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.[1][2]
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.[1][2]
Treatment of endometrial hyperplasia | |||||||||||||||||||||||||||||||||||||||||||||
Hyperplasia without atypia
| Hyperplasia with atypia | ||||||||||||||||||||||||||||||||||||||||||||
Conservative
| Desire for pregnancy? | ||||||||||||||||||||||||||||||||||||||||||||
Yes | No | ||||||||||||||||||||||||||||||||||||||||||||
Conservative
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Progestins (cyclic/continuous) | |||||||||||||||||||||||||||||||||||||||||||||
Options for the management of EH include surveillance, progestin therapy, or 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 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) losing weight, or, rarely, removing an estrogen-producing neoplasm.
- 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.
- For women with ovulatory dysfunction, the etiology should be treated (eg, prolactinoma)
- 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.
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.
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.
Oral progestins may be preferred by women with the following characteristics:
- Oral progestin preparations can effectively treat the majority of cases of EH without atypia and some milder forms of atypical EH.
- 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 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'.)
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.
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.
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.
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
- ↑ 1.0 1.1 Emons G, Beckmann MW, Schmidt D, Mallmann P, Uterus commission of the Gynecological Oncology Working Group (AGO) (2015). "New WHO Classification of Endometrial Hyperplasias". Geburtshilfe Frauenheilkd. 75 (2): 135–136. doi:10.1055/s-0034-1396256. PMC 4361167. PMID 25797956.
- ↑ 2.0 2.1 Baak JP, Mutter GL (2005). "EIN and WHO94". J Clin Pathol. 58 (1): 1–6. doi:10.1136/jcp.2004.021071. PMC 1770545. PMID 15623473.