Endometrial hyperplasia

What is endometrial hyperplasia?

Endometrial hyperplasia is an abnormal proliferation of the endometrium (ie greater than the normal proliferation that occurs during the menstrual cycle). It is a risk factor for the development of endometrial carcinoma.

Pathogenesis¹

The 2014 World Health Organization (WHO) classification divides endometrial hyperplasia into two types on the basis of presence or absence of cytological change:

• Hyperplasia without atypia

• Atypical hyperplasia

Atypical hyperplasia is considered a pre-malignant condition. Management is therefore dependent upon the presence of cellular atypia. Histological examination of endometrial tissue is mandatory for diagnostic classification.

For hyperplasia without atypia, the risk of progression to endometrial carcinoma is less than 5% over 20 years. The risk in atypical hyperplasia is as high as 28% over the same time period if untreated.^{2 3} There is also a risk of co-existing endometrial malignancy within the hyperplasia that can occur in up to 43% of samples.⁴

Risk factors³

Endometrial hyperplasia is caused by oestrogen, which when unopposed by progesterone, stimulates endometrial cell growth by binding to oestrogen receptors in the nuclei of endometrial cells. Most established risk factors are therefore those which cause raised oestrogen levels.

• Obesity (androgens are converted to oestrogen within adipose tissue).

• Exogenous oestrogen use (without cyclical progesterone).⁵

• Oestrogen-secreting ovarian tumour. (Up to 40% of those with granulosa cell tumours have endometrial hyperplasia.)

• Tamoxifen use; it has an anti-oestrogen effect on the breast but a pro-oestrogen effect on the uterus and bones.

• Polycystic ovarian syndrome (due to anovulation).

• Nulliparity.

• Hereditary non-polyposis colorectal carcinoma.

• Diabetes mellitus.

NB: use of combined oral contraceptive decreases risk.⁶

Endometrial hyperplasia symptoms and presentation

Endometrial hyperplasia usually presents clinically as abnormal vaginal bleeding - intermenstrual bleeding, irregular bleeding, menorrhagia or postmenopausal bleeding. There may be vaginal discharge.

Investigations¹

The National Institute for Health and Care Excellence (NICE) updated its guidance on recognition and referral of suspected cancer in January 2021.⁷ It recommends that urgent referral to gynaecological cancer service should be made if:

• Women over 55 years of age experience postmenopausal bleeding.

• Physical examination identifies ascites and/or a pelvic or abdominal mass (which is not obviously uterine fibroids); or

• Ultrasound scan appearances suggest ovarian cancer.

Endometrial biopsy

A definitive diagnosis of endometrial hyperplasia, and which type, is made by histology.

Historically, endometrial samples have been obtained by dilatation and curettage under general anaesthesia (GA). Nowadays it is more usual to obtain a sample by outpatient endometrial sampling, most commonly a pipelle biopsy. Occasionally this has to be performed under GA. All methods of sampling the endometrium will miss some hyperplasia and some cancers.

Hysteroscopy

Hysteroscopy and biopsy (curettage) should be considered as a more accurate method of diagnosis, and is the preferred diagnostic technique to detect polyps and other benign lesions. Where endometrial hyperplasia has been found within a polyp or other focal lesion, biopsy with direct visualisation by hysteroscopy is essential. Hysteroscopy may be performed as an outpatient procedure, although some women will require GA.

Transvaginal ultrasound

Ultrasound may be useful in both pre-menopausal and postmenopausal women in assessing abnormal vaginal bleeding, although if clinical suspicion is high, histological examination should take place regardless of the results.

• In postmenopausal women, the endometrial thickness may be used as a guide to help establish which women should have a biopsy and/or hysteroscopy. A cut off of 3-4 mm for endometrial thickness is usually advised; where the endometrium measures more than this, further investigation is required.^{8 9}

• In pre-menopausal women, no standardised cut-off threshold has been established but the thickness is less helpful due to cyclical change and the overlap between normal proliferative endometrium and hyperplasia. Ultrasound may be used to identify structural abnormalities such as polyps, and endometrial thickness below 7 mm is unlikely to represent hyperplasia.

Endometrial hyperplasia treatment and management¹

Management of hyperplasia without atypia

• Reassurance: explain to women that the risk of progression to cancer is less than 5% over 20 years and that most of this type of hyperplasia will return to normal either with or without treatment.

• Address any risk factors: help with obesity where this is an issue, and review hormonal medication which may be contributing.

• Watchful waiting: may be an option in asymptomatic women. Follow-up biopsies are required; women should be advised that regression is more likely with active treatment.

• Progestogen treatment: this is the usual management. The levonorgestrel intrauterine system (IUS) is the first-line option, as it is more effective in inducing regression and is associated with fewer adverse effects.¹⁰ The second-line option is continuous oral progestogen treatment, in the form of medroxyprogesterone (10-20 mg per day) or norethisterone (10-15 mg per day). Treatment with either is used for at least six months, although ideally the IUS should be left in situ for the full five years.

• Follow-up: endometrial biopsies are required six-monthly until two consecutive biopsies have been negative. Annual biopsy thereafter should be considered in women at higher risk (eg, BMI ≥35), and women should be educated to report any further bleeding as relapse may have occurred.

• Hysterectomy: this is not normally indicated but may be used where:

  • Regression has not occurred despite a year of progestogen treatment.

  • There is change to atypical hyperplasia.

  • There is relapse after treatment.

  • The woman wishes to have surgery rather than long-term medical treatment and regular biopsy.

Women on hormone replacement therapy (HRT) with endometrial hyperplasia should be advised to use the IUS as the progestogen, rather than a sequential HRT.

Women on tamoxifen are at higher risk of endometrial hyperplasia. The IUS probably slightly reduces the risk of hyperplasia; however, the balance of risks and benefits has not yet been established so this is not routinely recommended.¹¹

Management of atypical hyperplasia

Total hysterectomy is advisable for all women, due to the risk of malignant progression, with bilateral salpingo-oophorectomy in addition for postmenopausal women. A laparoscopic approach is preferable. For women who wish to preserve fertility, progestogen options may be used as above, with regular monitoring by three-monthly endometrial biopsy, and advice to have a hysterectomy as soon as potential fertility is no longer required. A 2018 Cochrane review concluded there is not yet the evidence of safety and efficacy for the routine use of IUS in women with atypical hyperplasia.¹²

Women who wish to conceive should be advised to wait until regression on medical treatment has occurred (at least one negative biopsy). Referral to a fertility specialist is advisable, and assisted conception may be considered.

Complications

Recurrence after treatment may occur. Endometrial hyperplasia may develop into endometrial carcinoma. Women who don't have atypical changes have a very small risk of developing a cancer. As many as 40% of women diagnosed with atypical hyperplasia are found to have a concurrent carcinoma.^{13 14} The rest with atypical changes are at significant risk as above. Risk increases after the menopause.