Describe the pathology and pathophysiology of endometriosis/adenomyosis

Clinical overview

Endometriosis is the presence of endometrial-like glands and stroma outside the uterine cavity. It affects approximately 10% of reproductive-aged women and accounts for a substantial fraction of dysmenorrhoea, chronic-pelvic-pain, deep dyspareunia, and infertility. Adenomyosis is the same tissue but inside the myometrium — endometrial glands and stroma surrounded by hypertrophied smooth muscle. The two diseases are conceptually similar (ectopic endometrial tissue) but clinically distinct (pelvic vs uterine, surgical lesions vs uterine bulk).

Pathophysiology matters because it shapes management: a disease driven by oestrogen-dependent inflammation responds to hormonal suppression; a disease maintained by ongoing peritoneal seeding from retrograde menstruation argues for menstrual suppression as a long-term strategy; a disease with deep nerve-fibre infiltration requires excisional surgery to relieve pain. Each of these mechanisms is supported by evidence.

A registrar should be able to (1) explain why ectopic endometrium causes pain and infertility; (2) describe the three classical phenotypes (superficial peritoneal, ovarian endometrioma, deep infiltrating); (3) outline mechanisms in adenomyosis; (4) discuss how hormonal therapy, surgery, and fertility treatment each address a different mechanism.

Core knowledge

Theories of origin

Retrograde menstrual fragments can reflux through the tubes and implant on pelvic peritoneum, ovary and the pouch of Douglas.

No single theory accounts for all cases. The four major theories:

1. Sampson's retrograde menstruation theory (1927) — viable endometrial fragments reflux through the fallopian tubes during menses, implant on pelvic peritoneum, and grow. Supported by: anatomical distribution (more posterior than anterior, more left than right because the sigmoid traps tissue), more disease in women with outflow tract obstruction, the absence of disease beyond the reach of refluxed material in most cases.

   • Limitations: retrograde menstruation occurs in ~90% of women but only ~10% develop endometriosis — there must be additional factors (immune clearance failure, susceptible peritoneum, hormonal milieu).

2. Coelomic metaplasia theory (Meyer) — peritoneal cells transform under oestrogen and inflammatory stimuli into endometrial-like cells. Supported by: endometriosis in prepubertal girls, in men on oestrogen therapy, and in remote sites (pleura, brain) impossible to reach by reflux.

3. Lymphovascular embolisation (Halban) — fragments seeded via lymphatic and vascular channels. Explains distant disease (lung, brain, umbilicus).

4. Stem cell theory — endometrial stem cells migrate and implant. Supported by recent identification of endometrial mesenchymal stem cells.

The current synthesis: retrograde menstruation provides the substrate; immune surveillance fails to clear it; ectopic implants develop their own pathology including local oestrogen synthesis (aromatase expression), inflammation, and neurogenesis.

Histopathology

Diagnostic histopathological criteria require both:

• Endometrial glands.
• Endometrial stroma.

Plus often: haemosiderin-laden macrophages (haemosiderin from old menstrual bleeding within the lesion).

Lesions undergo cyclical bleeding into surrounding tissue → inflammation → fibrosis → adhesion formation. Repeated cycles produce the macroscopic appearances:

• Red active lesions — recent haemorrhage, often most painful, neovascularised.
• Blue/black "powder burn" lesions — chronic, with haemosiderin.
• White scarred lesions — old, fibrotic, sometimes asymptomatic.

The three classic phenotypes

1. Superficial peritoneal endometriosis (SPE). Surface lesions on peritoneum (pelvic side wall, uterosacral, vesicouterine fold). Often the dominant cause of pain through prostaglandin- and nerve-mediated mechanisms despite small lesion volume.

2. Ovarian endometrioma. Cystic accumulation of menstrual blood within the ovary. The "chocolate cyst" — dark brown thick fluid. Forms by invagination of the cortex with implants on the inner surface, or de novo within an ovary. Associated with significant ovarian reserve impairment (both directly and from surgical excision).

