Endometrial hyperplasia medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Swathi Venkatesan, M.B.B.S.[2]

Overview

Progesterone is the preferred drug for the treatment of benign hyperplasia. The management of endometrial hyperplasia depends upon the desire for future childbearing.

Medical Therapy

• Patients with endometrial hyperplasia without atypia are treated conservatively through normalization of the menstrual cycles, whereas patients with atypical hyperplasia or endometrioid intraepithelial neoplasia are treated surgically.

Treatment of endometrial hyperplasia

Hyperplasia without atypia

Hyperplasia with atypia

Conservative

Desire for pregnancy?

Yes

No

Conservative

Total hysterectomy

Weight loss

Metformin

Oral contraceptive pills

Progestins (cyclic/continuous)

Options for the management of EH include surveillance, progestin therapy, or hysterectomy.

Other treatment approaches include pharmacologic treatments other than progestins or conservative surgical treatment. These modalities are not used commonly and have not been well studied. (See 'Other treatments' below.)

All management strategies should also be accompanied by removal of the extrinsic or intrinsic source of unopposed estrogen, since excess exposure to estrogen is the main etiology of endometrial neoplasia.

This may be identifying and stopping use of nonprescription medications or topical products that contain estrogen, stopping unopposed estrogen therapy, correcting ovulatory dysfunction (eg, due to polycystic ovarian syndrome or hyperprolactinemia) (table 1), losing weight, or, rarely, removing an estrogen-producing neoplasm. (See "Approach to abnormal uterine bleeding in nonpregnant reproductive-age women", section on 'Irregular bleeding (ovulatory dysfunction)'.)

Weight loss in obese women has multiple health benefits in addition to reducing high levels of endogenous estrogens due to estradiol and estrone production by adipocytes. Bariatric surgery may be of benefit in reducing this risk [4]. (See "Overweight and obesity in adults: Health consequences".)

For women with ovulatory dysfunction, the etiology should be treated (eg, prolactinoma), or if the ovulatory dysfunction is likely to be chronic (eg, polycystic ovarian syndrome), women may need maintenance progestin therapy after EH 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 (eg, patient with anovulation, now corrected, who had developed simple hyperplasia without atypia).

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.

Other treatments — Treatment with nonprogestin medications or conservative surgery is not standard clinical practice, but has been described [5,6].

●Nonprogestin medications

•Gonadotropin-releasing hormone (GnRH) agonists were used in combination with a levonorgestrel-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 [7].

•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) [8]. A small prospective study of 45 patients showed no simple EH following treatment [9].

•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 [10]. 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 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 females [11]. A small prospective study of 16 patients showed improved resolution of atypical EH when metformin was added to megestrol acetate. Patients with metabolic syndrome may find particular benefit [12]. (See "The metabolic syndrome (insulin resistance syndrome or syndrome X)".)

•Danazol has been used to successfully treat EH, but is seldom used due to significant side effects when taken orally [13-15]. 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 [13].

●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 [16].

•Bariatric surgery may show promise. There was a significant decreased rate of all cancers following bariatric surgery compared to obese controls (3.5 versus 5.8 percent) in a large retrospective study [4]. The most frequent cancer in the group who had bariatric surgery was breast (28.3 percent), followed by endometrial (17 percent). In the obese control group, the most common cancer was endometrial (62.3 percent). PROGESTIN THERAPY ADMINISTRATIONStudies have consistently shown that progestins are an effective treatment for EH [17-31].

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 [32].

Contraindications — Contraindications to progestin therapy include:

●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 etiology

●Pregnancy

●Known allergic reaction to progestins

Levonorgestrel intrauterine devices 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.

Medications, routes, and outcomes — There are many different progestin medications that have been used to treat EH with different routes of administration, doses, and regimens. Historically, the most common treatments were oral medroxyprogesterone acetate (MPA) or megestrol acetate, but the levonorgestrel-releasing intrauterine device, 52 mg with a release rate of 20 mcg/day over five years (Mirena; LNg52/5), is now first-line therapy.

General data regarding different progestin preparations are presented here. Information specific to each diagnostic category of EH is reviewed in the sections below.

