Alison F. Jacoby
History of present illness
A 42-year-old gravida 0 woman presents with a long history of irregular menstrual cycles. As a teenager her periods were unpredictable, occurring from every 16 days to every 6 months. In her twenties she was prescribed combined oral contraceptives (COCs). While she took them she had regular every 28-day cycles. At age 35, she discontinued COCs due to her tobacco use. In her late thirties she tried to become preg- nant but was unsuccessful. For the last several years she has only had two to three periods a year. For the last six months she has been bleeding off and on without any pattern. Last month she bled for 20 days with theflow varying from light to heavy. She denies cramps or pelvic pain. She is sexually active without using a birth control method. She takes no other medications. She has not had surgery.
Physical examination
General appearance: A moderately obese woman in no apparent distress
Vital signs:
Temperature: 37.0°C Pulse: 76 beats/min
Blood pressure: 138/88 mmHg Respiratory rate: 14 breaths/min BMI: 31 kg/m2
Weight: 175 lb Height: 63 inches
Abdomen: Soft, nontender, no palpable masses External genitalia: Unremarkable
Vagina: Normal rugae, 3 cc dark red blood in vault Cervix: Nulliparous, small amount of blood per os Uterus: Normal size, anteverted, nontender, mobile Adnexa: No palpable masses, nontender
Laboratory studies:
Urine pregnancy test: Negative Hct: 36.7%
Biopsy: An endometrial biopsy was performed to evaluate the abnormal uterine bleeding. The endometrial cavity sounded to 8 cm. A moderate amount of tissue was obtained by making three passes with a 3-mm endometrial Pipelle®
Pathology report:
Diagnosis: Simple endometrial hyperplasia
Microscopic description: Mildly crowded endometrial glands with cystic dilation, infrequent mitoses, and no nuclear atypia
How would you manage this patient?
This patient has several risk factors for developing endometrial hyperplasia including obesity and prolonged exposure to unopposed estrogen. Her pattern of infrequent bleeding suggests chronic anovulation. Anovulatory cycles, most com- monly associated with polycystic ovarian syndrome, lead to chronic estrogen stimulation of the endometrium, unopposed by the suppressive effects of progesterone. Simple endometrial hyperplasia can be treated with a variety of medications con- taining progestins such as COCs, medroxyprogesterone acetate (MPA) or a levonorgestrel-containing intrauterine device (LNG-IUD). Since the patient is older than 35 and smokes, COCs are contraindicated. Based on the side-effect profile of MPA and her desire for contraception, she chose the LNG- IUD. A follow-up endometrial biopsy was repeated three months later, and confirmed resolution of the hyperplasia.
Although initially she continued to have frequent bleeding and spotting, this improved and was significantly better after the LNG-IUD had been in place for six months. In addition, she began working out with a trainer and meeting with a nutritionist and succeeded in losing 25 lb. She has also set a date to quit smoking.
Simple endometrial hyperplasia
Two classification systems exist for describing endometrial hyperplasia. The World Health Organization (WHO) system is the most widely used classification. It is based on the archi- tectural pattern of the endometrial glands and the presence or absence of atypical nuclei [1]. The degree of gland crowding, or gland-to-stroma ratio, forms the basis for the terms simple and complex hyperplasia. The presence of nuclear atypia is the most important prognostic indicator for progression to endometrial cancer. The WHO system is useful because the categories correlate with the likelihood of progressing to endometrial cancer [2] (Table 18.1). It is limited by interobserver variability.
The endometrial intraepithelial neoplasia (EIN) system is used less often but has higher interobserver agreement [3].
This system divides endometrial changes into endometrial hyperplasia (EH) and EIN. Endometrium exposed to unopposed estrogen resulting in mildly crowded and branched glands would fall into the EH category, whereas endometrium with greater gland density and nuclear abnormalities would be
Acute Care and Emergency Gynecology, ed. David Chelmow, Christine R. Isaacs and Ashley Carroll. Published by Cambridge University Press.
© Cambridge University Press 2015.
described as EIN. Based on the results of the endometrial biopsy, this patient would meet criteria for simple endometrial hyperplasia in the WHO classification.
