Endometrial Hyperplasia

The endometrium is the lining of the uterus. The nature and characteristics of the endometrium change throughout the normal menstrual cycle. During the first portion of the menstrual cycle, termed the follicular phase, the endometrium is in a proliferative pattern of growth. During the second half of the menstrual cycle, called the luteal phase, the endometrium is in a secretory pattern of growth (see menstrual cycle).

Uterus with endometrium

Menstrual cycle summary

The endometrium is composed of two types of tissues; glands and stroma. The glands of the endometrium are functional in allowing the proper implantation of an embryo of fertilization of an egg occur and the stroma is the intervening connective tissue. The glands and stroma both proliferate in response to estrogen. The heightened progesterone levels of the luteal phase cause the endometrium to become secretory. These glands provided a source of nutrients and growth factors for early pregnancy.

 Proliferative and secretory endometrium

The endometrium may become abnormally proliferative in response to abnormal estrogen production or exposure, or through genetic causes. Endometrial hyperplasia is characterized by a proliferation of endometrial glands of irregular size and shape with an increased gland to stroma ratio. Normal proliferative endometrium exhibits no crowding of glands within the stroma (<50 percent ratio of glands to stroma).  In contrast, endometrial hyperplasia is characterized by a proliferation of endometrial glands resulting in a greater gland-to-stroma ratio (>50 percent). The proliferating glands vary in size and shape, and cells may look unusual (this is called cytologic atypia). Endometrial hyperplasia frequently results from chronic estrogen stimulation unopposed by the counterbalancing effects of progesterone

Endometrial hyperplasia is a benign condition, however some types may be precancerous. The classification of endometrial hyperplasia is predominantly based on whether the changes have a premalignant (precancerous) potential. Precancerous hyperplasia is also referred to as atypical complex hyperplasia. Endometrial hyperplasia which does not have a premalignant potential is referred to as non-neoplastic and includes simple hyperplasia and complex hyperplasia without atypia,

The WHO (World Health Organization) system is the most widely used for classification. It categorizes endometrial hyperplasias into two groups: hyperplasia without atypia (non-neoplastic) and atypical hyperplasia (endometrial intraepithelial neoplasm).

This system reflects that hyperplasia without atypical cells is a non-neoplastic change. By contrast, hyperplasia with atypical cells has been found to exhibit many cellular and genetic changes that are typically associated with invasive carcinoma and therefore is considered a precancerous condition and can also be called intraepithelial (EIN)

Cellular atypia generally refers to nuclear atypia, which is the presence of nuclear enlargement; the chromatin (substance within the chromosome consisting of DNA and proteins)  may be either evenly dispersed or clumped, and/or prominent nucleoli (a component of the nucleus of the cell where ribosomes are made – components of protein production) may be present. Gland crowding lined by atypical cells is the hallmark of endometrial intraepithelial neoplasia. Rarely, extreme complexity without  marked cytologic atypia warrants a diagnosis of atypical hyperplasia. 

Benign Endometrial Hyperplasia (EH, non-neoplastic)

Most simple and nonatypical complex hyperplasias fall into the benign endometrial hyperplasia category.

Changes typically observed with anovulation or other etiology of prolonged exposure to estrogen.

The morphology of endometrial hyperplasia varies from proliferative endometrium with a few cysts (persistent proliferative endometrium) to bulkier endometria with many dilated and contorted glands that in other systems have been designated as "cystic glandular hyperplasia," "mild hyperplasia," or "simple hyperplasia."

Endometrial Intraepithelial Neoplasia (EIN)

Some complex hyperplasia without atypia and essentially all complex hyperplasia with atypia fall into the EIN category.

These are considered endometrial precancers.

The risk of progression to cancer of EIN has been shown to be about 20%, compared to benign hyperplasia where the risk of progression is 2.3%.

It is sometimes difficult to distinguish a precursor lesion (EIN) from endometrial carcinoma. Atypical hyperplasia or EIN is distinguished from grade 1 endometrial carcinoma by histologic findings that suggest invasion. Variability is often noted across pathologists in distinguishing atypical hyperplasia/endometrial intraepithelial neoplasia from carcinoma. Additional pathologic evaluation such as Immunohistochemical markers may be used to distinguish atypical hyperplasia from endometrial carcinoma.

Endometrial Cancer

Women with neoplastic endometrial hyperplasia may have coexistent endometrial carcinoma or may progress to carcinoma. Using the WHO classification, the presence of nuclear atypia in endometrial hyperplasia is the most important indicator for the risk of coexisting carcinoma or progression. Women at the highest risk include those with: atypical endometrial hyperplasia or endometrial intraepithelial neoplasia (EIN) and those with complex hyperplasia who have significant risk factors for endometrial carcinoma. Up to 37 percent of women with a diagnosis of atypical endometrial hyperplasia on endometrial sampling have been found to have endometrial carcinoma on subsequent biopsy or hysterectomy.

Women with a finding of atypical endometrial hyperplasia on endometrial biopsy require further evaluation and intervention.  Older age, obesity, diabetes mellitus, and complex atypical endometrial hyperplasia are the strongest predictors of concurrent endometrial carcinoma among women with endometrial hyperplasia.

AGE AT DIAGNOSIS

The diagnosis of endometrial hyperplasia was made most commonly in woman ages 50 to 54 years and rarely was found in women younger than age 30. The incidences of simple and complex hyperplasia without atypia were highest in women age 50 to 54 years, whereas the rate of atypical hyperplasia was highest in women age 60 to 64.

