Benign Endometrial Hyperplasia and Endometrial Intraepithelial Neoplasia (EIN)

Liang A

Clinical Cases Applicability: Abnormal uterine bleeding, ovulatory dysfunction, post-menopausal bleeding, endometrial cancer

Learning Objectives:

1) Describe the histology of the endometrium, and changes associated with hormonal fluctuation

2) Describe the histopathology of endometrial hyperplasia and EIN

3) Understand the role of progestins in treating hyperplasia

NORMAL ENDOMETRIUM

What is the structure of the endometrium?

– Simple columnar epithelium with simple tubular glands; hormonally active (figure 1)

o Proliferative: No crowding of glands within the stroma, <50% ratio of glands to stroma

o Secretory: may have >50% glands to stroma ratio, glands are organized, not mitotically active

– Two layers: (figure 1 & 2)

1) Stratum functionale: temporary layer at the luminal surface, responds to hormones, changes during the menstrual cycle

2) Stratum basale: deeper, permanent layer containing basal portion of the endometrial glands, retained during menses

Why does the endometrium shed during menses?

– Blood supply to the endometrium: Uterine arteries  arcuate arteries (myometrium)  straight arteries (stratum basale)  spiral arteries (stratum functionale) (figure 2)

– Spiral arteries uniquely sensitive to progesterone – if no pregnancy implants, decline in progesterone causes constriction that leads to local ischemia of the functional layer

HYPERPLASIA

What causes benign endometrial hyperplasia? What changes are noted histologically?

– Estrogenic stimulation of the endometrium, unopposed by progestins (risks include Obesity, nulliparity, tamoxifen therapy, PCOS (chronic anovulation), unopposed estrogen therapy, early menarche, late menopause)

– Proliferative glandular epithelial changes (figure 3)

How is benign endometrial hyperplasia treated?

– Progestins counterbalance proliferative effects of estrogens and induce secretory differentiation

EIN (PRE-MALIGNANT)

How is endometrial intraepithelial neoplasia diagnosed? (figure 3)

– Histologic criteria: >50% glands to stroma ratio (gland crowding), altered cytology relative to background gland, size > 1 mm, & exclusion of adenocarcinoma, exclusion of mimics

What is the importance of diagnosing EIN? Difference in risk and treatment!

– Precursor lesion for type 1 endometrioid adenocarcinoma (80% of endometrial carcinomas)

– 27% risk of progression to cancer; ~40% of patients with EIN by biopsy may already have underlying carcinoma on hysterectomy specimen

How is EIN treated?

– Total hysterectomy provides definitive assessment of a possible concurrent carcinoma and effectively treats premalignant lesions

– Progestins in cases of uterine retention (desire for future fertility, poor surgical candidates) Benign Endometrial Hyperplasia and Endometrial Intraepithelial Neoplasia (EIN)

Liang A

Figure 1

Figure 2:

Figure 3:

Figures 1 & 3: Courtesy of Richard Lieberman MD

Figures 2: Aki Yao, Learning Design & Publishing, Medical School Information Services, University of Michigan

References:

– Endometrial intraepithelial neoplasia. Committee Opinion No. 631. American College of Obstetricians and Gynecologists. Obstet Gynecol 2015;125;1272-8.

– Giuntoli, RL, Zacur, HA. Classification and diagnosis of endometrial hyperplasia. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (2016)

– Paulsen, Douglas F.. “Chapter 23. Female Reproductive System.” Histology & Cell Biology: Examination & Board Review, 5e. Ed. Douglas F. Paulsen. New York, NY: McGraw-Hill, 2010.

– Mescher, Anthony L.. “The Female Reproductive System.” Junqueira’s Basic Histology, 14e. Ed. Anthony L. Mescher. New York, NY: McGraw-Hill, 2016.

Common Bleeding Problems

Heavy periods  and lengthy periods

• • may reflect an underlying mechanical abnormality inside the uterus (fibroids, polyps),
  • may be a cause of iron-deficiency anemia, and
  • may contribute to uncomfortable menstrual cramps.

