The Importance of Early Detection

and Diagnosis of Endometriosis

MA-M_VIS-ID-0011-1
Disclaimer
• These slides are for scientific and educational purposes only and is the
copyright of Bayer
• Bayer does not support or recommend the use of Visanne® in any countries
or indications in which it is not approved
• In Indonesia, Visanne® is registered for indications :
• Treatment of Endometriosis
Endometriosis
● Endometriosis is an often-painful disorder in which tissue similar to the tissue that normally
lines the inside of uterus — the endometrium — grows outside the uterus.

● Endometriosis most commonly involves ovaries, fallopian tubes and the tissue lining the
pelvis. However, it may also be found in other tissues.

● Endometriosis clinical presentation varies between patients and often has a personal, social
and economic impact on the patient.

● Historically estimated to affect ~10% of women of reproductive age.

● Endometriosis symptoms can occur in early adolescence, but diagnosis often occurs
in adulthood. Endometriosis is a chronic, relapsing disorder and requires long term Rx.

Endometriosis requires a
long-term plan for management

Fraser. J Hum Reprod Sci 2008;1:56–64; Agarwal et al. Am J Obstet Gynecol 2019;220:354.e1- 354.e12; Arruda et al. Hum Reprod 2003;18:756‒759; Leyland et al. J Obstet Gynaecol Can 2010;32:S1-S32; Practice Committee of the
American Society for Reproductive Medicine. Fertil Steril 2014;101:927–935; Sarria-Santamera et al. Healthcare (Basel) 2020:9:29.
Endometriosis is characterized by numerous symptoms,1 the
severity of which can vary between patients2

Pelvic pain and

dysmenorrhoea
25.2% Over one-third of women
“Only” “Only” pelvic pain diagnosed with Grade IV
dysmenorrhoea 6.5% disease did not have pain
12.7% included in their referral letter3
Dyspareunia + pelvic pain +
dysmenorrhoea

10.7%
34.4%
of women
Dysmenorrhoea + Pelvic pain + diagnosed with endometriosis
dyspareunia
dyspareunia do not have any pain
6.5% 3.3%
“Only” dyspareunia
0.7%

48.3% 9.9% Up to 25% of women reported

experiencing all 3 types of pain
Unbearable
No pain
pain typical of endometriosis*
0 1 2 3 4 5 6 7 8 9 10

Pain (numeric scale)

*Pelvic pain, pain after/during intercourse, painful menstrual bleeding.

1. Sinaii et al. Fertil Steril 2008;89:538–545; 2. Imthurn. Poster at SEUD, 25–28 April 2018, Florence; 3. Gordon et al. Aust N Z J Obstet Gynaecol 2022 Jan 29.
Phenotypic differences between adolescent and adult
endometriosis
Adolescent Adult
• Severe primary dysmenorrhoea
Sym ptoms • Moderate dysmenorrhoea
• Frequent resistance to OCs and NSAIDs

• Red, clear or vesicular implants • Black intraperitoneal implants

Peritoneal
• Minimal fibrosis • White, fibrotic

• Cortex
Ovarian endometrioma • Cortex • Dense adhesions
• Angiogenic adhesions • Stigma of inversion with implant
• Stigma of inversion with implant • Invaginated cortex
• Invaginated cortex • Dark pigmented
• White marble • Endometrial tufts
• Thick angiogenic mucosal lining • Thickened by fibrosis
• Medulla • Medulla
• Stretched • Smooth muscle metaplasia
• Fibrosis and devascularisation

• Adenomyoma
Deep endometriosis • Seldom
• Microendometrioma

• Rectal and bladder endometriosis

Concomitant pathology • Obstructive genital tract anomalies
• Uterine adenomyosis

NSAID, nonsteroid anti-inflammatory drug; OC, oral contraceptive.

Benagiano et al. Reprod Biomed Online 2018;36:102‒114.