RISK FACTORS

The risk factors for endometrial hyperplasia are similar to those for endometrial carcinoma. Most of these risk factors involve exposure of the endometrium to continuous estrogen unopposed by a progestin. This effect may be due to endogenous or exogenous hormone.

Physiologically, estrogen stimulates endometrial proliferation during the normal menstrual cycle; this effect is buffered by progesterone, which inhibits endometrial proliferation and stimulates differentiation in preparation for implantation of an embryo.

In addition, women with Lynch syndrome (hereditary nonpolyposis colorectal cancer) are at a greatly increased risk of endometrial hyperplasia.

Chronically increased estrogen levels or estrogenic activity

  • Exogenous Sources

    • Unopposed Estrogen Therapy For a woman with a uterus, systemic estrogen therapy from any route (oral, transdermal patch, vaginal ring) without concurrent administration of a progestin results in a markedly increased risk of developing endometrial cancer precursors. Low-dose vaginal estrogen therapy is a common treatment for symptoms related to vulvovaginal atrophy. The systemic absorption of these preparations is small; thus, most do not have adverse effects on the endometrium, but some may require use of an opposing progestin because of high systemic estrogen levels.

    • Hormone Replacement Therapy The body of evidence suggests that menopausal hormone therapy with combined estrogen-progestin preparations does not increase the risk of endometrial hyperplasia, with one notable exception. An analysis of unpublished data from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial showed a statistically significant increase in endometrial hyperplasia after two years of cyclic combined therapy (3.3 versus 0 percent in the placebo group) The regimen used in this trial was conjugated equine estrogen 0.625 mg daily plus medroxyprogesterone acetate 10 mg for 12 days/month

    • Tamoxifen The use of tamoxifen increases the risk of proliferative lesions in the uterus an effect that is dose- and duration-dependent.

    • Phytoestrogens Phytoestrogens are nonsteroidal compounds that occur naturally in many plants, fruits, and vegetables and have both estrogenic and antiestrogenic properties. The effect of phytoestrogens on proliferative lesions of the uterus is unclear The body of data from observational studies suggests no increased risk of endometrial hyperplasia or endometrial carcinoma with phytoestrogen supplements or dietary intake and actually a decreased risk. In a meta-analysis of seven case-control and cohort studies including over 3500 women with endometrial carcinoma, high compared with low soy intake was associated with a 30 percent decrease in endometrial carcinoma risk. Most randomized trials that have addressed this issue have had only 6 to 12 months of follow-up. In the only trial with longer follow-up, postmenopausal women assigned to soy isoflavone supplements (150 mg/day) for five years had a higher rate of endometrial hyperplasia (detected by endometrial biopsy) compared with the placebo group (3.8 versus 0 percent). However, the quality of this trial was limited since the total number of events was small.

  •  Endogenous Sources

    • Chronic Anovulation leads to production of estrogen without progesterone. As a result, normal endometrial turnover does not occur, and chronic estrogen production unopposed by adequate progesterone production allows continued proliferation of the endometrium, which can lead to endometrial hyperplasia and endometrial carcinoma.The menopausal transition and polycystic ovary syndrome (PCOS) are two common clinical settings associated with anovulation with endogenous production of unopposed estrogen. In both of these settings, the risk for development of endometrial hyperplasia and endometrial cancer is increased.

    • Obesity Obese women have high levels of endogenous estrogen due to the conversion of androstenedione to estrone and the aromatization of androgens to estradiol, both of which occur in peripheral adipose tissue. Obese women may also have lower circulating levels of sex hormone-binding globulin (leading to increased steroid hormone activity), alterations in the concentration of insulin-like growth factor and its binding proteins, and insulin resistance, all of which may contribute to the increased risk of EC in these women. Premenopausal obese women with PCOS are often anovulatory, which results in unopposed estrogen production.

    • Estrogen-secreting Tumors may also lead to endometrial hyperplasia. Granulosa cell tumors of the ovary are the tumor type most likely to be associated with endometrial hyperplasia and endometrial carcinoma. In women with these tumors, endometrial hyperplasia is detected in 25 to 50 percent and endometrial carcinoma in 5 to 10 percent.

Hereditary Factors Lynch syndrome (hereditary nonpolyposis colorectal cancer) is an autosomal dominant disorder caused by a germline mutation in one of several DNA mismatch repair genes. Women with Lynch syndrome have up to a 60 percent lifetime risk of developing endometrial carcinoma compared with 2.7 percent in the general population. Women with these mutations have also a higher risk of developing endometrial hyperplasia.

Personal Medical History Women with diabetes mellitus and hypertension are at increased risk for developing proliferative endometrial lesions.

PROTECTIVE FACTORS

Use of Hormonal Contraception The use of estrogen-progestin oral contraceptives (OCs) decreased the risk of EC by 30 to 40 percent in large epidemiologic studies, and the risk reduction persisted for years after discontinuation.

Summary

The endometrium (lining of the uterus) may develop endometrial hyperplasia, which includes precancerous (intraepithelial) neoplasms (atypical complex hyperplasia) and non-neoplastic entities (simple and many complex hyperplasias without atypia); these are characterized by a proliferation of endometrial glands of irregular size and shape. Neoplastic endometrial hyperplasia is characterized by a proliferation of endometrial glands that may progress to or coexist with endometrial carcinoma.

The presence of nuclear atypia is the most important indicator of the risk of endometrial carcinoma in women with endometrial hyperplasia. It is sometimes difficult to distinguish a precursor lesion from endometrial carcinoma. Approximately 17 to 48 percent of women with atypical hyperplasia are found to have coexistent endometrial carcinoma when a hysterectomy is performed.

