Case 7

Postmenopausal Bleeding
A 58-year-old woman presents to her gynecologist reporting a 2-month history of vaginal spotting.

QUESTIONS
What is the differential diagnosis of postmenopausal vaginal bleeding?
What details of the history and physical examination would be helpful?
DISCUSSION
Postmenopausal bleeding should never be ignored. In most women, the bleeding is benign, but in
approximately 15% of cases, the bleeding results from endometrial cancer. The most common cause of
postmenopausal bleeding is atrophy of the endometrium or vagina. Other causes include exogenous
estrogen use, endometrial or cervical polyps, and endometrial hyperplasia, as well as cervical cancer,
estrogen-producing ovarian tumors, urethral caruncle, and genital trauma.
The astute physician should ask about the quality, quantity, and timing of bleeding. A general
medical, surgical, and gynecologic history may identify risk factors for endometrial hyperplasia and
carcinoma. It is important to know what medications the patient is taking because use of exogenous
estrogen may cause as much as 30% of postmenopausal bleeding. This includes natural supplements
that the patient may not consider as medications. Physical examination, including pelvic examination, is
necessary to exclude obvious causes such as trauma, urethral caruncle, cervical polyp or cancer, and
ovarian masses that may produce estrogen. Atrophy of the genital tract is also usually apparent on pelvic
examination.

The patient reports that the bleeding is light and intermittent; she wears a sanitary pad
occasionally. She has diabetes mellitus type 1 and hypertension, for which she takes insulin and

hydrochlorothiazide, respectively. She has had no prior surgery. She has never been pregnant.
Until she was 53 years of age, her periods occurred normally every month. She does not have hot
flashes and does not use hormone replacement therapy or dietary supplements. She denies any
history of abnormal Pap smears or sexually transmitted disease. She is a widow and works as an
executive secretary. She does not smoke and denies illicit drug use but has one or two drinks per
week.
On physical examination, the patient is 5 feet 3 inches tall and weighs 254 lb. She is
moderately obese with no palpable abdominal masses. On pelvic examination, her vulva is free of
lesions, and her vagina shows only scant old blood in the vault. The cervix appears small but
otherwise normal. Because of her habitus, the uterus and adnexa are not palpable.

QUESTIONS
What is the next step in the workup of this patient?
What are the risk factors for endometrial cancer?
DISCUSSION
Endometrial biopsy is used to exclude endometrial cancer and hyperplasia in cases of abnormal vaginal
bleeding. This applies to both pre- and postmenopausal patients because, although the median age at
diagnosis of endometrial cancer is 61 years, 20% to 25% of cases are diagnosed before menopause, and
5% are diagnosed before 40 years of age. In most patients, endometrial biopsy may be performed in the
office with minimum discomfort. These outpatient techniques for endometrial sampling are about 90%
accurate for the diagnosis of carcinoma. Dilation and curettage, the gold standard, may be necessary in
the following situations: when cervical stenosis is present, the office procedure is nondiagnostic, bleeding
persists after a negative office procedure, or a patient cannot comfortably tolerate the procedure without
anesthesia.

Some physicians may use pelvic ultrasound as a diagnostic tool. Ultrasound may be necessary to
exclude a hormonally active ovarian tumor but is more commonly used in this instance to examine the
thickness of the endometrial stripe. No cases of cancer have been reported in postmenopausal patients
with an endometrial stripe thickness of 4 mm or less, but there is no consensus on the histologic diagnosis
for a given endometrial stripe thickness. The cost effectiveness of ultrasound has not been established for
the evaluation of vaginal bleeding; therefore, the preferred first step remains the office endometrial biopsy.
Most risk factors for endometrial cancer involve increased exposure to estrogen. One of the most
obvious sources of estrogen exposure is iatrogenic. Women who take unopposed estrogen replacement
therapy are at high risk for the development of endometrial hyperplasia and carcinoma. For this reason,
unopposed estrogen is not recommended as hormone replacement in women with a uterus. If, however,
unopposed estrogen is taken, these women should undergo yearly endometrial biopsy to screen for
abnormalities, even in the absence of symptoms. Tamoxifen, an antiestrogen that is frequently used to
treat breast cancer, has proestrogenic effects on the endometrium and may also predispose patients to
endometrial cancer.
Normal physiologic variations, such as obesity, nulliparity, and late menopause, also increase
endogenous estrogen exposure. Obesity increases the bodys exposure to estrogen through increased
peripheral production of estrogens by body fat and through decreased levels of both circulating
progesterone and sex hormonebinding proteins. Endometrial cancer is three times more likely in
individuals who are 20 to 50 lb. overweight when compared to those of a normal weight, and the cancer
is 10 times more likely in individuals who are more than 50 lb. overweight, as is the case with this patient.
In nulliparous women, the risk is two times greater than that of women with one child, and three times
greater than that of women with five or more children. Late menopause (beginning later than 52 years of
age) is associated with a greater than twofold risk.