The LNg52/5 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 [22-24]. It is typically better tolerated than oral progestins, although the meta-analysis of randomized trials cited above found no significant difference in rates of irregular vaginal bleeding with the LNg52/5 compared with oral progestins [33].

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.

Levonorgestrel-releasing intrauterine devices 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 EH to determine whether the lower progestin dose is as effective as the LNg52/5. We do not use them for this indication in our practice. (See "Intrauterine contraception: Candidates and device selection".)

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

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

●Women who decline or cannot tolerate an intrauterine device due to side effects (eg, dysmenorrhea).

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

●Women who plan to try to conceive a pregnancy as soon as a therapeutic response is achieved, since progestins are contraindicated in pregnancy and the patient can stop an oral medication without requiring a clinician to remove the device, as with an intrauterine device.

Oral progestins may be given as progestins alone (eg, megestrol acetate, MPA) 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 to the doses listed below have found no significant difference [29,34]. 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 [25,35]. This medication is considered a "chemotherapeutic agent," but it is best classified as a strong progestin [18]. 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.

●MPA 10 to 20 mg daily [36]. MPA was one of the first-line therapies for nonatypical EH before the LNg52/5 was studied for this indication.

●Norethisterone acetate (NETA; also known as norethindrone acetate) 15 mg daily has not been well studied [37]. Two studies with small numbers of women taking NETA suggest similar efficacy to MPA [29,37,38]. However, a randomized study of NETA (15 mg/day) compared with depot MPA (DMPA) showed that DMPA results in a higher rate of regression of nonatypical EH [39].

●Micronized progesterone 200 to 300 mg daily was beneficial in a single study of women with EH without atypia [40]. However this is a relatively weak progestin, and we do not consider it for first-line progestin treatment for EH. In our practice, we use it only for EH in 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. A small study of infertility patients found that vaginal micronized progesterone had similar effects on the endometrium as intramuscular progesterone, with no EH seen [41]. In theory, this progestin could be used as maintenance treatment, as its local effect achieves high endometrial concentrations.

In terms of dosing regimen for treating EH, continuous (daily dosing) progestins or progestin intrauterine devices 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) [42]. As an example of data supporting this, in 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 [36]. 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. We do not use implants in our practice. However, one of the authors uses DMPA.

DMPA is a long-acting progestin, provides contraception, and requires only four injections per year. Thus, one of the authors uses DMPA as second-line therapy for women who are intolerant of oral progestins or the LNg52/5.

One study found that the intramuscular DMPA (150 mg every three months) was more successful than NETA (15 mg daily for 14 days per cycle) in the treatment of nonatypical EH [39]. In this six-month randomized trial (n = 146) of women ages 35 to 50 years with simple or complex EH without atypia, rates of regression to normal endometrium among the subset of women with complex EH without atypia were higher with DMPA compared with NETA (91 versus 66 percent). Side effects were present with both medications, with more nausea and breast discomfort with NETA and more amenorrhea with DMPA.

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.

Some women experience bothersome progestin side effects (eg, irregular vaginal bleeding, bloating, irritability, depression, headaches) and may require an adjustment in dose or a switch to a different progestin formulation. Side effects are more likely on oral progestins than other formulations. For women on systemic progestins, we advise changing to the LNg52/5.

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. Appropriate follow-up for each EH type is discussed below. (See 'Management by type of hyperplasia' below.)

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.

In our practice, we prefer the use of the LNg52/5 for maintenance therapy. Given that women with EH often have abnormal uterine bleeding, the LNg52/5 is associated with a higher rate of amenorrhea and decreased rates of discontinuation compared with oral progestins [43].

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 ovarian 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. (See "Treatment of polycystic ovary syndrome in adults", section on 'Menstrual dysfunction'.)

•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.

●For 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, we treat with progestin only.

•For women with hot flashes, we offer a trial of progestin-only medication. Progestins may reduce hot flashes and have not been associated with increased breast cancer risk, although safety data are limited [44-47].

•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, we use the LNg52/5 combined with low-dose postmenopausal estrogen, and (2) for low-risk EH, we use a continuous estrogen/progestin regimen. Breast cancer risk with hormonal medication is discussed separately. (See "Menopausal hormone therapy: Benefits and risks", section on 'Breast cancer'.)