Molecular pathogenesis of endometriosis

Progesterone resistance 1,2

Impaired apoptosis3

Angiogenesis 4,5

Inflammation 6

Increased oestrogen activity7,8

Increased cell proliferation 9

Development of invasive properties10

1. Attia et al. J Clin Endometriol Metab 2000;85:2897‒2902; 2. Bulun et al. Sem Reprod Med 2012;30:39‒45; 3. Gebel et al. Fer til Steril 1998;69:1042‒1047; 4. Crosin et al. Fertil Steril 2009;92:1214‒1220;
5. Takehara et al. Hum Pathol 2004;35:1369‒1375; 6. Hornung et al. J Clin Endometriol Metab 1997;82:1621‒1628; 7. Bulun. N Engl J Med 2009:360:268‒279; 8. Xue et al. Biol Reprod 2007;77:681‒687;
9. Béliard et al. Fertil Steril 2004;82:80‒85; 10. Kapoor et al. Int J Mol Sci 2021;22:11700.
Endometriosis is a chronic
disease requiring life-long
treatment
There is NO permanent cure for endometriosis

Alleviate pain Aims of

and other endometriosis Reduce lesions
symptoms treatment

Maintain/
Avoid recurrence
restore fertility

Reduce the number

Improve the of unnecessary
quality of life surgeries and prevent
future surgeries
The Goal Of Medical Therapy For Endometriosis Should
Be Long-term Pain Relief Tailored To The Patient1
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 procedures1

Ideal hormonal therapy2

Ameliorate pain

Avoiding a Suitable for

hypo-oestrogenic state prolonged use

Improved quality of
Restore fertility
life3

1. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril 2014;101:927–935; 2. Tosti et al. Eur J Obstet Gynecol Reprod Biol 2017;209:61–66;
3. Dunselman et al. Hum Reprod 2014;29:400–412.
Life-long Patient Journey: Juggling Pain Management
And Fertility Desires
Pregnancy
Menstruation Tries OTC Pain w orsens, HCP tries stronger Pain returns in a desired
begins; heavy NSAIDs, hot w ater missing w ork/school NSAIDs, trial of few months to a
and/or painful bottle... OCs or refers to few years
OB/Gyn

Able to
Pain continues conceive

Prior family history — mom OB/Gyn tries different

takes daughter to Gyn, or OCs, progestins, IUD (if Pain Continue
patient self-refers if older pregnancy not desired manageable indefinitely or
immediately)* until
pregnancy
desired
Pain continues

Unable to
conceive

Pain continues, coping Pain returns in a Fertility

or depressed, waiting few months to a GnRHa, progestins
specialist if
for menopause few years as therapy
Laparoscopy for “definitive” severe
Laparoscopy or
diagnosis, surgery for pain
hysterectomy relief/to improve fertility

GnRHa, gonadotropin-releasing hormone agonist; HCP, healthcare prov ider; IUD, intrauterine dev ice; NSAID, non-steroidal anti-inf lammatory drug; OB/Gy n, obstetrician
gy naecologist; OC, oral contraceptiv e; OTC, ov er the counter
Importance of early diagnosis
Endometriosis Places A High Burden On Society And
The Individual1–5

There is a small increased risk of endometriosis

with early menarche 7 Individual
impact

Dysmenorrhoea and pelvic pain in general are the

most common symptoms of endometriosis 3
Delay in
diagnosis

Impact on sexual life is the main factor

affecting quality of life 3
Societal
impact
Up to 10.8 hours of overall work
productivity is lost each week for
women with endometriosis 2

1. Lev y et al. J Obstet Gy naecol Can 2011;33:830–837; 2. Nnoaham et al. Fertil Steril 2011;95:366–373; 3. Bernuit et al. J Endometr 2011;3:73–85; 4. Fourquet et al. Fertil Steril 2011;96:107–112; 5.
Simoens et al. Hum Reprod 2012;27:1292–1299; 6. National Institute f or Health and Care Excellence 2017; 7. Nnoaham et al. Fertil Steril 2012;98:702–712.e6; 8. Missmer et al. BMJ Open
2022;12:e052765; 9. Eisenberg et al. J Clin Med 2022;11:1133.
70% Of Women With Endometriosis Reported A
Negative Impact On Quality Of Life
Severity of impact on Activities negatively
quality of life impacted by symptoms