Endometrial hyperplasia/intraepithelial endometrioid neoplasm commonly results from excess estrogen and progesterone imbalance. This may be caused by obesity, anovulation, estrogen therapy without a progestin, or rarely estrogen-producing ovarian tumors . Women with hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome are at high risk for endometrial neoplasia.

Endometrial hyperplasia/intraepithelial neoplasm typically presents with abnormal uterine bleeding and is most common in women who are postmenopausal, and with increasing age in premenopausal women. Rarely, women with no abnormal uterine bleeding present only with abnormal findings on cervical cytology.

Endometrial hyperplasia/intraepithelial neoplasm is a histologic diagnosis made with sampling of the endometrium. Either an office endometrial biopsy or dilation and curettage may be performed.

Neither endometrial biopsy nor dilation and curettage detect all cases of endometrial carcinoma; up to 10 percent are falsely negative.

CLINCAL PRESENTATION

Endometrial hyperplasia typically presents with abnormal uterine bleeding and is most common in women who are perimenopausal or early postmenopausal, and with increasing age in premenopausal women. Among premenopausal women, obesity, polycystic ovarian syndrome, and chronic anovulation are commonly associated factors. Occasionally, in women with no abnormal uterine bleeding, endometrial hyperplasia is detected via abnormal glandular or endometrial cells on cervical cytology.

EVALUATION

Women with a clinical presentation suspicious for endometrial hyperplasia are evaluated initially with physical examination. Pelvic sonography may also be performed to evaluate for other etiologies of abnormal uterine bleeding or to assess endometrial thickness in postmenopausal women; however, ultrasound criteria have been set for detection of endometrial carcinoma, but not endometrial hyperplasia. Endometrial thickness is not a reliable test for endometrial neoplasia in premenopausal women. Endometrial sampling is the gold standard for diagnosis of endometrial hyperplasia

Endometrial hyperplasia is a histologic diagnosis made based upon the results of evaluation of an endometrial biopsy, endometrial curettage sample, or hysterectomy specimen.

Differential Diagnosis

Differential diagnosis of endometrial hyperplasia includes other conditions that casue abnormal uterine bleeding. Women with presumed uterine bleeding should be evaluated to confirm that the source of the blood is the uterus, and not another part of the genital tract or the anus or rectum.

Negative endometrial sampling

Insufficient cells on endometrial biopsy Women with an endometrial biopsy result that has insufficient endometrial cells and for whom there is a clinical concern for neoplasm should have sampling repeated with an office biopsy or dilation and curettage (D&C). If two office endometrial biopsies have been unsuccessful, a D&C should be performed.

Persistent or recurrent bleeding. If bleeding persists or recurs within three to six months after endometrial sampling with benign findings, further evaluation is required.

Abnormal uterine bleeding symptoms may be due to a missed diagnosis of endometrial neoplasia or to other etiologies. 

It is essential to repeat endometrial sampling to exclude endometrial neoplasm.

Transvaginal ultrasound, sonohysterography, or diagnostic hysteroscopy should be performed to exclude structural lesions (leiomyomas, endometrial polyps).

Positive endometrial sampling. Women with a diagnosis of endometrial hyperplasia on office endometrial biopsy or D&C may require further evaluation.

Follow-up of biopsy or curettage results

A diagnosis of atypical endometrial hyperplasia/intraepithelial neoplasm raises concern for a coexistent endometrial carcinoma. As noted above, coexistent endometrial carcinoma may be present in approximately 37 percent of women with a preoperative diagnosis of complex atypical hyperplasia at time of hysterectomy.

Some data suggest D&C is more effective than office endometrial biopsy at detecting coexistent carcinoma; however, neither is sufficient to exclude malignant neoplasm. Women who have had an endometrial biopsy positive for complex atypical hyperplasia may have an up to 47% chance of having endometrial cancer found at the time of hysterectomy. For women who have had complex endometrial hyperplasia diagnosed by dilatation and curettage, there is a 33% chance of finding endometrial cancer at the time hysterectomy. Among women who had an endometrial biopsy and then a dilatation and curettage which demonstrated complex endometrial hyperplasia, the risk of finding endometrial cancer at the time of hysterectomy is 16%.

It is generally recommended that for women with a diagnosis on office endometrial biopsy of atypical endometrial hyperplasia who desire medical management; a D&C hysteroscopy is also performed to exclude endometrial carcinoma.

If the results are less severe or negative, and no intervening treatment has occurred, a woman should be managed based upon the results of the initial endometrial hyperplasia classification. 

For women with endometrial hyperplasia planned for hysterectomy and who have not had a D&C, a pathologist should be available to evaluate if the intraoperative findings suggest endometrial carcinoma, and the ability to perform surgical staging should be considered.

Postmenopausal women with no known estrogen source 

Development of endometrial hyperplasia with or without atypia in a woman who should be estrogen-deficient requires an explanation. In the absence of other sources of estrogen (eg, estrogen therapy, obesity), such women require evaluation for an estrogen-producing tumor.

TREATMENT

The management of EH is determined by clinical factors and by classification, which is based upon histologic features and risk of progression to endometrial carcinoma.

