Endometriosis

Definition

Epidemiology

• Prevalence: ~10% of women of reproductive age; up to 20–90% of women with pelvic pain or infertility; up to 50% of women with unexplained infertility.
• Found in women of all ethnic and social groups; reported in adolescents and postmenopausal women on HRT.
• Economic burden is comparable to diabetes mellitus, Crohn's disease, and rheumatoid arthritis (WERF EndoCost study).

Risk Factors

Protective Factors

Etiology / Pathogenesis

1. Retrograde menstruation / Ectopic transplantation (Sampson's theory) — the most widely accepted. Viable endometrial cells shed retrogradely via the fallopian tubes implant on peritoneal surfaces. Not all women with retrograde menstruation develop endometriosis, suggesting immune factors play a role.
2. Coelomic metaplasia — peritoneal mesothelial cells undergo metaplastic transformation into endometrial-like tissue.
3. Lymphovascular spread — explains distant/extrapelvic sites.

Immunologic Factors

Genetic Factors

• ~5–8× increased risk in first-degree relatives.
• Genome-wide studies show association with SNPs on chromosomes 1p36, 2p25, 6p24, 7p15, 9p21, 10q26, 12q22.
• Somatic mutations (ARID1A, PIK3CA, KRAS) found in endometriotic lesions, especially those co-occurring with clear-cell or endometrioid ovarian carcinoma.

Environmental Factors

Clinical Presentation

Symptoms

1. Dysmenorrhea — most common; progressive, starting days before menstruation
2. Dyspareunia (deep) — especially with uterosacral/rectovaginal disease
3. Chronic pelvic pain — found in 15–40% of laparoscopies for CPP
4. Dyschezia — pain on defecation; associated with rectovaginal and posterior cul-de-sac disease
5. Infertility — endometriosis found in 33% of infertile women vs 4% of fertile women
6. Dysuria / urinary symptoms — with bladder involvement
7. Cyclic rectal bleeding, hemoptysis, or hemothorax — with bowel or thoracic endometriosis (rare)

Important: There is no correlation between the stage of disease and severity of pain. Up to 30–50% of patients have no pain regardless of stage.

Endometriosis-Related Pain Syndrome

Clinical Examination

• Nodularity or tenderness of the uterosacral ligaments and posterior cul-de-sac
• Fixed, retroverted uterus ("frozen pelvis") in advanced disease
• Tender adnexal masses (endometriomas)
• 40–60% of patients have no tenderness on examination regardless of stage

Imaging

Ultrasound

MRI

CA-125

Macroscopic & Laparoscopic Findings

Types of Lesions

• Peritoneal endometriosis: most common form; variable appearance
• Ovarian endometriomas ("chocolate cysts"): thick, viscous dark-brown fluid; typically on the anterior ovarian surface with adhesions to posterior peritoneum
• Deep infiltrating endometriosis (DIE): penetrates >5 mm beneath the peritoneum; involves rectovaginal septum, uterosacral ligaments, bowel, ureters, bladder

Figure 13-1: Pelvic endometriosis sites — Berek & Novak's Gynecology

Diagnosis

• Positive histology confirms the diagnosis; negative histology does NOT exclude it
• Histology is recommended for endometriomas >4 cm and deep endometriosis (to exclude malignancy)
• Visual inspection alone is usually adequate for peritoneal disease

Classification / Staging

rASRM Staging (Revised American Society for Reproductive Medicine)

⚠️ The rASRM system correlates poorly with pain and fertility outcomes (subjective, high inter-observer variability). The World Endometriosis Society still recommends its use for standardization.

Endometriosis Fertility Index (EFI)

• Historical factors: age, years of infertility, prior pregnancies
• Surgical factors: total rASRM score, ASRM endometriosis score, "least function score" (fallopian tube, fimbriae, ovary functionality)

ENZIAN Score

Endometriosis and Infertility

1. Prevalence 33% in infertile women vs 4% in fertile women
2. Reduced monthly fecundity rate (MFR) in women and primates with endometriosis
3. Endometriomas negatively affect spontaneous ovulation rates
4. Dose-effect relationship: higher rASRM stage → lower MFR and cumulative pregnancy rate
5. Reduced implantation rate per embryo in IVF compared to tubal-factor infertility

No good evidence that endometriosis increases spontaneous abortion rates.