Medical conditions commonly associated with endometrial cancer are hypertension and diabetes.
Prior oral contraceptive use and cigarette smoking appear to have a protective effect against the
development of endometrial cancer.

The physician performs an endometrial biopsy in the office. Because the uterus and adnexa are
not palpable, a pelvic ultrasound is ordered. The patient is instructed to make an appointment 2
weeks from now to discuss the test results.
At her next appointment, the physician reviews the results of the endometrial biopsy, which
shows complex hyperplasia without atypia. The ultrasound reveals normal-appearing ovaries and
a small uterus with an endometrial stripe of 12 mm.

QUESTIONS
What is the significance of complex hyperplasia?
What are the treatment options?
DISCUSSION
Endometrial hyperplasia is classified based on glandular architecture as simple (regular) or complex
(irregular with back-to-back crowding). Cytologic atypia may be present or absent. Of patients with
simple hyperplasia without atypia on biopsy, only about 1% progress to, or already have, concomitant
carcinoma. The rate or progression of concomitant carcinoma for patients with complex hyperplasia
without atypia is about 3%. These forms of hyperplasia often regress with progesterone therapy.
Treatment of hyperplasia without atypia depends on patient age, reproductive desire, and
symptoms. For perimenopausal patients, progesterone therapy, with biopsy in 3 to 6 months, may be
appropriate. For women interested in future childbearing, oral contraceptive pills for 3 months with
repeat biopsy to monitor regression of the lesion may be sufficient. Oral contraceptives may be continued

in patients who do not wish to have children immediately. Cyclic progesterone withdrawal may be used
instead of oral contraceptives in anovulatory patients. For patients who experience heavy bleeding or who
have a suspected estrogen-secreting ovarian neoplasm, hysterectomy with bilateral salpingooophorectomy may be warranted.
This patient has hyperplasia on the basis of obesity, which will not change unless she loses weight.
Transient treatment with progesterone will not correct the underlying problem and therefore will probably
not cure the hyperplasia

Because the patients symptoms are minor and she is reluctant to undergo major surgery, the
physician and patient agree on a course of progesterone therapy to treat the hyperplasia in
addition to a program for weight loss. The patient is given a schedule for medroxyprogesterone
acetate 10 mg daily with a follow-up endometrial biopsy in 4 months. At 4 months the patient has
not lost any weight and the repeat biopsy reveals complex hyperplasia with atypia.

QUESTIONS
What is the significance of atypical hyperplasia?
What are the treatment options for this patient?
DISCUSSION
Cytologic atypia is characterized by nuclear enlargement, irregularity, and hyperchromasia. These lesions
rarely respond to progesterone therapy and have a greater tendency to progress to carcinoma. For
patients with simple atypical hyperplasia, 8% either may possess a coexisting focus of carcinoma or will
eventually progress to cancer. For patients with complex atypical hyperplasia, this value increases to as
high as 29%.

Because of the high risk of carcinoma, the treatment of choice for this postmenopausal patient
with complex atypical hyperplasia is hysterectomy with bilateral salpingo-oophorectomy. This treatment is
appropriate for all patients except those who have serious concomitant medical problems that present
unacceptable surgical risks. In such cases, high-dose progesterone therapy may be attempted. Younger
patients, or those who wish to be able to bear children, may be treated with a trial of hormonal therapy
and followed closely with endometrial biopsy to monitor success of treatment.