Clinical factors to consider in choosing a management approach include the following:

  • Risk factors for recurrence or progression (eg, obesity, ovulatory dysfunction, increased genetic risk, increased age). Although risk increases with age, EH and endometrial cancer can be observed in women ages <25, most commonly in those with polycystic ovary syndrome and body mass index >30 kg/m2  Risk factors for progression are the same for all histologic types of EH

  • Desire for fertility 

  • Contraceptive needs

  • Postmenopausal women with endometrial thickness on transvaginal ultrasound ≥20 mm have a greater risk for concomitant endometrial cancer

Management Options

The three most common options for the management of EH are surveillance, progestin therapy, and hysterectomy.

All management strategies should also be accompanied by removal of the extrinsic or intrinsic source of unopposed estrogen since excess exposure to estrogen is a main etiology of endometrial neoplasia. This may include identifying and stopping use of nonprescription medications or topical products that contain estrogen, stopping unopposed estrogen therapy or adding a progestin, correcting ovulatory dysfunction (eg, due to polycystic ovary syndrome [PCOS] or hyperprolactinemia), losing weight, or, rarely, removing an estrogen-producing neoplasm. Weight loss, including from bariatric surgery, in obese women has multiple health benefits in addition to reducing high levels of endogenous estrogens due to estradiol and estrone production by adipocytes. For women with ovulatory dysfunction, the etiology should be treated (eg, prolactinoma), or if the ovulatory dysfunction is likely to be chronic (eg, PCOS), women may need maintenance progestin therapy after endometrial hyperplasia regression.

  • Surveillance

    • Surveillance alone may be utilized if the risk of an occult cancer or progression to cancer is low and the inciting factor that resulted in endometrial proliferation has been eliminated.

  • Progestin therapy

    • There are no US Food and Drug Administration (FDA)-approved therapies for the treatment of EH, although various progestins are approved for EH prevention, and megestrol acetate and depot medroxyprogesterone acetate are approved for treatment of endometrial carcinoma. Progestins are the most commonly used therapy, since they oppose the effect of estrogen on the endometrium. When appropriate and successful, progestin therapy allows for future attempts at pregnancy.

  • Hysterectomy

    • Total hysterectomy is definitive treatment but is a major surgical procedure and precludes future fertility. Hysterectomy is usually reserved for postmenopausal women, women who do not desire future fertility, or those with pathology suggesting high risk of concomitant endometrial carcinoma. Risk factors for concomitant endometrial cancer are increased age and transvaginal ultrasound showing endometrial thickness ≥20 mm.

  • Other treatments 

    • Nonprogestin medications

      • GNRH Agonsists. Gonadotropin-releasing hormone (GnRH) agonists were used in combination with levonorgestrel (LNg)-releasing intrauterine device with a release rate of 19.5 mcg/day for five years (Mirena; LNg52/5) to successfully treat 24 premenopausal women with either atypical EH or early-stage endometrial carcinoma.

      • Aromatase Inhibitors. Aromatase inhibitors have been administered to block endogenous estrogen production in patients with EH. Anastrozole was used successfully to treat 11 obese postmenopausal women with atypical (n = 2) and nonatypical EH (n = 9). A small prospective study of 45 patients showed no simple EH following treatment.

      • Ovulation Induction. Ovulation induction (eg, with clomiphene or aromatase inhibitors) in reproductive-age women will result in formation of a corpus luteum, exposure to endogenous progesterone, and resolution of EH in some women. Pregnancy is highly unlikely in the setting of ongoing EH. Careful surveillance is needed to assure EH regression. This approach is favored for women with EH without atypia who desire pregnancy.

      • Metformin Metformin has been shown to both have antiproliferative effects and to reduce insulin resistance, which may play a role in the development of endometrial carcinoma in overweight and obese women. A meta-analysis on the effects of metformin on endometrial cancer observed a reversion to normal histology in the majority of patients with atypical EH who received a course of metformin in association with progestin.

      • Danazol has been used to successfully treat EH, but is seldom used due to significant side effects when taken orally. In a series of postmenopausal women, danazol (400 mg per day for six months) caused complete regression in 83 percent of patients, with 8 percent with a relapse within four months of discontinuing therapy.

    •  Alternative surgical treatments

      •  Hysteroscopic resection of EH was reported to be effective in 68 of 73 treated women, but the long-term consequence of this treatment remains to be determined. A review of 36 patients treated with hysteroscopic tumor resection combined with hormone therapy reported an 88.9 percent response rate, with an 11.1 percent recurrence rate.

      •  Bariatric surgery may show promise. There was a significant decreased rate of all cancers following bariatric surgery compared with obese controls (3.5 versus 5.8 percent) in a large retrospective study.

PROGESTINS FOR TREATMENT

Progestins reverse EH by activation of progesterone receptors, which results in stromal decidualization and subsequent thinning of the endometrium. Progestin exposure also decreases estrogen and progesterone receptors and activates hydroxylase enzymes to convert estradiol to its less active metabolite estrone.

  • Contraindications to progestins

    • Current or past history of thromboembolic disorders, or stroke

    • Severe liver dysfunction

    • Known or suspected malignancy of progesterone receptor-positive breast cancer

    • Vaginal bleeding of unknown origins

    • Pregnancy

    • Known allergic reaction to progestins

    • Intrauterine Device Levonorgestrel (LNg) intrauterine devices (IUD) administer progestins locally to the uterus and result in minimal systemic absorption. Thus, these devices may be used in women with relative contraindications to progestins. Consultation with a specialist is needed for women with major contraindications.

Progestin types

Historically, the most common treatments have been oral medroxyprogesterone acetate or megestrol acetate.  The LNg-releasing IUD, 52 mg with a release rate of 20 mcg/day over five years (Mirena; LNg52/5), is now a first-line therapy.

