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Endometriosis - Clinical Notes

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Definition

• Bailey and Love's Short Practice of Surgery, 28th Ed.
• Robbins & Kumar Basic Pathology

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Epidemiology

• Predominantly a disease of reproductive age
• Higher incidence in women with infertility
• A significant proportion of affected women remain asymptomatic
• Gastrointestinal involvement occurs in 12-37% of cases

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Pathogenesis

Molecular drivers at implant level

• Elevated PGE2 and VEGF (proinflammatory, angiogenic)
• Recruited macrophages with upregulated COX-2 amplify the inflammatory loop
• High aromatase in stromal cells -> local estrogen production -> promotes implant survival
• Elevated matrix metalloproteinases (MMP) facilitating tissue invasion

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Types of Endometriosis

1. Superficial peritoneal endometriosis - small implants on peritoneal surface
2. Ovarian endometriosis (endometriomas) - cystic masses filled with old haemorrhage ("chocolate cysts"), 3-5 cm, reported in 17-44% of women with endometriosis
3. Deep infiltrating endometriosis (DIE) - tissue >5 mm beneath the peritoneum; involves uterosacral ligaments, vagina, bowel, bladder, ureters; highest risk of malignant transformation

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Sites of Involvement

• Ovaries
• Uterosacral ligaments
• Pouch of Douglas
• Fallopian tubes
• Serosal surfaces and peritoneum

• Sigmoid colon and rectosigmoid are most common
• Small bowel loops, caecum also affected
• Serosal implants invade the muscularis propria - causes fibrosis, wall contraction, mass effect; mucosal surface usually remains intact

• Lungs - recurrent haemoptysis or pneumothoraces at time of menstruation
• Periumbilical tissues, laparotomy scars

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Morphology

• Classic "powder burn" or "gunshot" lesions: black, dark brown or bluish puckered nodules/cysts containing old haemorrhage, surrounded by fibrosis
• Atypical/"subtle" lesions: red implants (petechial, vesicular, flame-like), serous/clear vesicles, white plaques, yellow-brown peritoneal discolouration
• Endometriomas - ovarian cysts with thick, tar-like fluid ("chocolate cysts"); densely adherent to the peritoneum of the ovarian fossa and posterolateral uterus

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Laparoscopic Appearances

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Clinical Features

Symptoms

• Pain is the most common symptom
• Symptoms correlate poorly with disease extent - significant disease may be asymptomatic
• Each symptom has overlapping differentials (IBS, interstitial cystitis, etc.)

Examination Findings (suggestive)

• Pelvic tenderness
• Fixed retroverted uterus
• Tender uterosacral ligaments
• Enlarged ovaries
• Deeply infiltrating nodules in the pouch of Douglas or uterosacral ligaments
• Visible blue-domed cystic lesions in the posterior fornix (vaginal DIE)
• Digital rectal examination: rectosigmoid involvement, lateral/dorsal extension (hypogastric vessel/nerve involvement)
• Note: examination may be entirely normal

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Diagnosis

Non-invasive imaging

Classification

• Various operative classification systems exist (e.g., rASRM staging)
• Poor correlation between classification/disease extent and symptom severity

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Management

1. Conservative (Watchful waiting)

• Appropriate for asymptomatic or mildly symptomatic women

2. Medical Management

• GnRH agonists are effective but have significant side effects (hot flushes, bone density loss)
• Costly drugs may require prolonged courses
• Women often require multiple treatments

3. Surgical Management

• Ablation or excision of endometriotic lesions
• Laparoscopic surgery is preferred over open approaches

• Proximity of disease to the ureter - risk of ureteric stricture, hydronephrosis, renal dysfunction
• Distance of bowel lesions from the anal verge: low rectal lesions (5-8 cm from anal verge) carry higher risk of anastomotic leak and transient neurogenic bladder dysfunction
• Repeat surgery increases risk: ureterolysis risk of ureteral ischaemia; repeated bowel shavings reduce bowel wall integrity (risk of fistula)
• Bowel integrity can be tested intraoperatively (air insufflation in water, methylene blue per rectum)
• Ureteral stents for bladder endometriosis near the trigone (removed at ~6 weeks); catheter for 8-10 days post-cystectomy

• Hysterectomy + bilateral salpingo-oophorectomy + total excision of all endometriotic disease = best chance of cure, reserved for women who have completed their family

Complications and Risks

• Laparoscopic complications: bowel, bladder, ureteric injury (2 in 1000 women); risk higher with DIE
• Tubo-ovarian abscess (rare, from infected endometrioma)
• Bowel resection: risk of faecal peritonitis

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Associations and Complications

• Infertility - 30-40% of patients present with this
• Malignant transformation - uncommon but recognised; mainly from DIE; endometrioid and clear cell carcinoma of the ovary are the most associated histological types
• Bowel obstruction (from fibrosis/adhesions)
• Hydronephrosis (ureteric involvement)

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Recent Evidence (2024-2026)

• Fibrosis in endometriosis (Vissers et al., Hum Reprod Update 2024, PMID 39067455): Systematic review highlighting fibrosis as a key driver of disease progression and pain in endometriosis - a potential therapeutic target distinct from the current hormonal approach.
• Exercise as adjunct therapy (Xie et al., PLoS One 2025, PMID 39946383): Meta-analysis showing physical activity is effective and safe for improving pain and quality of life in women with endometriosis.