Management

Principles

• Goal: relieve symptoms (pain/infertility), prevent progression, preserve fertility
• Severe/deep endometriosis should be managed in a multidisciplinary center with advanced laparoscopic expertise
• ESHRE guidelines are the primary reference

Treatment of Endometriosis-Associated Pain

1. NSAIDs

• First-line for dysmenorrhea; evidence is weak for endometriosis specifically
• Mechanism: local antinociceptive + anti-inflammatory effects; reduces central sensitization
• Avoid at ovulation if pregnancy desired (PG-dependent follicle rupture)

2. Hormonal (Medical) Treatment

Duration: 6 months of ovarian suppression is the standard evidence-based duration for pain relief. Pain often recurs after cessation of medical treatment.

3. Surgical Treatment (Pain)

• Conservative surgery (laparoscopic ablation/excision of lesions + adhesiolysis): more effective than diagnostic laparoscopy alone for pain relief in minimal–mild disease
• Deep endometriosis: complete surgical excision in a single procedure is recommended; involves possible bowel/bladder/ureter resection
• Radical surgery (hysterectomy ± oophorectomy): last resort; reserved for women who have completed childbearing with refractory disease
• Preoperative hormonal therapy is not recommended (no evidence of benefit on outcomes)

Treatment of Endometriosis-Associated Infertility

• Surgical treatment: Ablation/excision of minimal–mild disease improves fertility over diagnostic laparoscopy alone (↑ live birth rate)
• Medical treatment alone: Not effective for improving fertility — conception is impossible during hormonal suppression
• Postoperative medical treatment: Not indicated (delays spontaneous conception; highest pregnancy rates occur in first 6–12 months post-surgery)
• ART/IVF: Method of choice when tubo-ovarian anatomy is distorted; also used when surgery has failed
• Expectant management: Reasonable for minimal–mild disease in younger women

Management of Recurrent Endometriosis

• Risk factors for recurrence: young age at initial surgery, incomplete excision, no postoperative hormonal suppression
• Prevention: continuous OCs or progestins post-surgery
• Medical treatment of recurrence: same agents as primary treatment; GnRH agonists with add-back
• Surgical re-treatment: possible, but carries increased risk of complications

Management in Adolescents

• Most common symptom: cyclic pelvic pain
• Laparoscopy indicated for chronic pelvic pain not responding to NSAIDs/OCs
• Endometriosis found in up to 70% of adolescents with refractory CPP
• Stages I–II are most common in this age group; red/clear/white lesions (subtle) predominate
• GnRH agonists reserved for adolescents >17 years who have completed bone maturation

Endometriosis and Cancer

• Modest increased risk of endometrioid and clear-cell ovarian cancer (OR 1.3–1.9); causal relationship recognized but absolute risk is low
• Possible association with melanoma and non-Hodgkin lymphoma (requires confirmation)
• Endometriosis itself should not be regarded as a condition with clinically relevant cancer risk

Key Points Summary (from Berek & Novak's)

1. Diagnosis requires laparoscopic visualization ± histology; negative histology does not exclude it.
2. Associated with infertility, dysmenorrhea, dyspareunia, non-menstrual pain, and reduced QoL.
3. Severe/deep disease must be managed in a multidisciplinary center.
4. rASRM staging correlates poorly with pain and infertility outcomes.
5. EFI predicts non-IVF pregnancy rates after surgical treatment.
6. All hormonal drug classes are equally effective for pain; choice depends on side effects and cost.
7. Surgical excision in minimal–mild disease improves fertility over diagnostic laparoscopy alone.
8. Hormonal suppression does NOT improve fertility.

Endometriosis

Definition

Epidemiology

• 10% of reproductive-age women
• 33% of infertile women; 20–90% of women with pelvic pain
• Found in all ethnic groups; also in adolescents and postmenopausal women on HRT

Pathogenesis — Three Theories

Not all women with retrograde menstruation develop disease → immune factors (↓NK cell activity, ↓macrophage clearance) determine susceptibility.

Clinical Features — "5 Ds"

⚠️ No correlation between stage and severity of pain. 30–50% of patients have no pain regardless of stage.

Examination Findings

• Uterosacral ligament nodularity/tenderness
• Fixed retroverted uterus ("frozen pelvis")
• Adnexal masses (endometriomas)
• 40–60% have no tenderness on exam

Diagnosis

• Positive histology → confirms; negative histology does NOT exclude
• Histology mandatory for endometriomas >4 cm and deep disease (to exclude malignancy)

Laparoscopic Lesion Types

Sites

• Peritoneal (most common)
• Ovarian endometrioma — "chocolate cyst": thick dark-brown fluid, anterior ovarian surface, adhesions to posterior peritoneum
• Deep infiltrating endometriosis (DIE) — penetrates >5 mm; rectovaginal septum, uterosacral ligaments, bowel, ureter, bladder

Investigations

• TVUS: first-line; best for endometriomas ("ground-glass" cysts)
• MRI: best for mapping DIE preoperatively
• CA-125: low sensitivity; not for diagnosis — useful for monitoring

Staging — rASRM Classification

⚠️ rASRM correlates poorly with pain and fertility outcomes (subjective, high inter-observer variability).

