometriosis3–5
1. Mahmood TA, Templeton A. Hum Reprod 1991;
2. Gruppo Italiano per lo Studio dell’Endometriosis. Hum
Reprod 2001.
3. Koninckx PR, Meuleman C, Oosterlynck D et al. Fertil Steril
1996;
4. Chapron C, Dubuisson JB, Pansini V et al. Fertil Steril 2002;
5. Eskenazi B, Warner M, Bonsignore L et al. Fertil Steril 2001.
19
Endometriosis: Diagnosis
Laparoscopy
Laparoscopy: Advantages and
disadvantages
Advantages
Disadvantages2,3
Gold standard investigation technique1
Facilities/surgical expertise not
universally available
Possibility to diagnose and treat during one
procedure
Not all patients are suitable for
invasive techniques
False-positive and false-negative findings
Risk of complications
1. Kennedy S, Bergqvist A, Chapron C et al. Hum Reprod 2005;
2. Brosens IA, Brosens JJ. Eur J Obstet Gynecol Reprod Biol 2000;
3. Al-Jefout M, Dezarnaulds G, Cooper M et al. Hum Reprod 2009.
21
Laparoscopic Technique
22
Laparoscopic Technique
23
Laparoscopic Findings
– Lesions1
• ‘Powderburn’/‘gunshot’ lesions on ovaries, serosal surfaces,
peritoneum
– Black, dark-brown or bluish puckered lesions, nodules or small cysts
containing old hemorrhage surrounded by variable extent of fibrosis
• Atypical or ‘subtle’ lesions – implants (petechial, vesicular, polypoid,
hemorrhagic, red flame-like), serous/clear vesicles
• White plaques/scarring, yellow-brown discoloration of peritoneum
– Endometriomas (‘chocolate cysts’)1
• Contain thick tar-like fluid
– Deeply infiltrating endometriotic nodules1
• Extend >5 mm beneath peritoneum
• May involve uterosacral ligaments, vagina, bowel, bladder or ureters
• Depth of infiltration related to type and severity of symptoms
1. Kennedy S, Berggvist A, Chapron C et al. Hum Reprod. 2005.
24
Laparoscopic Disease Classification
(rASRM Score)
rASRM, revised American Society for Reproductive Medicine.
Revised American Society for Reproductive Medicine. Fertil Steril 1997.
25
Laparoscopic Disease Classification
(rASRM Score)
MINIMAL
Stage 1 (1–5 points)
Small superficial implants, not widespread, filmy adhesions
MILD
Stage 2 (6–15 points)
Small to medium implants (1–3 cm), slightly deeper in peritoneum and ovary,
filmy adhesions
MODERATE
Stage 3 (16–40 points)
Large widespread implants, extensive scar tissue, filmy/dense adhesions
SEVERE
Stage 4 (>40 points)
Large implants and endometriomas, extensive scar tissue,
deep and dense adhesions
– Lesion assessment based on points system at laparoscopy1
– Classification may help determine risk of infertility
– No correlation between classification and symptoms2
1. Revised American Society for Reproductive Medicine. Fertil Steril 1997;
2. Kennedy S, Berggvist A, Chapron C et al. Hum Reprod 2005.
26
Endometriosis: Diagnosis
Laparoscopic Images
Laparoscopic Images
28
Laparoscopic Images
29
Laparoscopic Images
30
Endometriosis: Diagnosis
The Outlook
Diagnosis
Non-invasive techniques
remain under investigation
Detection of nerve
fibres in endometrial
biopsy1
Biopsy
Laboratory tests
(e.g. serum cancer
antigens CA 125,
CA 19-9, serum
IL-6, peritoneal fluid
TNFα), fail to show
predictive value4,5
Lab-based
tests
Imaging
Ultrasound,
computerised
tomography scan or
magnetic resonance
imaging – may be
useful adjunctive
investigations2,3
Transvaginal
ultrasound can detect
e.g. endometriomas
(but not lesions)1
1. Kennedy S, Bergqvist A, Chapron C, et al. Hum Reprod 2005;
2. Mounsey AL, Wilgus A, Slawson DC. Am Fam Phys 2006;
3. Matorras R, Rodríguez F, Pijoan JI, et al. Am J Obstet Gynecol
1996;
4.
5.
6.
7.
Bazot et al. J Minim Invasive Gynecol 2005;
Bedawy et al. Clin Chem Acta 2004;
Matalliotakis et al. Arch Gynecol Obstet 2005;
Fraser et al. J Hum Reprod Sci 2008.
32
Endometriosis: Treatment
Current Treatment Options
Overview
– No permanent cure for endometriosis
– Aims of treatment (patient-dependent):
•
•
•
•
•
Alleviate pain and other symptoms
Reduce lesions
Maintain/restore fertility
Avoid recurrence
Improve quality of life
34
Individualisation of Therapy
– No single approach ideal for all patients
– Tailor therapy to needs and choices of patient1
– Objective of individualised therapy:
• Manage complaint (pain/infertility)
• Optimise balance of efficacy, safety and tolerability profiles
• Enhance adherence
1. Kennedy S, Berggvist A, Chapron C et al. Hum Reprod 2005.
35
Surgical Therapy
– Aimed at removing endometrial implants and restoring fertility
– Efficacy reflects the skill of the surgeon
– Recurrence is common: 40–50% at 5 years1,2
1. Mounsey AL, Wilgus A, Slawson DC. Am Fam Phys 2006;
2. Guo SW. Hum Reprod Update 2009.
36
Medical Therapy
Non-specific therapies –
not approved in endometriosis
Specific therapies –
approved in endometriosis
Including non-steroidal
anti-inflammatory drugs and
combined oral contraceptives
e.g. gonadotropin-releasing
hormone agonists, danazol and
some progestins
37
Treatment Approach
•‘Endometriosis should be viewed as a chronic disease that
requires a life-long management plan with the goal of
maximising the use of medical treatment and
avoiding repeated surgical procedures’
Practice Committee of the American Society for Reproductive Medicine. Fertil Steril 2008.
