Endometrial Hyperplasia

Endometrial hyperplasia is an increase in the proportion of endometrial glands to stroma, resulting from unopposed oestrogen stimulation, and it is the precursor of endometrial adenocarcinoma. It is classified into two categories according to the presence of cytological atypia: hyperplasia without atypia (formerly simple and complex hyperplasia without atypia) and atypical hyperplasia or endometrioid intraepithelial neoplasia.

Progression to cancer over 20 years is about 1 to 3 percent for hyperplasia without atypia, and 25 to 30 percent for atypical hyperplasia, with a concurrent carcinoma already present in 25 to 40 percent of women diagnosed with atypical hyperplasia on biopsy.

Risk factors: obesity (peripheral conversion of androstenedione to oestrone in adipose tissue), chronic anovulation (polycystic ovary syndrome, perimenopause), unopposed oestrogen therapy, tamoxifen, oestrogen secreting tumours (granulosa cell tumour), diabetes, nulliparity, early menarche and late menopause, Lynch syndrome, and age above 45.

• Abnormal uterine bleeding: heavy, prolonged or irregular menstrual bleeding in premenopausal women; postmenopausal bleeding in older women.
• Intermenstrual bleeding, oligomenorrhoea with episodes of heavy bleeding after amenorrhoea.
• Sometimes asymptomatic, found incidentally on a biopsy or on thick endometrium on imaging.
• Examination often shows obesity, features of PCOS, and a normal pelvic examination.

• Transvaginal ultrasound: endometrial thickness above 4 mm in postmenopausal women with bleeding (some centres use above 3 mm) suggests the need for sampling; in premenopausal women thickness varies with cycle and is of limited value.
• Endometrial sampling is the diagnostic test: office pipelle biopsy (sensitivity about 80 to 90 percent for global lesions but lower for focal ones), or hysteroscopy with directed biopsy or dilatation and curettage if the pipelle is inadequate, if symptoms persist, or if focal lesions (polyp) are seen.
• Indications for sampling: age above 45 with abnormal bleeding; younger women with persistent bleeding, failed treatment, or risk factors; any postmenopausal bleeding; thickened endometrium on imaging.
• Histology: hyperplasia without atypia shows crowded glands with preserved architecture and no nuclear atypia; atypical hyperplasia shows glandular crowding with nuclear enlargement, rounding, loss of polarity and prominent nucleoli. Atypical hyperplasia on biopsy is reviewed by a gynaecological pathologist; PTEN loss and mismatch repair deficiency testing are used when Lynch syndrome is suspected.
• Baseline tests: full blood count, glucose or HbA1c, body mass index and blood pressure; chest and pelvic imaging as preparation if surgery is planned. Where cancer is suspected, MRI pelvis.

Hyperplasia without atypia

• Weight loss and treating risk factors (bariatric surgery has a strong effect on regression), stopping unopposed oestrogen, and glycaemic control.
• First line medical treatment: levonorgestrel releasing intrauterine system (52 mg), left for at least 6 months, with a regression rate of about 90 to 95 percent. Continue for 5 years if the patient wishes.
• Oral progestogen when the intrauterine system is declined: medroxyprogesterone acetate 10 to 20 mg daily for 12 to 14 days per cycle or continuously, or norethisterone 5 mg three times daily, or megestrol 80 to 160 mg daily, for at least 6 months. Continuous regimens have higher regression rates (about 70 percent versus 55 percent cyclical).
• Biopsy every 3 to 6 months until two consecutive negative biopsies are obtained, then annual surveillance in those at continued risk; if the patient is premenopausal, a biopsy once treatment ends is advised.
• If hyperplasia persists after 12 months of treatment, or if bleeding persists, or if the patient declines or is intolerant of medical therapy, hysterectomy is considered. Hysterectomy is also the choice after a recurrence.
• Metformin, as an adjunct in insulin resistant women, has some effect.

Atypical hyperplasia

• Total hysterectomy is the recommended treatment because of the high rate of concurrent cancer. Bilateral salpingo oophorectomy is added in postmenopausal women and considered in premenopausal women with risk factors for ovarian involvement or genetic risk. Laparoscopic or vaginal approaches are preferred.
• Preoperative evaluation should exclude cancer: imaging, and frozen section or sentinel node assessment if available, because about 25 to 40 percent harbour cancer. Hysterectomy for atypia should be done by a surgeon able to continue to staging if cancer is found.
• Fertility sparing treatment for women who strongly wish to preserve fertility, or who are unfit for surgery, after careful counselling and exclusion of invasive cancer by imaging and hysteroscopic sampling: levonorgestrel intrauterine system (with or without oral megestrol 160 mg daily or medroxyprogesterone 400 to 600 mg daily) with 3-monthly biopsies; response is expected within 6 months, and treatment continues until two negative biopsies and then pregnancy is encouraged (often with assisted reproduction); relapse rate is 25 to 40 percent. Hysterectomy after childbearing is completed.
• Surveillance of residual risk: women treated medically have long term endometrial biopsies every 6 to 12 months.

Pregnancy and fertility

• Anovulation is addressed with ovulation induction (letrozole) once the endometrium has regressed.