  • The LNg52/5 releasing IUD has been found in randomized trials to be more effective than oral progestins. In addition to higher efficacy, the other advantages of the LNg52/5 are that it offers long-acting contraception and does not require daily dosing. It is typically better tolerated than oral progestins. The LNg52/5 starts with an initial dose of 20 mcg/day; by five years the daily dose is approximately 10 mcg/day. As with other progestin-only medications, the LNg52/5 initially results in irregular bleeding, but eventually most women using the LNg52/5 become amenorrheic or have light tolerable bleeding. LNg-releasing IUDs are also available in lower daily doses (13.5, 17.5, and 18.6 mcg/day) and vary from three- to five-year formulations, but these have not been studied in women with endometrial hyperplasaia to determine whether the lower progestin dose is as effective as the LNg52/5. These lower dosage IUDs are generally not used for the treatment of endometrial hyperplasia.

  • Oral progestin preparations can effectively treat the majority of cases of EH without atypia and some milder forms of atypical endometrial hyperplasia.

    • Oral progestins may be preferred by women with the following characteristics:

      • Women who decline or cannot tolerate an IUD due to side effects.

      • Women with uterine factors that make placement or retention of an IUD difficult (eg, severe distortion of the uterine cavity due to fibroids, a congenital anomaly, or recurrent expulsion of the IUD).

      • Women who plan to try to conceive a pregnancy as soon as a therapeutic response is achieved,

    • Oral progestins may be given as progestins alone or as estrogen-progestin oral contraceptives (OCs).

    • In oral progestin regimens, women are usually treated for three to six months with continuous dosing. Studies comparing higher-dose progestins with the doses listed below have found no significant difference.

    • For women with EH who are treated with noncontraceptive oral progestins, medications, doses, and regimens that have been reported are:

    • Megestrol acetate 40 to 160 mg daily. Although there is practice variation based on shared decision-making with patients, megestrol is often our first choice of an oral progestin to treat atypical EH because it is a strong progestin.

    • Medroxyprogesterone acetate (MPA) 10 to 20 mg daily. MPA was one of the first-line therapies for nonatypical EH before the LNg52/5 was studied for this indication.

    • Norethindrone acetate (NETA) 15 mg daily has not been well studied.

    • Micronized progesterone 200 to 300 mg daily was beneficial in a single study of women with EH without atypia. However, this is a relatively weak progestin, and is not generally considered for first-line progestin treatment for EH. It may be reserved for it only for women who are at low risk for progression and who cannot tolerate stronger synthetic progestins or refuse the LNg52/5.

    • There are no studies on the use of vaginal micronized progesterone for the treatment of EH.

    • Continuous dosing (daily dosing) progestins or progestin IUDs are superior to cyclic progestin regimens (dosing varies, medication is typically taken for at least 12 to 14 days and then the patient receives no medication for the remainder of the month. A small prospective study of 170 women, the LNg52/5 was the most effective therapy; cyclic therapy was found to be inferior to both LNg52/5 and continuous oral progestins. Continuous dosing schedules are not only more effective, but they may be better tolerated than a cyclic regimen if amenorrhea can be achieved. Irregular vaginal bleeding can be bothersome at the inception of continuous regimens and may ultimately lead to changing to LNg52/5 if bleeding cannot be controlled.

  • Progestin injections and implants have not been well studied for the treatment of EH. Depot medroxyprogesterone acetate (DMPA) may be utilized by some physicians. DMPA is a long-acting progestin, provides contraception, and requires only four injections per year. DMPA may be utilized as second-line therapy for women who are intolerant of oral progestins or the LNg52/5.

  • Side effects of progestins

    • Nausea

    • Breast discomfort

    • Mood disturbance

    • Abnormal vaginal bleeding

    • Loss of menses

    • Weight gain

    • Bloating

    • Headache

    • Liver abnormalities

    • Clotting abnormalities

    • Elevated cholesterol

  •  Combined estrogen/progestin contraceptives (pills, patches, rings) have not been studied for treatment of EH. In theory, the amount of progestin in an oral contraceptive, either a combined or progestin-only pill, is sufficient to reverse simple EH and the majority of cases of complex EH.

Follow-up

Every woman with EH requires careful follow-up and appropriate surveillance for persistent or recurrent EH or progression to carcinoma, regardless of type.

Maintenance Therapy

Once complete regression of EH is achieved, progestin maintenance therapy is often appropriate. Maintenance therapy consists of continued progestin therapy. There are no high-quality data supporting the use of one maintenance regimen over another. Choice of regimen therefore depends upon patient preference, cost, adherence, convenience, and side effects.

Many physicians prefer the use of the LNg52/5 for maintenance therapy.

During the follow-up or maintenance therapy phase, sources of excess estrogen exposure should be corrected, if this has not already been done.

Factors to consider in choosing maintenance therapy include:

  • Premenopausal women

    • For women with chronic ovulatory dysfunction that cannot be corrected (eg, polycystic ovary syndrome), an estrogen-progestin contraceptive is a good option in women who do not desire pregnancy. Progestin therapy may be continued as long as chronic anovulation is present and there are risk factors for the development of EH.

    • For those who cannot or prefer not to take a progestin-containing contraceptive, alternative options for endometrial protection include cyclic or continuous progestins not approved for contraception.

  • Postmenopausal women

    • The decision to continue progestins should be based on risk factors for endometrial cancer and patient tolerance of the progestin regimen.

