Case 18.4 – Endometriosis

HISTORY

Pain: Nature, site, radiation, severity, onset. Frequency and duration. Relationship to menstrual cycle / sexual intercourse. Aggravating/ relieving factors. Assess impact on lifestyle e.g. Days off work

Menstrual history

Gynae/ surgical/ obstetric history

Social history including relationship and sexual partners. History mental/physical abuse including domestic violence

Pyschiatric and orthopedic history including postural problems

Previous therapy and effectiveness, allergies

Gynae cause more likely where related to specific phases of menstrual cycle/ sexual intercourse. Otherwise urinary gastro and musculoskeletal symptoms should be elicited.

EXAMINATION

General and Gynae examination (if never been sexually active nil vaginal examination)

Clinical presentations:

Asymptomatic endometriosis: Factors assoc with reduced risk of endometriosis are an irregular cycle, >2 births, >1 TOP. May present with an adnexal mass.

Pain: Progressively increasing dysmenorrhoea, deep dyspareunia and chronic pelvic pain. There is often a poor correlation between symptoms and extent of disease. May have dyschezia or cyclical changes in bowel movements.

Infertility: Mechanisms; interference with ovum transport, mechanical disruption of normal tubo-ovarian anatomy, impaired oocyte quality, (cytokines released from ectopic endometriotic deposits adversely affecting oocyte and embryo quality), Iatrogenic (suppressive hormone therapy and destructive surgery), relative endometrial progesterone resistance.

Cyclic bleeding: In any organ system may be due to endometriosis

Examination:

• Normal
• Fixed retroversion of the uterus
• Tender nodularity of uterosacral ligaments
• Ovarian endometriomas

Theories of Pathogenesis:

• Retrograde menstruation – described in up to 80% of menstrual cycles
• Immunological theory – interplay of enhancing/suppressing genes + environment
• Abnormal proliferation – Angiogenesis, release of cytokines and inflammatory mediators appear to be part of disease process
• Direct spread – Via surgical transplantation, blood vessels, lymphatics. Explains remote locations and presence in episiotomy/abdominal wounds
• Metaplasia – constant irritation by retrograde menstruation may cause metaplasia of similarly derived embryonic tissue such as the pelvic peritoneum.

PERITONEAL ENDOMETIROSIS

Superficial lesions scattered over the peritoneal, serosal and ovarian surfaces.

• Menstrual effluent containing viable cells is transported into the peritoneal cavity in a retrograde direction along the fallopian tubes, and implants on exposed tissue. Increased risk where this is increased menstrual exposure (short cycles, prolonged bleeding, obstructed outflow)
• Expression of cell adhesion molecules, proteolytic enzymes and cytokines affecting the implantation and proliferation of tissue may differ between women.
• Changes in systemic humoral immunity have been implicated (higher rates of endometriosis in women with autoimmune diseases)

OVARIAN ENDOMETROSIS

Ovarian endometriomas

• Superficial lesions on the ovarian cortex become inverted and invaginated, and that endometriomas are derived from functional ovarian cysts or metaplasia of the coelomic epithelium covering the ovary.
• Endometriomas have features in common with neoplasia such as clonal proliferation, and are associated with subtypes of ovarian malignancy (e.g. endometrioid and clear cell carcinoma)

DEEPLY INFILTRATING DISEASE

DIE nodules extend >5mm beneath the peritoneum and may involve the uterosacral ligaments, vagina, bowel, bladder and uterus.

Endometriosis can only be accurately diagnosed by laparoscopy (and confirmed by histology of biopsy).

Ultrasound may detect small endometriomas within the ovary, presence of pelvic adhesions by a lack of mobility of the bowel and "fixation" of the ovaries.

Laparoscopy is the gold standard for diagnostic purposes, unless disease is visible in the vagina or elsewhere. Histological confirmation of at least one peritoneal lesion is ideal (and mandatory if DIE or >3cm). The entire pelvis, appendix and upper abdomen should be examined.

Indication	Number of studies	% with disease
Pelvic pain	15	4.5 – 62%
Infertility	32	2.1 – 78%
Sterilisation	13	0.7 – 43%

• Pain – dysmenorrhoea, dyspareunia, chronic pelvic pain, ovulation pain
• Chronic Fatigue
• Subfertility

Treatment aims may be:

• Improve natural fertility
• Enhance chances of success at assisted reproduction
• Pain relief

Hormonal treatment (COCP, progestagens, danazol, gestrinone, GnRH agonists)

• All appear to induce atrophy and decidualization of peritoneal deposits by suppressing ovarian function.
• Peritoneal and DIE lesions decrease in size, during therapy but reappear rapidly after treatment. Endometriomas rarely decrease in size and adhesions will be unaffected
• All reduce the total amount of pain, but the effects on non-menstrual pain is variable
• Hormonal treatment for subfertility does not improve the chances of natural conception.

