Transcript Visanne Slide Deck 1

Endometriosis
– The Disease
• Definitions and Epidemiology
• Aetiology
• Symptomatology
– Diagnosis
• Laparoscopy
• Laparoscopic Images
• The Outlook
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Endometriosis (continued)
– Treatment
•
•
•
•
•
•
•
•
– Summary
Current Treatment Options
Non-specific Therapies
Specific Therapies
Progestins
Danazol
GnRH Agonists
Surgery
Guidelines
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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.
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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.
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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.
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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.
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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.
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Endometriosis: The Disease
Symptomatology
Symptomatology
– Typical symptoms:
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•
•
•
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.
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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.
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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.
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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.
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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.
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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.
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Diagnostic Pathway
Clinical presentation:
typical symptoms
Endometriosis
suspected
History
Examination
Investigations
Consider differential
diagnoses
Likely diagnosis of
endometriosis –
management
considerations
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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.
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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.
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Laparoscopic Technique
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Laparoscopic Technique
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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.
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Laparoscopic Disease Classification
(rASRM Score)
rASRM, revised American Society for Reproductive Medicine.
Revised American Society for Reproductive Medicine. Fertil Steril 1997.
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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.
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Endometriosis: Diagnosis
Laparoscopic Images
Laparoscopic Images
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Laparoscopic Images
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Laparoscopic Images
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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.
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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
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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.
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Laparoscopic Technique
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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
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Endometriosis
Questions?