MANAGEMENT BY TYPE OF HYPERPLASIAThe management of EH is guided by the diagnostic category, which is organized by increasing risk of progression to endometrial carcinoma.

●Review of terminology – Terminology regarding EH has varied (table 2). In the 2015 World Health Organization (WHO) terminology system, the diagnostic categories are EH with atypia and EH without atypia. On the 1994 WHO system, EH without atypia and EH with atypia each have two subcategories: simple and complex; however, simplex EH with atypia is a rare entity. In the Endometrial Intraepithelial Neoplasia (EIN) classification system, the categories are benign EH (BEH) and EIN. EIN is nearly synonymous with EH with atypia; however, the definition of EIN includes the presence of glandular crowding, even without atypia. Thus, the WHO category of EH without atypia has some overlap with both BEH and EIN. (See "Classification and diagnosis of endometrial hyperplasia".)

The 2015 WHO system is preferred by most institutions, but not all pathologists have incorporated the 2015 WHO classification system into their assessment and reporting of endometrial specimens [2]. Given that this may result in heterogenous results depending on the system used, both the 2015 and 1994 WHO classification systems are used below to refer to diagnostic categories and management recommendations. Some institutions prefer to use the EIN terminology, and we have included this at the top of each section.

PROLIFERATIVE ENDOMETRIUMA 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.

As an example, on a series of 219 perimenopausal females with abnormal uterine bleeding, 30.5 percent had proliferative endometrium noted on endometrial sampling [48]. In a similar study of 119 perimenopausal and menopausal patients with abnormal uterine bleeding, proliferative endometrium was the most common pattern seen in perimenopausal women (35 percent) [49].

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. In our practice, we favor the levonorgestrel-releasing intrauterine device for premenopausal patients. For postmenopausal patients, consideration can be given to either the levonorgestrel-releasing intrauterine device 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 (AND SOME EIN)EH without atypia is 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 — Women with simple EH without atypia may be managed with progestin-only therapy, oral contraceptives, or 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 who require treatment with first-line therapy: the levonorgestrel-releasing intrauterine device, 52 mg with a release rate of 20 mcg/day over five years (Mirena; LNg52/5) (table 3).

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-quoted case series included 93 women with simple hyperplasia. Only one woman developed carcinoma at 11 years after diagnosis. Of note, she had an intervening term pregnancy and no progestin therapy. She developed EH with atypia subsequent to her pregnancy and ultimately had a hysterectomy that showed grade 1 endometrial carcinoma. She did not die of her disease [50].

●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 [51]. However, the study did not account for medical therapy.

Progestin therapy — Treatment of simple EH without atypia varies by menopausal status:

●Premenopausal women – In our practice, we treat premenopausal women who have simple EH without atypia or benign hyperplasia, and do not have risk factors for endometrial carcinoma (table 3) with three to six months of progestins.

Progestin therapy options include oral progestins, the levonorgestrel-releasing intrauterine device, 52 mg with a release rate of 20 mcg/day over five years (Mirena; LNg52/5), and combined estrogen and progestin oral contraceptives (OCs). In our practice, we treat with the LNg52/5 in women with any risk factors for endometrial cancer. Choice of therapy is also guided by whether the patient requires contraception, since some oral progestins do not provide contraception.

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 [52,53].

●Postmenopausal women – We treat postmenopausal women with simple EH without atypia with progestins alone rather than OCs, since they have no need for contraception and it is preferable to avoid unnecessary exposure to estrogen. Progestin therapy may be oral or intrauterine [54]. (See 'Medications, routes, and outcomes' above.)

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 (table 3) [29]. 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.

Follow-up — For women with simple EH without atypia, follow-up with progestin therapy or expectant management includes:

●For premenopausal women with simple EH without atypia, if the menstrual pattern normalizes (table 4), repeat endometrial biopsy is not required. With a normal menstrual pattern, it is highly likely that the desired outcome of a balanced endometrium has been achieved. However, if the bleeding pattern does not normalize, a repeat endometrial biopsy is performed every three to six months. Endometrial biopsy can be performed with an intrauterine device in place.