The diagnosis of endometrial hyperplasia is most common in perimenopausal women between the ages of 50 and 54 years.
Atypical endometrial hyperplasia and endometrial cancer are typically diagnosed a decade later. Hyperplasia is rarely detected in women younger than age 30. Abnormal uterine bleeding (AUB) is the most frequent presenting symptom. Occasionally, women with endometrial hyperplasia will present without AUB but will have abnormal endometrial cells on cervical cytology.
Although this patient was younger than most women with endometrial hyperplasia, she was at increased risk due to many years of unopposed estrogen from anovulation and obesity.
The bleeding pattern of women with endometrial hyperpla- sia caused by anovulation is typically initially characterized by infrequent bleeding episodes followed by frequent and pro- longed bleeding with varying amounts of flow. Initially, the bleeds are infrequent because without ovulation, a corpus luteum does not develop and the ovary does not produce pro- gesterone. Without progesterone withdrawal, there is no trigger to initiate menses. The endometrium is exposed continuously to estrogen, leading to endometrial proliferation. Eventually, the fragile vascular endometrium begins to slough. The haphazard sloughing results in erratic and prolonged uterine bleeding.
The first step in evaluating women suspected of having endometrial hyperplasia is a pelvic examination. Important features to note are the size and mobility of the uterus and the presence or absence of an adnexal mass. All premenopausal women should have a urine or serum pregnancy test.
A complete blood count can be helpful in women with pro- longed bleeding or symptoms of anemia.
The next step in the evaluation of a woman with irregular bleeding is an endometrial biopsy performed in the office. This is the method of choice for diagnosing endometrial hyperplasia.
Operating room procedures should be restricted to women who cannot tolerate an office biopsy, those with cervical stenosis preventing passage of the sampling instrument, and those with insufficient tissue on prior biopsies. There is no clear evidence that one method of endometrial sampling is superior to another [4]. The American College of Obstetricians and Gynecologists guidelines recommend that all women older than 45 years who present with suspected anovulatory uterine bleeding be
evaluated with endometrial biopsy [5]. Use of age 45 as the threshold is supported by evidence that the risk of endometrial hyperplasia and carcinoma is fairly low prior to age 45 and increases with advancing age. However, women like this patient, with risk factors for endometrial hyperplasia such as obesity and years of unopposed estrogen from chronic anovulation should undergo an endometrial biopsy regardless of their age.
Although a pelvic ultrasound can be useful for detecting the presence of uterine fibroids, endometrial polyps, and adnexal masses, it is not sensitive or specific for diagnosing endometrial hyperplasia. Regardless of the endometrial thick- ness, an endometrial biopsy is recommended for premenopau- sal women with AUB at risk for endometrial hyperplasia due to chronic anovulation.
Although the chance of developing endometrial cancer is very low for women with simple endometrial hyperplasia, treat- ment is warranted to reduce this risk and to regulate the bleeding. Since endometrial hyperplasia develops as a result of unopposed estrogen, most treatments consist of medications containing a progestin (Table 18.2). The two most common and effective progestin therapies for treating simple hyperplasia are oral MPA and the LNG-IUD. MPA at a dose of 10 mg daily can be prescribed in a continuous or a cyclic regimen for 3–6 months. When used cyclically, it is most effective to take it for at least 12 days each month. It is not unusual for women on MPA to experience side effects such as bloating, mood instability, depression, headaches, and irregular bleeding. Con- traindications to progestin therapies include women with
Table 18.1 Comparison of follow-up of patients with simple and complex hyperplasia and simple and complex atypical hyperplasia (Nẳ170) No. of patients Regressed
No. (%)
Persisted No. (%)
Progressed to cancer No. (%)
Simple hyperplasia 93 74 (80) 18 (19) 1 (1)
Complex hyperplasia 29 23 (80) 5 (17) 1 (3)
Simple atypical hyperplasia 13 9 (69) 3 (23) 1 (8)
Complex atypical hyperplasia 35 20 (57) 5 (14) 10 (29)
From Kurman et al. [2].