Don’t Know 5%
Sexual life 50%

Relationship/
family 36%
No impact 28%
Performance at
work/school/university 35%

Housekeeping 34%
Mild negative impact 16%

Attendance at 32%
work/school/university

Moderate negative impact 26% Social activities 29%

Sports 21%

Type/colour of clothes 17%

Severe negative impact 25%
Others 9%

N = 1026

Bernuit et al. J Endometriosis 2011;2:73–85.

Effect Of Endometriosis On Ovarian Reserve
F P
Confounding variable
value value
Multivariate analyses with Presence of superficial
possible confounding variables 0.20 0.66
endometriosis
found that fibrosis and Volume of cortex (mm 3) 0.60 0.45
endometriomas were significantly
and independently associated Presence of cortical-specific stroma 2.02 0.17
with follicular density Age, y 3.05 0.09
Presence of fibrosis 5.90 0.02
Cortex from ovaries with
6.76 0.02
endometrioma

● Endometriotic cyst formation and associated structural tissue changes in overtly normal ovarian cortex
may contribute to reduced ovarian reserve
● Therefore, early diagnosis and management may be beneficial in women with endometriomas to
protect ovarian function

Kitajima et al. Fertil Steril 2011;96:685–691.

Current Limitations in
diagnosis
Early Diagnosis Of Endometriosis Is Critical

To explain the pain

• Provide validation
• Reduce feelings of isolation

To provide earlier treatment

To impact the natural history

• Reduce risk of chronic pain
• Reduce risk of associated pain syndromes
• Reduce risk of infertility
Acceptance of symptoms and misdiagnosis contribute
to the endometriosis diagnostic delay
Reasons for diagnostic
Wait1 Frequent misdiagnosis1 delay in adolescents 2

Idiopathic Physician related

Women wait 2.3 years before subfertility Chronic pelvic
pain syndrome
seeking medical attention Appendicitis Physician Physician
6% knowledge gap resistance
9%
PID
9% 33%
Normalisation by
Lack of research
physician
Overactive
bladder 11%

Psychosexual 12% Adolescent

complaints 26% patient related
12%

Food intolerance 19% Patient Patient

Bleeding
knowledge gap normalisation
disorder
Irritable colon

74% of women receive ≥1 false diagnosis

PID, pelvic inflammatory disease.

1. Hudelist et al. Hum Reprod 2012;27:3412–3416; 2. Simpson et al. Cureus 2021;13:e15143

Sequential Use Of Ineffective Or Inappropriate Therapies Delays
Definitive Diagnosis And Effective Treatment Of Endometriosis

Delayed referral Cycling through COCs

>40% of women with

2.7 years from onset to endometriosis have been prescribed
gynaecology consultation1 >3 different COCs4
2%

>30% had ≥6 primary care 15%

28%
appointments before diagnosis2,3

28%
28%
49% had ≥2 secondary care
referrals before diagnosis2
1 2

COC, combined oral contraceptive. .

1. Hudelist et al. Hum Reprod 2012;27:3412–3416; 2. Pugsley et al. Brit J Gen Pract 2007;57:470–476; 3. Nnoaham et al. Fertil Steril 2011;96:366–373; 4. Casper.
Fertil Steril 2017;107:533–536.
Interventions To Reduce Diagnostic Delay: The Patient
Perspective
Focus group of women
Improve knowledge about Improve knowledge in other
normal menstruation and with endometriosis medical specialists and
endometriosis collaboration

Recognising of Faster referral to

symptoms by GPs gynaecologists

Taking symptoms seriously Improve quality of physical

and acknowledgement examination

More publicity about Multidisciplinary teams

menstruation and
endometriosis

No fertility treatment until Reduce waiting lists for

complete diagnosis centres of expertise

van der Zanden et al. Diagnosis (Berl) 2021;8:333–339.