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Summary Table

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The Menstrual Cycle - Clinical Notes

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Overview

• Average cycle length: 28 days (normal range: 26-34 days)
• Cycle variation is almost entirely due to variation in the follicular phase; the luteal phase is relatively constant (~14 days)
• Day 1 = first day of menstrual bleeding
• Average duration of flow: 4-6 days; average blood loss: ~30 mL

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The Hypothalamic-Pituitary-Ovarian (HPO) Axis

Hypothalamus

• GnRH (gonadotropin-releasing hormone) - controls LH and FSH
• CRH - controls ACTH
• GHRH - controls GH
• TRH - controls TSH

Gonadotropin-Releasing Hormone (GnRH)

• A decapeptide produced by neurons in the arcuate nucleus of the hypothalamus
• GnRH neurons originate embryologically in the olfactory pit and migrate to the hypothalamus
• Secreted in a pulsatile fashion into the portal circulation
• Pulse frequency governs the LH:FSH ratio: high frequency favours LH, low frequency favours FSH
• GnRH has a self-priming effect: each dose potentiates the response to subsequent doses
• Continuous (non-pulsatile) GnRH administration causes pituitary desensitisation and gonadotropin suppression - the basis of GnRH agonist therapy

Feedback Loops

• Tonic negative feedback centre (basal medial hypothalamus) - responds to low/baseline E2 and to progesterone+E2 in the luteal phase
• Cyclic positive feedback centre (anterior hypothalamus) - activated by the high pre-ovulatory E2 surge -> triggers the LH surge

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The Phases of the Menstrual Cycle

Phase 1: Follicular Phase (Days 1-14) = Proliferative Phase

1. Days 1-5 (early follicular): Rising FSH recruits a cohort of antral follicles. LH begins to rise around mid-follicular phase.
2. Days 5-7: A single dominant follicle is selected - the one with the most FSH receptors and richest estrogenic microenvironment. All others undergo atresia.
3. Progressive E2 rise: The dominant follicle produces increasing E2, which:
   • Causes negative feedback → FSH falls
   • Stimulates endometrial proliferation
   • Causes cervical mucus to become copious, watery, and elastic ("ferning" pattern)
4. Pre-ovulatory (Day ~13): E2 reaches a critical threshold (peak ~250-400 pg/mL) → switches from negative to positive feedback on the hypothalamus → LH surge triggered

Two-Cell, Two-Gonadotropin Theory (Follicular Steroidogenesis)

• Granulosa cells lack early enzymes in the steroidogenic pathway and need androgen substrate from theca cells
• Theca cells lack aromatase and need granulosa cells to complete oestrogen synthesis
• FSH + local E2 further stimulate FSH receptor expression and granulosa cell proliferation
• Increasing ovarian inhibin B also suppresses FSH to create a competitive environment

Clinical note: Androgen excess (e.g., PCOS) suppresses FSH → blocks dominant follicle emergence → chronic anovulation

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Ovulation (Day ~14)

• Preovulatory E2 peak activates the cyclic positive feedback centre → increased GnRH pulse frequency + increased pituitary sensitivity to GnRH → LH surge
• LH surge onset occurs 16-58 hours before ovulation in 90% of women; LH peak occurs 3-36 hours before ovulation
• A smaller FSH surge also occurs at midcycle (triggered by progesterone), thought to stimulate plasminogen activator and increase granulosa cell LH receptors
• LH surge triggers:
  • Completion of meiosis I in the oocyte (previously arrested at prophase I)
  • Prostaglandin release and proteolytic enzyme activation → follicular wall rupture
  • Ovulation of the secondary oocyte + first polar body
• Androgens also peak at midcycle

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Phase 2: Luteal Phase (Days 14-28) = Secretory Phase

• The ruptured follicle is transformed into the corpus luteum (luteinisation)
• Granulosa and theca cells hypertrophy and accumulate lipid-containing yellow pigment (lutein)
• Progesterone production increases 10-20× to peak ~8 days after the LH surge (day ~22)
• E2 also rises again from the corpus luteum

• Progesterone + E2 exert negative feedback on both the hypothalamic tonic centre and pituitary → LH and FSH are suppressed
• A low level of LH is still needed to sustain corpus luteum function

• Corpus luteum regresses (~day 24-26)
• E2 and progesterone fall
• Endometrium is shed (menstruation)
• Falling E2 → removes negative feedback → FSH begins to rise → next cycle begins

• Trophoblast produces hCG (structurally homologous to LH, binds LH receptors)
• hCG rescues the corpus luteum → progesterone continues to rise
• Sustained progesterone maintains the endometrium for implantation

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Endometrial Changes

Endometrial Layers

• Stratum functionale - shed at menstruation; regenerates each cycle
• Stratum basale - permanent layer; source of regeneration

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Cervical Mucus Changes

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Basal Body Temperature (BBT)

• Progesterone has a mild thermogenic effect
• BBT rises ~0.3-0.5°C after ovulation and remains elevated throughout the luteal phase
• The transient dip just before the rise corresponds to the E2 peak at ovulation
• BBT charts can retrospectively confirm ovulation

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Hormone Summary Across the Cycle

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Key Reference Values

A mid-luteal progesterone > 3 ng/mL (or ideally >5-10 ng/mL) confirms ovulation

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Inhibins and Other Modulators

• Inhibin B - produced by granulosa cells of small/medium follicles; suppresses FSH in follicular phase
• Inhibin A - produced mainly by the dominant follicle and corpus luteum; suppresses FSH in mid-late luteal phase
• Activin - stimulates FSH secretion (opposing inhibin)
• IGF-1 - amplifies FSH and LH actions in the follicle

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Clinical Correlates

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