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.

• 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). Choice of therapy is also guided by whether the patient requires contraception, since some oral progestins do not provide contraception.

• Progestin therapy administration has consistently shown that progestins are an effective treatment for EH .

• 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).

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.

• Nonprogestin medications
• Gonadotropin-releasing hormone (GnRH) agonists
  • 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.
• Aromatase inhibitors have been administered to block endogenous estrogen production in patients with EH.
• 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 has been shown to both have antiproliferative effects and to reduce insulin resistance
  • Plays a role in the development of endometrial carcinoma in overweight and obese females.
• Danazol has been used to successfully treat EH.
  • Seldom used due to significant side effects when taken orally

Alternative surgical treatments

• Hysteroscopic resection of EH was reported to be effective, 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

Medical Therapy Follow- up

• 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.

• 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.
• 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: at high risk of progression, we use the LNg52/5 combined with low-dose postmenopausal estrogen, and for low-risk EH, we use a continuous estrogen/progestin regimen.

References

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