Laparoscopy Is No Longer The Diagnostic Gold Standard

ESHRE 2022 Guidelines

“Laparoscopy is no longer the

diagnostic gold standard, and it is
now only recommended in patients
with negative imaging results and/or
where empirical treatment was
unsuccessful or inappropriate.”

ESHRE, European Society of Human Reproduction and Embryology

ESHRE: Endometriosis Guideline of European Society of Human Reproduction and Embryology. 2022.
What if………..

…there was a simple checklist

to use when examining or
considering whether a patient
has endometriosis?
 Evaluate presence of symptoms
• Persistent and/or worsening cy clic or constant pelv ic pain • Sev ere pain, amenorrhoea or cramping without menstruation in an
• Dy smenorrhoea adolescent could indicate a reproductiv e tract anomaly
• Deep dy spareunia • Concomitant sy mptoms
• Cy clic dy schezia – Sev ere noncy clic constipation and diarrhoea suggests irritable
• Cy clic dy suria bowel sy ndrome
• Cy clic catamenial sy mptoms located in other sy stems – Painf ul v oiding or f lank pain could suggest urinary tract stones
Consistent with endometriosis

Consider Other Diagnosis in

(e.g. lung, skin) – Urinary sy mptoms (e.g. haematuria, f requent urination) could

Addition to Endometriosis*
indicate interstitial cy stitis/painful bladder sy ndrome

Review patient history

• Inf ertility • Absence of menses or other obstructiv e conditions in adolescence
• Dy smenorrhoea in adolescence; current chronic pelv ic pain • History of pain directly associated with surgery (e.g. post-operativ e nerv e
• Prev ious laparoscopy with diagnosis entrapment or injury , bowel adhesions)
• Dy smenorrhoea unresponsiv e to nonsteroidal anti-inf lammatory drugs
• Positiv e f amily history

Perform physical examination

• Nodules in cul-de-sac • Pelv ic f loor spasms
• Retrov erted uterus • Sev ere allody nia along pelv ic f loor/ v ulva or elsewhere
• Mass consistent with endometriosis • Mass is not consistent with endometriosis
• Obv ious endometrioma that is external (seen on speculum or on skin) (e.g. f ibroids)

Perform/order imaging
• Endometrioma on ultrasound • Adenomy osis and f ibroids (although these may be present with
• Presence of sof t markers (e.g. sliding sign) endometriosis)
• Nodules and masses

Agarwal et al. Am J Obstet Gynecol 2019;220:354.e1-354.e12.

Protocol For Early Diagnosis
Questions for women of reproductive age

Pelvic-abdominal pain Gynaecological symptoms Non-gynaecological cyclical Adolescents w ith

and/or infertility? (dysmenorrhoea, non-cyclical pelvic symptoms (dyschezia, dysuria, intractable pain
pain, deep dyspareunia or fatigue)? haematuria, rectal bleeding or unresponsive to NSAIDs?
shoulder pain)?
Ye
If the answer is: s
Pelvic examination, including vaginal palpation, speculum and rectovaginal examination

Painful induration, Visible vaginal lesions, nodules Adnexal mass Normal/no pathological
tenderness of the in the posterior vaginal fornix and Endometrioma suspected findings
DE uterus
suspected retroverted uterus Endometriosis
DE suspected suspected

If TVS is not
Imaging/TVS appropriate, use
Clinical TAS or TRS
diagnosis
Endometriosis
(including endometrioma and DE)

DE, deep endometriosis; NSAIDs, non-steroidal anti-inflammatory drugs; TAS, transabdominal sonography; TRS, transrectal sonography; TVS, transvaginal sonography.

Kim et al. Presented at SEUD 2021.

Take Home Messages
• It is important to diagnose endometriosis ASAP. Not all period pain is
normal.
• Laparoscopy is no longer gold standard to diagnose endometriosis.
• Medical therapy before and after surgery can reduce recurrence of
surgery.