    • In the absence of hot flashes, treatment with progestin only is acceptable.

    • For women with bothersome hot flashes that do not respond to a progestin and who are candidates for postmenopausal estrogen therapy: (1) for EH at high risk of progression, the use the LNg52/5 combined with low-dose postmenopausal estrogen may be utilized for low-risk EH  a continuous estrogen/progestin may be considered.

General Principles for Follow-up

  • Endometrial biopsy may be performed with an intrauterine device in place.

  • Some experts advise waiting for a withdrawal bleed before sampling, while others sample the endometrium while the patient is on progestin therapy. The decidual reaction that occurs with progestin therapy may make it more difficult to interpret pathologic findings.

SUMMARY FOR TREATMENT STRATEGIES

Proliferative endometrium

Proliferative endometrium suggests active estradiol secretion, akin to that seen in the proliferative phase of the menstrual cycle, and is not a form of EH. However, proliferative patterns observed in anovulatory premenopausal women or in postmenopausal women, if not corrected, signify an excess of estrogen that may place women at higher risk of developing EH.

Treatment of proliferative endometrium should be solely based on the nature of the patient’s symptoms that prompted the biopsy and the effect of such symptoms on quality of life. The levonorgestrel (LNg)-releasing intrauterine device (IUD) for premenopausal patients. For postmenopausal patients, consideration can be given to either the LNg-releasing IUD or oral progestins. Patients with medical comorbidities leading to the presence of excess estradiol (eg, obesity) should be counseled on long-term health effects.

Nonatypical hyperplasia/benign endometrial hyperplasia

This is a non-neoplastic and may exhibit increasing degrees of endometrial gland crowding. Management is guided by the severity of histologic features, menopausal status, and fertility and contraception plans.

Simple hyperplasia without atypia/benign endometrial hyperplasia/disordered proliferative endometrium 

  • Progestin-only therapy

  • Oral contraceptives,

  • Expectant management

  • Hormonal therapies result in resolution of EH and a return to a normal uterine bleeding pattern in most women. Expectant management is also reasonable for some women, but may not lead to resolution of EH in patients with continued exposure to excess estrogen or with other risk factors for endometrial cancer. These patients require treatment with first-line therapy, the levonorgestrel (LNg)-releasing intrauterine device (IUD), 52 mg with a release rate of 20 mcg/day over five years (Mirena; LNg52/5).

  • Risk of progression to cancer 

    • The risk of progression of simple EH without atypia to endometrial carcinoma has not been well studied. Available studies include:

    • An often-cited case series included 93 women with simple hyperplasia. Only one woman developed carcinoma at 11 years after diagnosis. Another study from a large, managed care organization showed a cumulative risk of progression to endometrial carcinoma at 19 years of 5 percent for women with EH without atypia.

  • Progestin therapy 

    • Treatment of simple EH without atypia varies by menopausal status:

      • Premenopausal women

      • Premenopausal women who have simple EH without atypia with three to six months of progestins. Expectant management is also an option.

      • Premenopausal women Progestin therapy options include oral progestins, the LNg-releasing IUD (52 mg with a release rate of 20 mcg/day over five years [Mirena; LNg52/5]), and combined estrogen and progestin oral contraceptives (OCs).

      • There are no high-quality data regarding OCs for treatment of EH, but progestin doses provided by OCs in theory are sufficient to treat simple or benign hyperplasia.

      • Postmenopausal women 

      • Postmenopausal women with simple EH without atypia with progestins alone. Progestin therapy may be oral or intrauterine.

      • Hysterectomy may be considered in postmenopausal women with simple EH without atypia who have risk factors for endometrial cancer or who have a contraindication to progestin therapy.

  • Expectant management 

    • Expectant management is an option for simple EH without atypia, especially for women with normal menses and without risk factors for endometrial carcinoma. With ovulation and formation of a corpus luteum, the endometrium is exposed to high endogenous progesterone levels. This is often sufficient to cause regression of and maintenance of regression in women with EH without atypia, particularly simple EH.

    • In addition, expectant management is an option for women who have contraindications to or cannot tolerate progestins.

  • Follow-up

    • For women with simple EH without atypia follow-up for progestin therapy or expectant management includes:

      • Premenopausal women with simple EH without atypia, if the menstrual pattern normalizes repeat endometrial biopsy is not required. However, if the bleeding pattern does not normalize, a repeat endometrial biopsy is performed at six months.

      • Postmenopausal women with simple EH without atypia who are treated with progestins, an endometrial biopsy is repeated every three to six months for a period of time based on risk factors and clinical findings.

  • Maintenance therapy 

    • Premenopausal women who have simple EH without atypia who do not have resumption of normal menses should be treated with some form of progestin (including estrogen/progestin contraceptives) indefinitely. Some women will experience bothersome progestin side effects and may require an adjustment in dose or a switch to a different progestin formulation.

    • Postmenopausal women with regression to a normal endometrium, prescribing maintenance progestin therapy depends upon whether postmenopausal bleeding continues. If no further bleeding; expectant management is reasonable. Endometrial biopsy is advised if abnormal uterine bleeding recurs. If postmenopausal bleeding continues and endometrial biopsy is normal; maintenance progestin therapy and hysteroscopy may be recommended to evaluate for focal lesion and resample endometrium in three to six months. Maintenance therapy may be continued if a woman has risk factors for endometrial carcinoma.

    • Women with persistent abnormal uterine bleeding, even with complete regression of EH, may desire hysterectomy. In such cases the indication for hysterectomy is symptoms, not EH.