●For postmenopausal women with simple EH without atypia who were treated with progestins, we repeat the endometrial biopsy every three to six months.

In premenopausal or postmenopausal patients, if repeat endometrial biopsy shows atypical EH or persistent nonatypical EH, we typically perform a dilation and curettage to confirm that more severe EH or endometrial carcinoma is not present.

Maintenance therapy — Premenopausal women who have simple EH without atypia who do not have resumption of normal menses and have risk factors for endometrial cancer should be treated with some form of progestin indefinitely. (See 'Maintenance therapy' above.)

●Some women will experience bothersome progestin side effects and may require an adjustment in dose or a switch to a different progestin formulation. (See 'Progestin therapy administration' above.)

●For premenopausal women with regression to a normal endometrium, prescribing maintenance progestin therapy depends upon the menstrual pattern:

•Normal menstrual pattern (table 4) – Expectant management is reasonable. Endometrial biopsy is advised if abnormal uterine bleeding recurs.

•Normal menstrual pattern is not present – If after three to six months of treatment an endometrial biopsy documents normal endometrium, but normal cyclic menstrual function has not resumed, we give maintenance progestin therapy indefinitely.

●For postmenopausal women with regression to a normal endometrium, prescribing maintenance progestin therapy depends upon whether postmenopausal bleeding continues:

•No further bleeding – Expectant management is reasonable. Endometrial biopsy is advised if abnormal uterine bleeding recurs.

•Postmenopausal bleeding continues and endometrial biopsy is normal – We give maintenance progestin therapy and perform hysteroscopy to evaluate for focal lesion and resample endometrium in three to six months.

Women with persistent abnormal uterine bleeding, even with complete regression of EH, may desire hysterectomy. In such cases the indication for hysterectomy is bothersome 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. The LNg52/5 had a higher response rate at six months in four trials (88 versus 69 percent; odds ratio [OR] 3.16, 95% CI 1.84-5.45) and a lower hysterectomy rate (OR 0.26, 95% CI 0.15-0.45) [33]. 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) [55].

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 [56]. As noted above, expectant management may not lead to resolution in patients with risk factors for endometrial cancer (table 3).

Complex hyperplasia without atypia benign endometrial hyperplasia (some EIN)/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 those women with complex EH without atypia, who do not have hysterectomy within six weeks their diagnosis, the cumulative risk of progression to endometrial carcinoma is low (<5 percent) [51,57]. The goal of treatment is to decrease the risk of cancer in a small proportion of women and to control abnormal uterine bleeding by providing progesterone balance to an abnormally proliferative endometrium.

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 [33]. For women with complex EH without atypia, we recommend the LNg52/5 rather than oral progestins. However, if women cannot tolerate the LNg52/5, we use megestrol acetate for three to six months. 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 progestin or a patient who declines or cannot tolerate therapy. (See 'Contraindications' above.)

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

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

●For premenopausal women with complex EH without atypia, repeat endometrial biopsy is performed every three to six months for one to two years until the biopsy shows normal endometrium. If normal endometrium is not achieved, hysterectomy is recommended. Endometrial biopsy can 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 [58]; the decidual reaction that occurs with progestin therapy may make it more difficult to interpret pathologic findings.

•If a premenopausal patient desires pregnancy, this can be pursued once biopsy shows resolution of the hyperplasia, and pregnancy has been found to be feasible and achievable [30].

•If repeat endometrial biopsy shows atypical EH or persistent nonatypical EH, we perform a dilation and curettage, and, if appropriate, hysteroscopy, to exclude more severe EH or endometrial carcinoma.

•If regression to normal endometrium does not occur after six months of progestin therapy, further treatment is required. A prior review showed that the median time to complete response of EH to progestin was six months [30]. Possible interventions in the setting of persistent complex EH include:

-For women who do not desire future pregnancy, we advise a hysterectomy.

-Alternatively, the patient may be treated with a combination of the LNg52/5 and an oral progestin or a higher dose of oral progestin. However, there are currently no studies to support this approach, so careful surveillance with endometrial biopsy at three to six months is advised.