3. Deep infiltrating endometriosis (DIE). Lesions >5 mm beneath the peritoneal surface, invading rectovaginal septum, uterosacral ligaments, bowel wall, bladder wall, or ureters. Most associated with severe pain. Surgical management often requires multidisciplinary input (colorectal surgery, urology). See ENZIAN classification in endometriosis-staging.

Inflammatory and biochemical milieu

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Endometriotic implants sustain bleeding, inflammation, prostaglandin release, neurogenesis and fibrosis.

Endometriotic lesions are intensely inflammatory:

• Macrophage infiltration with altered function.
• Elevated cytokines: IL-1, IL-6, IL-8, TNF-α, MCP-1.
• Prostaglandin synthesis from cyclooxygenase-2 (COX-2).
• Local oestrogen synthesis from aromatase — the ectopic tissue makes its own oestrogen, which is why aromatase inhibitors work.
• Reduced 17β-hydroxysteroid dehydrogenase type 2 → impaired conversion of estradiol to estrone, sustained local oestrogenic effect.
• Progesterone resistance — reduced progesterone receptor expression; endometriotic tissue does not respond normally to progestogens, requiring higher doses and explaining some treatment failures.

Mechanisms of pain

Multiple, overlapping:

• Prostaglandin release driving local pain and dysmenorrhoea.
• Nerve fibre proliferation (neurogenesis) within and around lesions — increased nerve fibre density correlates with pain severity.
• Compression and infiltration of nerves (e.g., sciatic, obturator, pudendal) in deep disease.
• Adhesions causing tethering of organs.
• Central sensitisation over time (see chronic-pelvic-pain).
• Endometriosis-associated bowel and bladder symptoms mediated via shared visceral innervation.

Mechanisms of infertility

• Distorted pelvic anatomy → impaired tubal pickup and transport.
• Inflammatory peritoneal fluid → impaired gamete function (sperm motility, ovum fertilisation).
• Ovarian endometrioma reducing functional ovarian tissue and reserve.
• Altered endometrial receptivity (implantation defects).
• Reduced oocyte quality.

Adenomyosis pathophysiology

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Adenomyosis begins where basal endometrium invaginates through a disordered junctional zone into hypertrophied myometrium.

The current best model: invagination of basal endometrium into a disordered junctional zone (the inner myometrium). Drivers include:

• Disruption of the endometrial–myometrial interface (trauma — uterine surgery, instrumentation, multiparity).
• Tissue injury–repair–regeneration cycles (TIAR theory).
• Oestrogen-driven proliferation and hyperinnervation.

The myometrium responds with hypertrophy and hyperplasia → bulky uterus. Cyclical bleeding within the myometrial islands → inflammation, fibrosis, abnormal contractility. Junctional zone disordered architecture impairs sperm transport and embryo implantation, explaining infertility associations.

Genetic and immunological factors

• Familial clustering — first-degree relative with endometriosis = 6–10× risk.
• Polygenic — GWAS has identified loci near WNT4, GREB1, IL1A, others.
• HLA-B7 associations.
• T-regulatory cell dysfunction; NK cell impairment.
• Increased risk of certain cancers (clear-cell, endometrioid ovarian; in deep disease, low absolute risk but real).

Environmental factors

• Dioxin exposure (some animal data; human evidence weaker).
• Reproductive characteristics: early menarche, short cycles, heavy menses, nulliparity → higher risk.
• Late menarche, multiparity, prolonged breastfeeding, smoking → lower risk (smoking through lower oestrogen levels — not a recommended preventative).

Assessment

Diagnostic principles

The gold standard for endometriosis diagnosis is laparoscopy with histological confirmation. However, current practice (ESHRE, NICE) increasingly accepts clinical diagnosis supported by imaging, particularly when committing to empiric medical therapy. Surgical confirmation is reserved for: diagnostic uncertainty, suspected DIE before complex surgery, failed medical management.