  • Outcome 

    • The LNg52/5 was more effective than oral progestins for the treatment of nonatypical EH in a meta-analysis of seven randomized trials, some of which included simple or benign hyperplasia. A systematic review of 24 observational studies including 1001 women found that treatment with LNg52/5 compared with oral progestins had a higher regression rate for complex EH (92 versus 66 percent).

    • In a small review of 35 patients with simple hyperplasia managed expectantly, 75 percent of cases spontaneously regressed, 17 percent persisted, and 8.6 percent progressed to complex and/or atypical hyperplasia. Expectant management may not lead to resolution in patients with risk factors for endometrial cancer.

Complex hyperplasia without atypia/benign endometrial hyperplasia/gland crowding

Complex EH without atypia may be managed with progestins or expectant management. For women with complex hyperplasia without atypia that progresses to EH with atypia on progestin therapy, hysterectomy is the preferred treatment. Also, hysterectomy is reasonable in postmenopausal women who decline or have contraindications to progestins.

  • Risk of progression to cancer 

    • Among women with complex EH without atypia, the cumulative risk of progression to endometrial carcinoma is low (<5 percent).

  • Progestin therapy  Progestin therapy is the standard treatment for women with complex EH without atypia. The LNg52/5 is the most effective progestin treatment, is easy to comply with, and provides contraception. For women with complex EH without atypia, the LNg52/5  is recommended rather than oral progestins. However, if women cannot tolerate the LNg52/5, megestrol acetate  for three to six months is recommened. For patients who decline or cannot take progestins, hysterectomy is an option.

  • Expectant management Expectant management is an option for selected women with complex EH without atypia. Reasons to use expectant management include patients with a contraindication to progestins or a patient who cannot tolerate therapy.

  • Follow-up For women with complex EH without atypia, follow-up for either expectant management or progestin therapy includes:

    • Repeat endometrial biopsy is performed every three to six months for one to two years. A literature review showed that the median time to complete response of EH to progestin was six months.

  • Maintenance therapy — For women with complex EH without atypia, after regression to normal endometrium, maintenance progestin therapy may be required indefinitely if patients have risk factors for endometrial carcinoma (eg, obesity, diabetes, polycystic ovary syndrome) or persistent postmenopausal bleeding.

  • Evaluation for bothersome progestin side effects may require an adjustment in dose or a switch to a different progestin formulation.

  • Some women may have persistent or recurrent abnormal uterine bleeding, despite no disease progression on serial endometrial sampling. In such cases, women may choose hysterectomy to address these bothersome symptoms, but the indication is symptoms, not EH.

  • Outcome. Women with complex EH without atypia treated with the LNg52/5 have rates of regression to normal endometrium of approximately 90 percent [37,60]. Randomized trial data demonstrate the LNg52/5 is more effective than oral progestins, as discussed above. Oral progestins can also be effective, as illustrated in a study that showed that endometrial carcinoma risk over 20 years of follow-up was diminished two- to threefold in women diagnosed with complex EH and dispensed oral progestin as compared with women who did not receive oral progestin; hysterectomy risk was also decreased.

  • Risk of relapse A cohort study with long-term follow-up showed a relapse rate of 12.7 percent for complex hyperplasia without atypia.

Atypical Hyperplasia with Atypia

This is also referred to as endometrial intraepithelial neoplasia [EIN]) has a high risk of progression to endometrial carcinoma and a potential for concurrent invasive disease. Hysterectomy is the treatment of choice for most women with atypical EH. Progestin therapy is a reasonable option for women who wish to preserve fertility or who cannot tolerate surgery.

Historically, the recommendation of hysterectomy for atypical EH was even stronger, and few exceptions were made. This was based upon the high risk of concurrent endometrial carcinoma or progression to endometrial carcinoma and the limited data regarding efficacy of pharmacologic therapy. Since that time, progestin therapy with the levonorgestrel  (LNg)-releasing intrauterine device (IUD), 52 mg with a release rate of 20 mcg/day over five years (Mirena; LNg52/5), has been introduced and studies of this progestin option show regression of atypical EH and grade 1 endometrial carcinoma in up to 75 to 85 percent of women. However, hysterectomy is curative and thus, is still the many time recommended treatment. The high efficacy of the LNg52/5 allows it to be a treatment option for reproductive-age women who desire future fertility or for women who have a high risk of surgical complications.

If the diagnosis of atypical EH is based on an office endometrial biopsy, many experts advise further evaluation with dilation and curettage prior to proceeding with management. This is to exclude coexistent endometrial carcinoma. Coexistent endometrial carcinoma may be present at hysterectomy in approximately 37 percent of women with a preoperative diagnosis of complex atypical EH.

  • Risk of progression to cancer — The risk of progression of atypical EH to endometrial carcinoma is 15 to 28 percent, based on studies with up to 20 years of follow-up; it is important to note that many of the women in these studies received oral progestin therapy Rate of progression is largely dependent on continued exposure to unopposed estrogen. This may be through medications or endogenous sources (eg, obesity, chronic anovulation).

  • Postmenopausal women and women who do not desire fertility. For most women with atypical EH/EIN who are postmenopausal or who are premenopausal and have completed childbearing, hysterectomy is recommended rather than progestin therapy. Women who are at a high risk of surgical complications due to medical comorbidities or surgical history should be evaluated and counseled regarding whether surgery or progestin therapy is the preferable option.