-If atypical EH or endometrial carcinoma develops, the patient may be treated with hysterectomy. Some women are candidates for fertility preservation. (See 'Atypical hyperplasia/EIN' below.)

●For postmenopausal women with complex EH without atypia, repeat endometrial biopsy is performed every three to six months for up to one year until the biopsy shows normal endometrium. Hysterectomy is advised if normal endometrium is not achieved. Endometrial biopsy can be performed with an intrauterine device in place.

•If repeat endometrial biopsy shows atypical EH or persistent nonatypical EH, we perform a hysteroscopy with dilation and curettage to exclude more severe EH or endometrial carcinoma.

•If regression to normal endometrium does not occur after six months of progestin therapy, further treatment is required. A prior review showed that the median time to complete response of EH to progestin was six months [30]. Possible interventions in the setting of persistent complex EH include:

-Hysterectomy is the standard treatment approach.

-Alternatively, the patient may be treated with a combination of the LNg52/5 and an oral progestin or a higher dose of oral progestin. However, there are currently no studies to support this approach, so careful reevaluation of the endometrium with endometrial biopsy at three to six months is advised. If atypical EH or endometrial carcinoma develops, the patient may be treated with hysterectomy. Some women are candidates for fertility preservation. (See 'Atypical hyperplasia/EIN' below.)

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 (obesity, diabetes, polycystic ovarian syndrome) (table 3). (See 'Maintenance therapy' above.)

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 [33,55]. Randomized trial data demonstrate the LNg52/5 is more effective than oral progestins, as discussed above. (See 'Outcome' 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 to women who did not receive oral progestin; hysterectomy risk was also decreased [57].

Some data suggest that regression rates with expectant management are not different than regression rates with an oral progestin. As an example, a study that included 139 women with complex EH without atypia compared progestin treatment (continuous or cyclical for at least three months) with no progestin and found comparable rates of regression (71.6 versus 70.0 percent) [29]. In a small randomized trial of levonorgestrel-releasing intrauterine device, oral progestin, or observation, 50 percent of patients on observation had regression [59]. Success rates of regression with oral progestins vary from approximately 70 to 85 percent [18,29].

Risk of relapse — A cohort study with long-term follow-up showed a relapse rate of 12.7 percent for complex hyperplasia without atypia [60]. A review of patients with complex atypical EH managed with progestin therapy showed a recurrence rate of 23.2 percent [30]. For patients who have a relapse of EH, consideration is given to either continuous progestin therapy or to hysterectomy.

ATYPICAL HYPERPLASIA/EINEH with atypia (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-releasing intrauterine device, 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 [30]. However, hysterectomy is curative and thus, is still the preferred 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 [61]. (See "Classification and diagnosis of endometrial hyperplasia", section on 'Positive endometrial sampling'.)

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 [24,51,57]. Representative studies include:

●In the largest study of long-term follow-up of women with EH (n = 7835), among women with atypical EH (n = 76) rates of endometrial carcinoma were: at four years (8.2 percent, 95% CI 1.3 to 14.6 percent), nine years (12.4 percent, 95% CI 3.0 to 20.8 percent), and 19 years (27.5 percent, 95% CI 8.6 to 42.5 percent) [51]. Subjects were diagnosed with carcinoma an average of six years later (range, 1 to 24 years). The majority of women received progestin treatment (86 to 92 percent) [62].

●Another observational study found that women with atypical EH who received progestin therapy (n = 180) compared with untreated women (n = 62) had higher rates of endometrial carcinoma (20.5 versus 101.4 per 1000 woman-years) and hysterectomy (61.4 versus 297.3 per 1000 woman-years) [57].

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 who are postmenopausal or who are premenopausal and have completed childbearing, we recommend hysterectomy 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 [58]. Supracervical hysterectomy is not an appropriate procedure for these patients, since the potential for local extension of endometrial neoplasia into the cervix outweighs any possible benefits of this surgical approach. During hysterectomy, gross inspection and frozen section should be performed to evaluate for endometrial carcinoma.

For women undergoing hysterectomy as treatment for atypical EH, we suggest 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.