Table 18.2 Treatment options for simple endometrial hyperplasia without atypia
Dose Regimen
MPA 10 mg Continuous: daily
MPA 10 mg Cyclic: daily, 12–14
days/month
LNG-IUD 20μg
Combined oral
contraceptives Variable Daily
Micronized progesterone 100–200 mg Daily
LNG-IUD, levonorgestrel-containing intrauterine device (LNG-IUD); MPA, medroxyprogesterone acetate.
Case 18: A 42-year-old woman with irregular bleeding
progesterone receptor-positive breast cancer or other hormone- sensitive malignancies.
Other progestin-containing treatment options include COCs, depot MPA 150 mg IM every 3 months, micronized progesterone 200 mg in a vaginal cream daily or cyclically, norethindrone acetate 5–10 mg daily or cyclically, and meges- trol acetate 20 mg daily. Single-rod progestin implants con- taining etonogestrel (Nexplanon®, Implanon®) have not been studied for the treatment of endometrial hyperplasia. Nonhor- monal treatment options shown to be effective for endometrial hyperplasia are gonadotropin-releasing hormone (GnRH) agonists or antagonists and danazol. Simple hyperplasia is treated medically. Hysterectomy is reserved for women who develop hyperplasia with atypia or women who have persistent AUB unresponsive to medical therapies.
Resolution of simple hyperplasia usually occurs within three to six months of treatment. An endometrial biopsy should be performed three months after initiating treatment.
An endometrial biopsy can be performed with an IUD in place. If the hyperplasia has resolved then treatment can be discontinued; however, women with chronic anovulation benefit from ongoing progestin treatment. For women who stop taking a progestin, an additional biopsy should be per- formed three months later to confirm the hyperplasia has not recurred. If the hyperplasia persists or progresses while on therapy, then the progestin dose should be increased or the treatment changed to a different progestin.
For this patient, although the endometrial hyperplasia has resolved, she is at risk for recurrence off treatment since she has chronic anovulation. A LNG-IUD is a particularly good long-term option for her because it will provide a continuous low-dose of progestin to the endometrium and meet her con- traceptive needs. Alternatives for long-term management for her include MPA, combined hormonal contraceptives (COCs, patch, vaginal ring), depot MPA, and etonogestrel implants. Of note, oral MPA is not a contraceptive while the other treat- ments are. Obese women should be encouraged to lose weight to reduce production of endogenous estrogens and to promote the resumption of ovulation.
Key teaching points
Endometrial hyperplasia develops when the endometrium is exposed to unopposed estrogen for prolonged periods.
Anovulation and obesity are common risk factors for simple endometrial hyperplasia.
Medroxyprogesterone acetate (MPA) 10 mg daily and the levonorgestrel-containing intrauterine device (LNG-IUD) are well-tolerated effective treatments for simple
hyperplasia.
Endometrial sampling should be repeated three to six months after completing therapy to confirm resolution.
Progestin should be continued for as long as chronic anovulation persists.
References
1. Scully RE, Bonfiglio TA, Kurman, et al.
Uterine corpus. InHistological Typing of Female Genital Tract Tumours, 2nd edn. New York, Springer-Verlag, 1994, p. 13.
2. Kurman RJ, Kaminski PF, Norris HJ.
The behavior of endometrial hyperplasia. A long-term study of
“untreated”hyperplasia in 170 patients.
Cancer1985;56(2):403–12.
3. Mutter GL. Endometrial intraepithelial neoplasia (EIN): Will it bring order to chaos? The Endometrial Collaborative Group.Gynecol Oncol2000;76:
287–90.
4. Ben-Baruch G, Seidman DS, SchiffE, Moran O, Menczer J. Outpatient
endometrial sampling with the Pipelle curette.Gynecol Obstet Invest1994;
37(4):260–2.
5. American College of Obstetricians and Gynecologists. Diagnosis of abnormal uterine bleeding in reproductive-aged women. Practice Bulletin No. 128.Obstet Gynecol 2012;120:197–206.