  • Hysterectomy. Total extrafascial hysterectomy is the procedure of choice. Supracervical hysterectomy is not an appropriate procedure. For women undergoing hysterectomy as treatment for atypical EH, it may be suggested that hysterectomy without bilateral oophorectomy rather than with bilateral oophorectomy. The choice depends upon the risk of premature menopause and potential risks of oophorectomy, even in postmenopausal women, versus the risk of a second surgery if endometrial carcinoma is found postoperatively. Professional societies have not issued guidelines regarding oophorectomy in women with atypical EH. For women who do undergo oophorectomy, menopausal symptoms may be treated with postmenopausal hormone therapy, if there are no contraindications. This is based on the safety of postmenopausal hormone therapy in women with early-stage endometrial carcinoma.

  • Women who wish to preserve fertility, decline hysterectomy, or are at high surgical risk. For women with atypical EH who are premenopausal and wish to preserve fertility or are of any menopausal status and decline hysterectomy and/or are at high risk of surgical complications, it is reasonable to treat with a progestin rather than hysterectomy]. These women must be able to comply with medical therapy and follow-up endometrial sampling.

    • Progestin therapy has been found to be an effective treatment for atypical EH in meta-analyses of observational data. The LNg52/5 appears to be the most effective progestin treatment, is easy to comply with, is well tolerated, and provides contraception. The LNg52/5 is associated with rates of regression to normal endometrium of approximately 90 percent.

    • For atypical EH in particular, there are few high-quality data that have evaluated treatment with the LNg52/5. A randomized trial including 19 women with EH with atypia found higher regression rates with the LNg52/5 compared with medroxyprogesterone acetate   (MPA; oral, 10 mg administered for 10 days per cycle or daily; LNg52/5: 6 of 6 patients versus MPA: 10 of 13 Megestrol acetate is the typically the oral progestin used for atypical EH because it is more potent than MPA. Megestrol acetate has been dosed at 80 to 160 mg twice per day; studies showing increased benefit with these higher doses are lacking.

  • Follow-up — Median time for regression of atypical EH to normal endometrium on progestin therapy appears to be six to nine months.. Follow-up during progestin therapy for atypical EH includes:

    • For premenopausal women:

      • Endometrial sampling is repeated every three to six months for up to one year.

      • If regression to normal endometrium occurs within 12 months, it is reasonable to repeat one to two biopsies after regression to confirm the absence of EH or concomitant carcinoma.

      • If normal menses resume, no further biopsies may be needed. However, patients who have subsequent abnormal bleeding need repeat sampling.

      • If the patient has nonatypical EH at 6 to 12 months, progestin therapy should be continued. Endometrial sampling is repeated at three to six months.

      • If persistent atypical EH/EIN is present at 6 to 12 months: The total progestin dose may be increased. An oral progestin may be given in combination with the LNg52/5 or the oral progestin dose may be increased.

      • Endometrial sampling is then repeated in three months from inception of the additional therapy. If endometrium is normal, the patient may try to conceive a pregnancy. If the sample shows nonatypical EH, therapy may be continued, and repeat sampling can be done every 3 to 6 months until there is no EH. However, if there is persistent atypical EH or cancer at any time, the patient should have a hysterectomy.

    • For postmenopausal women who are not surgical candidates:

      • Perform transvaginal ultrasound or endometrial sampling every six months for one to two years. If abnormal transvaginal ultrasound findings (endometrial thickness >4 mm) are found, hysteroscopy and dilation and curettage should be performed. If there is progression to endometrial cancer on biopsy the appropriate treatment is recommended. If regression cannot be achieved, subsequent evaluations should be tailored to the individual woman’s current and future risk for endometrial carcinoma, the presence or absence of abnormal uterine bleeding, and/or the severity of medical comorbidities precluding surgical management.

  • Maintenance therapy When endometrial sampling has demonstrated successful regression to a normal endometrium, the premenopausal patient may attempt to conceive a pregnancy in the near future, or if plans for pregnancy are not immediate, should be managed with progestin maintenance therapy. All postmenopausal women require maintenance therapy.

    • Premenopausal women

    • Women who choose to immediately try to become pregnant should stop progestin therapy. Progestin medications are contraindicated during pregnancy. If the patient does not become pregnant within a year, surveillance endometrial biopsies should be performed

    • Following pregnancy, maintenance progestin therapy and/or surveillance with endometrial biopsy is not required if the patient has regular cycles. The patient may use hormonal contraceptives, as she desires. If regular cycles do not resume, a repeat endometrial biopsy should be performed.

    • Hysterectomy is not recommended after birth in the absence of recurrent EH. In the case of recurrent EH with atypia in women who desire further fertility, retreatment with progestins has been utilized. However, a patient's risk factors for EH should be re-addressed, and hysterectomy should be considered after she has completed childbearing.

    • If the patient has no short-term plans to become pregnant, maintenance progestin therapy is advised to prevent recurrent EH. Maintenance therapy should be continued indefinitely or until it is clear that the inciting risk factors for EH are no longer present.

    • Postmenopausal women 

    • Maintenance progestin therapy is advised to prevent recurrence. Maintenance therapy should be continued indefinitely or until it is clear that the inciting risk factors for EH are no longer present.

    • Recurrence of atypical EH is usually symptomatic, with abnormal uterine bleeding. It can be evaluated with office endometrial biopsy. In the setting of recurrent EH with atypia, progestin therapy may be given again however, a stronger consideration of hysterectomy should be undertaken.

  • Fertility and pregnancy after treatment  Many women who choose progestin therapy are able to successfully conceive a pregnancy after regression of atypical EH (30%).