Management

Pain — Medical Treatment

Duration: 6 months of suppression standard. Pain recurs after stopping treatment.

Pain — Surgical Treatment

• Laparoscopic ablation/excision + adhesiolysis: superior to diagnostic laparoscopy alone
• DIE: complete excision in one procedure; may require bowel/bladder/ureter resection; refer to specialized center
• Hysterectomy ± oophorectomy: last resort for refractory disease in women who have completed childbearing
• Preoperative hormonal therapy: NOT recommended (no evidence of benefit)

Infertility Treatment

Endometriosis and Cancer

• Modest ↑ risk of endometrioid and clear-cell ovarian cancer (OR 1.3–1.9)
• Not considered a condition with clinically significant cancer risk overall

High-Yield Exam Points

1. Definition: endometrial glands/stroma outside uterus
2. Diagnosis: surgical (laparoscopy); negative histology does not exclude
3. Best theory: Sampson's retrograde menstruation
4. Stage ≠ severity of pain — key examiner favourite
5. All hormonal agents equally effective for pain
6. Medical treatment does NOT improve fertility
7. Surgical excision (not suppression) improves fertility in minimal–mild disease
8. GnRH agonists: need add-back therapy >6 months
9. Danazol: androgenic side effects; voice change is irreversible
10. EFI: predicts non-IVF pregnancy rates (not pain outcomes)

Endometriosis

Definition

• Endometriosis interna (Adenomyosis) — endometrial tissue within the myometrium
• Endometriosis externa — endometrial tissue outside the uterus (this chapter deals with externa)

Incidence

• Affects 10–15% of women of reproductive age
• Found in 25–35% of infertile women
• Peak incidence: 25–35 years (reproductive age)
• Rare before menarche; may occur postmenopausally in women on HRT

Sites of Endometriosis

Pelvic (Common)

1. Ovaries — most common site (~60%); "chocolate cysts" (endometriomas)
2. Pouch of Douglas / posterior cul-de-sac
3. Uterosacral ligaments
4. Posterior surface of uterus and broad ligament
5. Fallopian tubes
6. Rectovaginal septum
7. Pelvic peritoneum
8. Sigmoid colon and appendix
9. Urinary bladder and ureters

Extrapelvic (Rare)

Pathogenesis — Theories

Morbid Anatomy

Ovarian Endometriosis ("Chocolate Cyst")

• Cyst contains thick, dark-brown tarry fluid (degenerated blood — hemosiderin)
• Wall is lined by endometrial epithelium
• Adhesions to surrounding structures (posterior uterine wall, broad ligament)
• Repeated bleeds → enlargement of cyst

Peritoneal Implants

• Early/Active: Red, flame-like vesicles — bleed cyclically
• Old/Inactive: Black "powder-burn" spots — hemosiderin deposits
• Fibrotic: White stellate scars — may mimic normal peritoneum

"Frozen Pelvis"

Pathophysiology of Symptoms

• Produces prostaglandins → pain
• Inflammation damages pelvic structures → infertility

Clinical Features

Symptoms — Classic Triad

1. Dysmenorrhea — congestive, progressive, spasmodic; starts 2–3 days before flow; key feature: worsens over years
2. Dyspareunia (deep) — due to involvement of rectovaginal septum and uterosacral ligaments
3. Infertility — in ~30–40% of cases

Other Symptoms

• Menstrual abnormalities — menorrhagia, irregular bleeding (due to co-existing anovulation)
• Dyschezia (painful defecation) — rectal/rectovaginal disease
• Dysuria, hematuria — bladder involvement
• Cyclical rectal bleeding — bowel endometriosis
• Cyclical pain at scar sites — umbilical or incisional scar endometriosis
• Hemoptysis — rare; thoracic endometriosis

⚠️ "Pain is out of proportion to the disease" — extent of endometriosis does NOT correlate with severity of pain (DC Dutta emphasis)

Signs on Examination

Abdominal Examination

• Usually normal in early disease
• Large endometrioma → palpable mass

Pelvic Examination (Bimanual + Speculum)