The disadvantages of performing oophorectomy in all women at time of hysterectomy for atypical EH is that this practice exposes patients to potential additional perioperative morbidity or negative long-term health effects. Increased surgical risk is usually minimal with the addition of oophorectomy, but there are studies of adverse long-term health effects associated with elective oophorectomy. Premenopausal women who undergo oophorectomy will have adverse effects of premature or early menopause, but other long-term adverse effects (eg, increased risk of cardiovascular disease, cognitive decline) have also been reported in postmenopausal women. (See "Elective oophorectomy or ovarian conservation at the time of hysterectomy", section on 'Risks of elective oophorectomy'.)

On the other hand, despite preoperative endometrial sampling and intraoperative evaluation, some women with atypical EH will have endometrial carcinoma detected only on final pathology evaluation. All measures should be taken to detect endometrial carcinoma before or during hysterectomy (ie, dilation and curettage, intraoperative gross examination, and frozen section). However, these measures may fail to detect malignancy. Reports of the sensitivity of frozen section to detect endometrial carcinoma mostly range from to 73 to 88 percent [63-65], although one study reported a sensitivity of 27 percent [66].

Even in cases of endometrial carcinoma, the ovaries have metastatic disease in only 5 percent of cases [67,68]. Also, women with concurrent atypical EH and endometrial carcinoma are likely to have low-risk disease, and the likelihood of an impact on survival with retaining the ovaries in a woman with stage I, grade 1 endometrial carcinoma is low [69,70]. However, it is not unreasonable to perform bilateral salpingo-oophorectomy (BSO) because of the high risk of concomitant endometrial carcinoma and because BSO is a standard part of staging (table 5) [71,72]. Alternatively, if endometrial carcinoma is found postoperatively, subsequent laparoscopic BSO is an acceptable option for most patients.

Some women may choose to avoid oophorectomy, but to undergo bilateral salpingectomy alone for possible prevention of ovarian, fallopian tubal, or peritoneal cancer. (See "Opportunistic salpingectomy for ovarian, fallopian tubal, and peritoneal carcinoma risk reduction".)

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. (See "Overview of approach to endometrial cancer survivors", section on 'Menopausal symptoms'.)

Outcome and follow-up — Hysterectomy is curative for women with EH. In a longitudinal study of women with hyperplasia, the only related deaths were in women with endometrial cancer at the time of surgery [57]. Women with endometrial carcinoma detected at surgery should undergo full staging and be treated as appropriate. (See "Endometrial carcinoma: Staging and surgical treatment".)

Following total hysterectomy, if there is no endometrial carcinoma in the specimen, no further surveillance related to EH is necessary.

Following total hysterectomy, vaginal cytology is not required for most women, regardless of whether there is EH or endometrial carcinoma in the surgical specimen. Vaginal cancer is rare. Cytology of the vaginal cuff should be performed only if there is an indication based on the patient’s history of cervical intraepithelial neoplasia or other conditions, not on the history of EH. (See "Cervical and vaginal cytology: Interpretation of results (Pap test report)", section on 'Vaginal cytology'.)

Women who wish to preserve fertility 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 are at high risk of surgical complications, it is reasonable to treat with a progestin rather than hysterectomy [58]. These women must be able to comply with medical therapy and follow-up endometrial sampling.

Progestin therapy options and outcome — There are many different progestin medications that have been used to treat EH in different routes of administration, doses, and regimens, as noted above. For women treated with progestin therapy for atypical EH, we suggest that first-line therapy be the levonorgestrel-releasing intrauterine device, 52 mg with a release rate of 20 mcg/day over five years (Mirena; LNg52/5) rather than other progestin therapies.

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 [55]. Efficacy of progestin therapy for EH with atypia is discussed below.

For atypical EH in particular, there are few high-quality data that have evaluated treatment with the LNg52/5 [73]:

●The only randomized trial included 19 women with EH with atypia and 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) [36].

●A systematic review included 14 studies with 189 women with atypical hyperplasia [55]. The LNg52/5 for treatment of atypical EH found a higher regression rate for atypical EH in women treated with the LNg52/5 compared with oral progestins (90 versus 69 percent).