If the examination, Pap smear, and pregnancy test are normal, then the chance of malignancy is very low and need not be further considered in those under age 40 unless symptoms persist. Those over 40 should have an endometrial biopsy.

In taking your history on these patients, it is a good idea to inquire about medications. Aspirin, for example, even if taken in very modest amounts, can effectively block platelet function for up to a week. By itself, I wouldn’t expect aspirin usage to cause abnormal bleeding, but if the patient has any other coagulation issue, no matter how trivial, then the addition of aspirin to the mix could be enough to push her over the edge into  a bleeding problem. If she is taking aspirin, I would recommend both stopping the aspirin and also looking for other coagulopathies.

To control heavy, lengthy periods, one good approach is to give birth control pills. The effect of the BCPs is to reduce the heaviness and duration of flow. If the patient is anemic, taking oral iron preparations will usually restore their iron and return their blood count to normal. If the BCPs fail to reduce the flow appreciably, then an alternative approach is to take the BCPs continuously, without the usual “week off.” This will postpone the menstrual period indefinitely. Even though their period may still be heavy or lengthy, the fact that they only rarely have it will have a major impact on their quality of life and anemia, if present.

Alternatively, you could start the patient on DMPA (depot medroxyprogesterone acetate) injections. This will usually disrupt the normal period and she probably won’t continue to have heavy periods. There are some significant drawbacks to this approach, however. Light spotting or bleeding are common among women taking DMPA, so you will be substituting one nuisance for another nuisance.

If sonohysterography demonstrates an endometrial polyp, removal of the polyp will often restore a normal menstrual flow. OCPs will sometimes reduce the flow due to fibroids enough to allow the patient to tolerate these flows for extended lengths of time.

Extremely light periods, so long as they occur at the right time, are not dangerous and really are not a medical problem.

This condition is most often seen among women taking low dose birth control pills. Ideally, the birth control pills will block the normal ovarian functions of production of hormones and ovulation. Then, they provide their own hormones to restore the woman to a more or less normal status, but without ovulation. Usually, the result of this exchange is that the cumulative circulating estrogen levels are little lower than if the woman were not taking BCPs. It is this feature of reduced estrogen levels that results in lighter, shorter periods with fewer cramps that we see among women taking BCPs.

In some women, however, the estrogen levels are significantly lower than before they started taking the BCPs. In this case, they will notice their menstrual periods getting lighter and lighter and possibly even disappearing altogether.

This is not dangerous, has no impact on future fertility, and will resolve spontaneously if the BCPs are stopped. Stopping the BCPs is not necessary, however, because there are other safe alternatives. If the periods are simply very light (1-2 days), you can reassure the patient that this poses no threat to her.

If periods have totally stopped: You should first Rule out pregnancy. Then you have three options.

• • You may change to a different BCP with different hormone in it. This will often lead to recognizable periods because the different hormone is metabolized differently.
  • You may add a little estrogen such as Premarin .625 mg to each BCP to increase the estrogen stimulation of the uterine lining, increasing its’ thickness and leading to heavier periods.
  • You may safely reassure the patient and allow her to not have periods while taking the BCPs. As long as she otherwise feels well, the absence of periods while taking BCPs is not known to have any adverse effects and some women prefer to avoid monthly flows.

If a patient is Late for a Period, First, rule out pregnancy.

If the pregnancy test is negative and the patient is not taking hormonal contraception, then simple observation for a single missed period is the usually the wisest course. Delay of periods in stressful settings is common. In Navy Boot Camp, among women not already taking BCPs, about 1/3 of women will skip periods for up to three months. The same observation is found among college freshman women.

If the patient remains without a period for an extended length of time (3 months or more), then the following are often done:

• • Normal menstrual flows are re-established with either BCPs, or oral Provera. Provera works well if ovarian function is not deeply depressed, but will not work for some women, notably those whose estrogen production is so low that virtually no endometrial priming is happening. BCPs will usually work regardless of the degree of ovarian suppression.
  • These patients should be tested for thyroid malfunction with a TSH.
  • These patients are frequently tested for prolactin disorders with a serum prolactin
  • Finally, these patients may be tested for premature ovarian failure with an FSH.