• Fixed retroverted uterus — classic finding
• Tender nodules along uterosacral ligaments (best felt during menstruation)
• Tender adnexal mass (endometrioma) — restricted mobility
• Tenderness in pouch of Douglas
• Blue-black spots visible in posterior vaginal fornix (rectovaginal endometriosis)

Investigations

Diagnosis

• Positive histology confirms; negative histology does NOT exclude
• Laparoscopy performed ideally during menstruation or premenstrual phase (lesions most active)

Classification — American Fertility Society (AFS) / rASRM Scoring

Treatment

Principles

• Depends on: age, symptoms, desire for fertility, stage of disease
• Options: Expectant / Medical / Surgical / Combined

A. Expectant Management

• For asymptomatic minimal/mild disease and women actively trying to conceive (mild disease)
• Spontaneous remission can occur in mild disease

B. Medical Treatment

1. Pseudopregnancy Regimen

• Combined OCP — continuous (not cyclic); 6–9 months
• Progestins — MPA (Medroxyprogesterone acetate) 10–30 mg/day; norethisterone
• Mechanism: decidualization and necrosis of implants

2. Pseudomenopause Regimen

• Danazol — 400–800 mg/day for 6 months
  • Mechanism: ↓GnRH/gonadotropins, ↓estrogen, ↑androgens → atrophy of implants
  • Side effects: weight gain, acne, hirsutism, voice change (irreversible), hepatotoxicity
• GnRH Agonists (Buserelin, Leuprolide, Goserelin) — 6 months
  • Mechanism: pituitary down-regulation → medical oophorectomy
  • Side effects: menopausal symptoms, osteoporosis (add-back therapy if >6 months)
  • Add-back therapy: low-dose estrogen + progestin or tibolone

3. Newer Agents

• Gestrinone (anti-progestin + anti-estrogen): 2.5 mg twice weekly
• LNG-IUS (Mirena): effective for pain, especially dysmenorrhea
• Aromatase inhibitors (Letrozole): refractory cases; combined with OCP or GnRH agonist

⚠️ Medical treatment does NOT improve fertility — it suppresses ovulation and conception is impossible during treatment

C. Surgical Treatment

Conservative Surgery (fertility-preserving)

• Laparoscopic (preferred): ablation/fulguration/excision of implants, adhesiolysis, drainage of endometriomas (cystectomy preferred over drainage alone)
• Laparotomy: severe/complex disease
• Indications: desire for fertility, failed medical treatment, endometrioma >4 cm
• Post-op: highest pregnancy rates in first 6–12 months — attempt conception immediately

Semi-Conservative Surgery

• Hysterectomy + conservation of ovaries: for women who want to preserve ovarian function but have completed family

Radical Surgery

• TAH + BSO (Total Abdominal Hysterectomy + Bilateral Salpingo-Oophorectomy)
• For: severe disease, completed family, failed other treatments
• Curative in most cases

D. Combined (Medical + Surgical)

• Pre-operative hormonal therapy (GnRH agonist × 3 months): reduces vascularity, makes surgery easier — though ESHRE guidelines do not support this
• Post-operative medical therapy: OCP/progestins to suppress recurrence (not if fertility desired)

Endometriosis and Infertility

1. Mild disease → Laparoscopic surgery → expectant conception
2. Moderate–severe → Surgery → ART if spontaneous conception fails
3. Advanced age / bilateral endometriomas → Direct ART (IVF)

Prognosis and Recurrence

• Recurrence rate: 20–40% within 5 years after conservative surgery
• Definitive cure: radical surgery (TAH + BSO)
• Medical treatment: symptom relief only; disease recurs after cessation
• Malignant transformation: rare (~1%); → clear-cell or endometrioid ovarian carcinoma

High-Yield Points (DC Dutta Style)

1. Most common site = Ovary
2. Gold standard diagnosis = Laparoscopy + histology
3. Pathognomonic finding = Chocolate cyst / powder-burn spots
4. Classic symptom triad = Dysmenorrhea + Dyspareunia + Infertility
5. Pain ≠ Stage — severity of pain does NOT correlate with extent of disease
6. Danazol: androgenic side effects; voice change is irreversible
7. GnRH agonists: need add-back therapy beyond 6 months
8. Medical Rx ≠ fertility improvement — cannot conceive during treatment
9. Post-op: attempt conception within 6–12 months (peak fertility window)
10. Definitive treatment: TAH + BSO