Scott G. Chudnoff, MD

Disclosures

June 28, 2005

Question

What is the optimal dose and schedule of treatment of endometrial hyperplasia using the various progestins? Is the use of depot medroxyprogesterone a good option for treatment?

Response From the Expert

Scott G. Chudnoff, MD

A response to this question requires a little background information. Endometrial hyperplasia is generally considered a precursor to endometrial cancer. The presence of unopposed estrogen - which, for example, may result from exogenous estrogen therapy, anovulatory cycles, polycystic ovary syndrome (PCOS), or obesity -- has been shown to increase the likelihood of developing endometrial hyperplasia and cancer. Certain rare but dangerous conditions may generate unopposed estrogen, including granulosa cell tumors and ovarian thecomas as well as androgen-secreting tumors of the cortex. These conditions must be ruled out when there is suspicion in patients with endometrial hyperplasia (eg, the presence of an adnexal mass on ultrasound in a patient with abnormal bleeding).

Patients with endometrial hyperplasia commonly present with abnormal bleeding; this may be menorrhagia, metrorrhagia, menometorrhagia, or postmenopausal bleeding. Endometrial cancer must be ruled out particularly in patients older than 35 years of age who present with these conditions. The most common method used to diagnose hyperplasia and cancer is endometrial aspiration with a pippelle -- also known as an endometrial biopsy. This is an easy procedure to perform in the office with minimal discomfort to the patient and relatively high sensitivity and specificity. Other methods include measuring endometrial echo in postmenopausal women and hysteroscopy with directed biopsy of the endometrium. Although much debate exists in the literature regarding the optimal method for evaluating the endometrium, any of the above -- either alone or in combination -- represent appropriate diagnostic modalities.

The important consideration when dealing specifically with the treatment of hyperplasia is the classification of the type of hyperplasia that is present. Endometrial hyperplasia is defined as a proliferation of glands of irregular size and shape with an increase in the glands/stroma ratio. In general, there are 4 types of hyperplasia: simple, complex, simple with atypia, and complex with atypia ( Table 1 ). The primary consideration in this classification is the risk that each hyperplasia presents for progression to endometrial cancer (a good pneumonic to remember the approximate risks is "penny, nickel, dime, quarter" for 1%, 5%, 10%, and 25%, respectively). The primary differentiating factor is the presence of cytologic atypia, which significantly increases the likelihood of progression to cancer. Therefore, the management of these cases typically warrants more aggressive therapy.

Classification of Endometrial Hyperplasia

Type Description Risk of Progression to Endometrial Cancer
Simple Dilated glands that may contain some outpouching and abundant endometrial stroma ~ 1%
Complex Glands are crowded with very little endometrial stroma, and a very complex gland pattern and outpouching formations ~ 3%-5%
Simple with atypia Is the same as above, but also contains cytologic atypia. This refers to hyperchromatic, enlarged epithelial cells with an increased nuclear to cytoplasmic ratio. ~ 8%-10%
Complex with atypia ~ 25%-30%

Although there is a very high rate of spontaneous regression (80% in cases without atypia and over 50% in complex with atypia), therapy should be instituted since some patients will progress to cancer nonetheless. The 2 primary considerations in the management of the endometrial hyperplasia are the class and the desire for future childbearing. As a rule, medical management with a progesterone agent best manages patients with hyperplasia -- simple or complex -- who do not have atypia. In the presence of atypia, the ideal management is hysterectomy given the high rate of potential progression to cancer.

In hyperplasia without atypia, cyclical progestin therapy is the recommended choice in women not seeking contraception. In women desiring contraception, particularly younger women, oral contraceptive pills can be used, which provides the combined benefit of cycle control and contraception. If oral contraceptive pills are used, it is probably better to use a monophasic formulation. For women in whom contraception is not an issue, therapy with a cyclical progestin agent should be started. Typically, we use 10 mg medroxyprogesterone acetate for 10 to 14 days a month for 3 to 6 months. Patients are typically resampled after this time, and if they have a normal biopsy and are asymptomatic, we discontinue therapy. If the hyperplasia is persistent, then continuous-dose progestin therapy is instituted with 20 mg/day for 3 to 6 months. The continuous dose treatment can also be used from the outset if so desired. The other oral preparations may be used in a similar fashion ( Table 2 ).

Commonly Used Progesterone-Only Agents

Generic Name Common Trade Names Common Dosage
Progesterone Crinone; Progestasert; Prometrium 200 mg PO
Medroxyprogesterone acetate Provera; Depo-Provera 10-20 mg PO
150 mg IM
Megestrol acetate Megace 40-320 mg PO
Levonorgestrel Mirena IUS 1 intrauterine every 5 years

Aside from the above-mentioned regimens, other progesterone delivery systems may help treat endometrial hyperplasia. An injectable depot preparation of medroxyprogesterone acetate ( Depo-Provera ) can be administered in the normal dose used for contraception - 150 mg every 12 weeks. Additionally, the levonorgestrel intrauterine system ( Mirena ) is effective for 5 years. The advantages that these methods offer are the decreased dosing (eg, once the Mirena is inserted the patient does not need to take additional medications) and the contraceptive benefits they confer.

For patients who present with cellular atypia, the general recommendation would be to perform hysterectomy. If hysterectomy is not a viable option (eg, the patient is young and desires future childbearing or the patient is a very poor surgical candidate), then high-dose continuous progestin therapy can be used. Typically, we would use 20 mg of medroxyprogesterone acetate daily. Another option is 40 to 160 mg megestrol acetate daily for 6 months. It is critical that these patients receive repeat biopsies every 6 months because of the high risk of recurrence.

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