Surgical Treatment

• The goal of surgery is to eliminate all visible peritoneal lesions, endometriomas, DIE and assoc adhesions and to restore normal anatomy.
• Ablation of lesions + LUNA (laparoscopic uterine nerve ablation) in mild-mod disease reduces pain at 6 months compared to diagnostic laparoscopy. LUNA is not common in practice, excision of lesions rather than ablation (diathermy / laser) where possible.
• Ablation of lesions + adhesiolysis in min-mild endometriosis enhances fertility. No RCT have been conducted for mod-severe disease.
• Ovarian endometriomas should be removed via laparopscopic cystectomy
• If there is clinical evidence of DIE, the possibility if ureteric, bladder and bowel involvement should be considered pre-op.

Rationale for drug use:

• Relieve pain (dysmenorrhoea, dyspareunia, other pelvic pain) and other symptoms.
• Induce atrophy within ectopic endometrium (hormonal treatment)

Drug choice:

Treatment should be individualised according to age, symptoms, extent of disease and pregnancy plans. Hormonal treatments include COCs, progestogens, danazol, gestrinone and GnRH agonists. They induce atrophy within ectopic endometrium either by suppressing oestrogen activity or by suppressing ovarian oestrogen production. All are equally effective in reducing pain but they differ in terms of adverse effects and cost.

NSAIDs: May be adequate for symptom relief in some women and can be used with other treatments. They are effective in relieving dysmenorrhoea, however, evidence is inconclusive regarding their effect on pain due to endometriosis.

Combined oral contraceptives: Can be taken long term and are usually well tolerated. Both cyclical and continuous regimens are used but there is no evidence that one regimen is more effective than the other. However, 'tricycling' (having a pill-free interval once every 3 months) may be useful in women with dysmenorrhoea.

Progestogens: Norethisterone, dydrogesterone and IM or oral medroxyprogesterone can all be used long term. Adverse effects include irregular bleeding and weight gain. Continuous oral progestogens and IM medroxyprogesterone also provide contraception if no doses are missed. Limited evidence suggests the levonorgestrel IUD may also be effective in reducing pain associated with endometriosis.

Danazol, gestrinone: Danazol and gestrinone both have androgenic adverse effects that limit their use: duration of treatment is 6–9 months with danazol and 6 months with gestrinone. An effective non-hormonal method of contraception must be used during treatment.

Gonadotrophin-releasing hormone agonists: The GnRH agonists are associated with hypo-oestrogenic adverse effects such as hot flushes, vaginal dryness and decreased BMD. Duration of treatment is limited to 6 months due to loss of BMD. Adding combined HRT allows treatment for up to 2 years (reduces these adverse effects and protects against BMD loss while maintaining efficacy). An effective non-hormonal method of contraception must be used during treatment (to avoid pregnancy in the event of missed doses).

Feature	Danazol	GnRH agonists
Contraindications	History of thromboembolic disorder Androgen-dependent tumour Severe hepatic impairment Unexplained vaginal bleeding—(investigate first) Pregnancy and breastfeeding (If taken by the mother at or after 8 weeks post conception, danazol can cause virilisation of the female foetus)	Unexplained vaginal bleeding Women at risk of low BMD, e.g. weight-related amenorrhoea, immobilisation, corticosteroid use, family history of osteoporosis Polycystic ovarian disease—risk of cystic enlargement at the beginning of the treatment. Pituitary adenoma—risk of pituitary apoplexy; avoid use. Pregnancy and Breastfeeding
Precautions	Cardiac disease, epilepsy, migraine—may be worsened due to fluid retention. Diabetes—glucose tolerance may be impaired. Renal - risk of oedema Contraception - may not inhibit ovulation in all women
Side effects	Weight gain, Bloating, Increased body hair, Acne and oily skin, Deep voice (irreversible), Decreased breast size, Muscle cramps, Headaches, Hot flushes, Limb tingling, Decreased libido, Menstrual spotting	Hot flushes, Night sweats, Headaches, Vaginal dryness, Irritability, Insomnia, Decreased libido, Palpitations, Joint stiffness
Complications	Liver tumours, Adverse effects on lipids	Bone loss, 'Flare' effect