Irregular Periods means menstrual periods coming at unpredictable intervals, rather than the normal once-a-month cycles.

If the flows, whenever they come, are normal in character and length, this is not a dangerous condition and no treatment or evaluation is required. If the patient finds the irregular character of her periods to be troublesome, then starting low dose BCPs will be very effective in giving her quite normal, once-a-month menstrual flows.

If the flows, whenever they come, are not consistent; are sometimes heavy, are sometimes light, are sometimes only spotting, then they are likely not true menstrual cycles, but are anovulatory bleeding (which is uterine bleeding occurring in the absence of ovulation). This condition should be treated with re-establishment of normal, regular periods, usually with BCPs. Unresolved anovulatory bleeding may, over many months to years, lead to cosmetic problems (unwanted hair growth due to relative excess of male hormones) and uterine lining problems (endometrial hyperplasia due to a lack of the protective hormone progesterone).

Patients with infrequent periods, particularly if associated with overweight status, acne, and multiple follicles on the ovary when visualized with ultrasound, usually have “polycystic ovary syndrome.” This condition may be effectively treated with OCPs, but also can respond well to the use of Metformin.

Patients with hypothyroidism may also have this type of menstrual cycle, and screening for thyroid disease with a TSH is helpful.

Too Frequent Periods

Periods that are too frequent (more often than every 26 days, “metrorrhagia”) can be related to several predisposing factors:

• • If the periods are otherwise normal, then a short “luteal phase” or insufficient ovarian production of progesterone may be responsible.
  • If the periods are inconsistent, then failure to ovulate and the resulting anovulatory bleeding may be responsible.
  • If the periods are actually normal and once a month, but there are episodes of bleeding in between the periods, then mechanical factors such as fibroids or polyps may be responsible.
  • Women with hyperthyroidism are classically described as experiencing frequent, heavy periods., In real life, they rarely show that pattern, but we usually screen these patients for thyroid disease anyway.

Constant Bleeding

Women who experience significant daily bleeding for a very long time (weeks) sometimes develop another kind of problem unique to this circumstance, denuding of the uterine lining.

Normally, small breaks or tears in the uterine lining are promptly repaired. For women who have been bleeding for weeks, with the accompanying uterine cramping, the uterine lining becomes very nearly completely lost. There is so little endometrium left that the woman will have difficulty achieving repair and restoration of the normal lining without external assistance. A common example of this situation would be a teenager who has been bleeding for many weeks but who, through embarrassment, has not sought medical attention. On arrival, she continues to bleed small amounts of bright red blood. She is profoundly anemic, with a hemoglobin of 7.0 or less.

These patients don’t respond to simple BCP treatment because the BCPs are so weak in estrogen and so strong in progestin that the uterine lining barely has a chance to grow and cover up the denuded, bleeding areas inside the uterus.

These patients need strong doses of plain estrogen, to effectively stimulate the remaining uterine lining, causing it to proliferate. Premarin, 2.5 to 5 mg PO per day, or IV will provide this strong stimulus to the uterine lining and if combined with bedrest, will usually slow or stop the bleeding significantly within 24to 48 hours. The estrogen is stimulating the uterine lining to grow lush and thick. Once the bleeding has slowed, continue the estrogen for several days, but at somewhat lower dosages (1.25 to 2.5 mg per day) until the bleeding completely stops. Then, add a progestin, such as Provera 5-10 mg PO per day for 5-10 days. A progestin is necessary at this point because the lush, thick uterine lining is also very fragile and easily broken. Progesterone provides a structural support to the uterine lining, making it less likely to tear or break.

Once a normal, thick, well-supported lining has been re-established, first with estrogen, then with the addition of progesterone, it will need to be shed, just like a normal lining is shed once a month. Stopping all medication will trigger a normal menstrual flow about 3 days later. The lining will have been restored and the vicious cycle of bleeding leading to more endometrial loss leading to more bleeding will be broken. Future periods may then be normal, although many physicians will start BCPs at this point to prevent recurrence of the constant bleeding episode.

Dr. Hughey