●A subsequent cohort study had a mean follow-up of 5.8 years and found that among the 34 women with atypical EH, regression rates were higher with the LNg52/5 compared with oral progestins (76 versus 46 percent) [74]. Subsequent relapse occurred in 3 of 11 women treated with LNg52/5 and 3 of 6 treated with oral progestins [60]. A systematic review did not find high-quality randomized trials that addressed this issue [75].

One meta-analysis that included 12 studies with a total of 117 women with complex atypical EH treated with progestins noted a relapse rate of 20.1 percent with a mean follow-up of 45 months [73]. Another meta-analysis of 14 studies with a total of 151 women with atypical EH treated with progestins (mostly oral, but some via intrauterine device) reported a regression rate of 86 percent, relapse rate of 26 percent, and live birth rate of 26 percent; median follow-up was 11 to 77 months [31].

Megestrol acetate is 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 [25,76]; studies showing increased benefit with these higher doses are lacking.

Other oral progestin treatment options are similar to those for complex EH without atypia, although oral norethisterone and micronized progesterone have not been adequately studied in women with atypical EH. Often higher progestin doses are used for atypical EH, as compared to doses recommended for EH without atypia, although there are minimal data to support this approach.

Multiple factors have been evaluated as predictors of response and/or relapse. The presence of progestin receptors has been proposed as a predictor of successful treatment, but this has not been supported by research [77]. A review of pretreatment pathology evaluations from 46 patients with atypical EH or well-differentiated endometrioid carcinoma treated with progestin therapy found that estrogen/progesterone receptor status did not predict response to treatment [78]. Another study assessed 152 women with complex or atypical EH who were treated with LNg52/5. Poor expression of estrogen and progesterone receptor was only weakly associated with persistent EH [79].

Follow-up — Median time for regression of atypical EH to normal endometrium on progestin therapy appears to be six to nine months [25,30,76]. 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. Endometrial sampling 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 [58]; the decidual reaction that occurs with progestin therapy may make it more difficult to interpret pathologic findings.

●If regression to normal endometrium occurs within 6 to 12 months, it is reasonable to repeat one to two biopsies after regression to confirm the absence of EH or concomitant carcinoma [80]. If normal menses resume, no further biopsies may be needed. However, patients who have subsequent abnormal bleeding need repeat sampling.

•After several normal endometrial biopsies and once a normal bleeding pattern is established, timing of repeat sampling should be based on individual risk factors.

●If persistent atypical EH is present after 6 to 12 months of therapy:

•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. Should the sample show nonatypical EH, therapy may be continued, and repeat sampling can be done until no EH. If no EH, consideration can be given to allow for pregnancy to occur. However, if there is persistent atypical EH or cancer at any time, the patient should be recommended to 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, we refer the patient to a gynecologic oncologist. 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 [81].

For all patients, if endometrial carcinoma develops, the patient should be treated as appropriate. (See "Endometrial carcinoma: Staging and surgical treatment".)

Maintenance — 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. 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.

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, we perform a repeat endometrial biopsy.

Hysterectomy is not recommended after birth in the absence of recurrent EH. For patients with recurrent EH with atypia who desire further fertility, retreatment with progestins has been utilized [82]. However, re-addressing a patient’s risk factors for EH should be done, and hysterectomy should be considered if the patient has completed her childbearing. (See "Fertility preservation in women with endometrial carcinoma".)

•If the patient has no short-term plans to become pregnant, 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 [83].

•Endometrial sampling is not performed routinely, but only if the patient has subsequent abnormal uterine bleeding.

●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 [83]. Routine surveillance in the absence of recurrent postmenopausal bleeding is not required.

Recurrence of atypical EH is usually symptomatic, with abnormal uterine bleeding. It can be evaluated with endometrial biopsy. In the setting of recurrent EH with atypia, progestin therapy can be given again. In our practice, however, stronger consideration is given to hysterectomy for patients with recurrent EH with atypia following relapse.

There is no standard maintenance therapy; various progestin preparations may be used but the LNg52/5 is preferred in our practice.

Fertility and pregnancy after treatment — Many women who choose progestin therapy are able to successfully conceive a pregnancy after regression of atypical EH. A meta-analysis reported that 30 percent (111 of 370) of patients from 24 studies achieved one or more pregnancies after treatment [84].

References

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