Adenomyosis diagnosis is now largely sonographic/MRI (MUSA criteria) — see endometriosis-staging. Histology requires hysterectomy.

Clinical features that raise suspicion

• Dysmenorrhoea with progressive severity, often starting years after menarche.
• Deep dyspareunia (uterosacral or pouch of Douglas involvement).
• Cyclical pelvic pain becoming more constant over years.
• Dyschezia (painful defaecation) — especially perimenstrual; suggests bowel/rectovaginal involvement.
• Dysuria + cyclical haematuria → bladder involvement.
• Infertility — both unexplained and with identified factors.
• Menorrhagia + bulky tender uterus → adenomyosis.
• Family history of endometriosis.

Imaging features

Transvaginal ultrasound (skilled operator):

• Endometrioma: unilocular cystic ovarian mass with low-level homogeneous internal echoes ("ground glass" appearance), often bilateral, often with surrounding adhesions ("kissing ovaries").
• Deep posterior compartment: hypoechoic linear or nodular lesions in the uterosacral ligaments, rectovaginal septum, or anterior rectal wall.
• Adenomyosis (MUSA): asymmetric myometrial thickening, myometrial cysts, fan-shaped shadowing, irregular junctional zone.

MRI:

• High sensitivity for deep infiltrating endometriosis.
• Anatomical mapping for surgical planning — assessing bowel wall depth of infiltration, ureteric involvement, location of all lesions.
• Adenomyosis: junctional zone >12 mm, myometrial cysts, asymmetric uterus.

Management

Pathophysiology dictates management strategy. Management is detailed in endometriosis-staging and broader chronic pain management in chronic-pelvic-pain; here we link mechanism → treatment:

• Cyclical bleeding into implants → menstrual suppression (continuous combined hormonal contraception, progestogens, GnRH analogues).
• Local aromatase activity → aromatase inhibitors (specialist use; not first-line; reserved for refractory cases).
• Progesterone resistance → use of progestogens specifically designed for receptor profile (dienogest 2 mg daily — strong evidence).
• Lesion-driven mechanical pain and nerve infiltration → excisional surgery (excision > ablation evidence).
• Endometrioma and ovarian reserve → balance pain control vs ovarian damage; cystectomy preserves more reserve than drainage + ablation.
• Adenomyosis with bulky uterus and completed family → hysterectomy is definitive.
• Adenomyosis wanting fertility → progestogens (Mirena particularly), GnRH analogues, IVF.
• Infertility despite optimal disease management → assisted reproduction; surgery + IVF can be additive.

Red flags / pitfalls

• Dismissing teenage dysmenorrhoea as "normal" — early endometriosis is common in teenagers; early diagnosis improves outcomes.
• Confusing dyschezia with constipation — perimenstrual painful defaecation is a deep endometriosis flag.
• Operating on a "simple cyst" without considering endometrioma — pre-op MRI clarifies and avoids inadequate surgery.
• Hormonal suppression without explaining mechanism — patients abandon therapy when not properly counselled about why ongoing suppression matters.
• Ablating deep disease — incomplete; needs excision.
• Forgetting adenomyosis as a coexisting cause of pain — present in up to 80% of women with severe endometriosis.
• Quoting fertility outcomes from rASRM stage alone — use EFI.
• Not screening for IBS — coexists in up to 50%.

Evidence anchors

• ESHRE Guideline: Endometriosis (2022).
• NICE NG73 — Endometriosis: diagnosis and management.
• Vercellini P, et al. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol 2014.
• Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril 2012.
• Bulun SE. Endometriosis. N Engl J Med 2009 (still a foundational review).
• Vannuccini S, Petraglia F. Recent advances in understanding and managing adenomyosis. F1000Res 2019.
• Harmsen MJ, et al. MUSA criteria 2022.
• World Endometriosis Society Consensus.