38
NSAIDs
–
–
–
–
General, non-specific pain relief
Controlled trial data lacking1,2
No single NSAID shows superior efficacy1
Potential adverse effects in gastrointestinal tract1,2
NSAID, non-steroidal anti-inflammatory drug.
1. Allen C, Hopewell S, Prentice A. Cochrane Database Syst Rev 2005;
2. Kennedy S et al. Hum Reprod 2005.
39
Combined Oral Contraceptives
– Combined oral contraceptives are widely used off-label for
endometriosis
– Lack of randomised controlled trials1,2
– Limited guidance on optimal regimens
– Estrogen in oral contraceptives appears counter-productive for
endometriosis treatment2
• Hormonal therapies indicated for endometriosis counteract estrogen
effects on endometrial tissue
– Estrogenic adverse effects (nausea, weight gain, water
retention, increased thromboembolic risk)1
1. Davis LJ, Kennedy SS, Moore J et al. Cochrane Database Syst Rev 2007;
2. Crosignani P, Olive D, Bergqvist A et al. Hum Reprod Update 2006.
40
Endometriosis: Medical therapy
Specific Therapies
Hormonal Therapy*
GnRH agonists
Progestins / antiprogestin
(suppression of FSH/LH via desensitisation
and down-regulation of pituitary GnRH
receptors)
(suppression of FSH/LH, some have
additional properties, e.g. antiinflammatoric)
•
•
•
•
•
•
•
•
•
•
•
Leuprolin
Goserelin
Buserelin
Triptorelin
Nafarelin
Avorelin
MPA (oral/im/sc)
Dydrogesterone
Norethisterone
Dienogest
Gestrinone
Androgens
(suppression of FSH/LH, anti-estrogenic and hyperandrogenism)
• Danazol
* Not all products are available in all countries.
FSH, follicle stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; MPA, medroxyprogesterone acetate
Vercellini et al. Best Pract Res Clin Obstet Gynaecol 2008;
Mihalyi et al. Expert Opin Emerg Drugs 2006.
42
Endometriosis treatment:
Progestins
Progestins
– Synthetic hormones with progesterone-like activity1,2
– First used to treat endometriosis in the 1950s3, most have not been
developed for the treatment of endometriosis
– Derived from different steroids (e.g. progesterone, testosterone),
differ in their actions
– Limited evidence from controlled (especially placebo-controlled) trials,
scarcity of data also hampers the selection of one progestin over
another
– Adverse events include irregular bleeding and (especially with older
agents) weight gain, headaches, acne and adverse lipid changes4,5
– Newer types selectively bind progesterone receptors specifically to
minimise androgenic, estrogenic or glucocorticoid side-effects1
1. Sitruk-Ware R. Hum Reprod Update 2006;
2. Schindler AE et al. Maturitas 2003;
3. Kistner RW. Am J Obstet Gynecol 1958;
4. Winkel CA & Scialli AR. J Womens Health Gend Based Med
2002;
5. Vercellini P et al. Hum Reprod Update 2003.
44
Endometriosis treatment: GnRH
Agonists
GnRH Agonists
– Synthetic peptides modelled on hypothalamic GnRH
– Mechanism of action: down-regulation of pituitary gonadotropin
secretion, inducing a hypoestrogenic anovulatory state1,2
– Considered ‘standard’ treatment for endometriosis due to high
efficacy1–4
– Hypoestrogenic side-effects, including BMD decrease
– Limited to short-term use (6 months) in absence of ‘add-back’ therapy
• ‘Add-back’ therapy adds to expense; optimal regimens not established
• Caution in younger women not reached maximum BMD
GnRH, gonadotropin-releasing hormone; BMD, bone mineral density.
1.
2.
3.
4.
Winkel CA et al. J Women’s Health Gender-Based Med 2001;
Sinaii N et al. Fertil Steril 2007;
Crosignani P et al. Hum Reprod Update 2006;
Mounsey AL et al. Am Fam Phys 2006.
46
Endometriosis: Surgical therapy
Surgery
Surgical Treatment
– Usually performed as laparoscopy in one procedure combining
diagnosis and treatment
– Surgical intervention includes: excision or ablation of
endometriotic lesions, removal of endometriotic cysts,
adhesiolysis1
– Frequently combined with follow up medical therapy
– Preferred approach in infertile patients2
– Role in pain relief unclear2
– Success reflects the skill of practitioner
– Recurrence of endometriosis is common –
5-year recurrence rate approximately 40–50%3
1. Mounsey AL, Wilgus A, Slawson DC. Am Fam Phys 2006;
2. Jacobson TZ et al. Cochrane Database 2008;
3. Guo SW. Hum Reprod Update 2009.
48
Laparoscopic Technique
49
Endometriosis: Summary
Summary
•Burden
– Physical, mental and social well-being, fertility and quality of life
•Awareness
– Lack of awareness
•Diagnosis
– Difficulties and delays
•New therapies
– Need for more effective therapies with acceptable tolerability
•Progestins
– Recommended therapy, efficacious in treating symptoms
51
Endometriosis
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