Abnormal uterine bleeding due to ovulatory dysfunction (AUB-O) is abnormal uterine bleeding that, after examination and ultrasonography, cannot be attributed to the usual causes (structural gynecologic abnormalities, cancer, inflammation, systemic disorders, pregnancy, complications of pregnancy, use of oral contraceptives or certain drugs). Treatment is usually with hormone therapy, such as oral contraceptives, or with nonsteroidal anti-inflammatory drugs.
(See also Vaginal Bleeding.)
Abnormal uterine bleeding due to ovulatory dysfunction, the most common cause of abnormal uterine bleeding (AUB), occurs most often in women > 45 (> 50% of cases) and in adolescents (20% of cases).
About 90% of cases are anovulatory; 10% are ovulatory.
Pathophysiology of AUB-O
During an anovulatory cycle, the corpus luteum does not form. Thus, the normal cyclical secretion of progesterone does not occur, and estrogen stimulates the endometrium unopposed. Without progesterone, the endometrium continues to proliferate, eventually outgrowing its blood supply; it then sloughs incompletely and bleeds irregularly and sometimes profusely or for a long time. When this abnormal process occurs repeatedly, the endometrium can become hyperplastic, sometimes with atypical or cancerous cells.
In ovulatory abnormal uterine bleeding, progesterone secretion is prolonged; irregular shedding of the endometrium results, probably because estrogen levels remain low, near the threshold for bleeding (as occurs during menses). In obese women, ovulatory AUB can occur if estrogen levels are high, resulting in amenorrhea alternating with irregular or prolonged bleeding.
Chronic bleeding may cause iron deficiency anemia.
If AUB is due to chronic anovulation, infertility may also be present.
Etiology of AUB-O
Causes of AUB in nonpregnant women of reproductive age may be classified as structural or nonstructural to aid in identification of the cause and in treatment. The PALM-COEIN classification system may be used (1). PALM-COEIN is a mnemonic for the structural causes (PALM) and nonstructural (COEIN) causes of abnormal bleeding (see figure PALM-COEIN classification system).
PALM-COEIN classification system
Anovulatory AUB can result from any disorder or condition that causes anovulation (see table Some Causes of Anovulatory Amenorrhea). Anovulation is most often
- Secondary to polycystic ovary syndrome
- Idiopathic (sometimes occurring when gonadotropin levels are normal)
Sometimes anovulation results from hypothyroidism.
During perimenopause, anovulatory AUB may be an early sign of ovarian insufficiency or failure; follicles are still developing but, despite increasing levels of follicle-stimulating hormone (FSH), do not produce enough estrogen to trigger ovulation. About 20% of women with endometriosis have anovulatory AUB due to unknown mechanisms.
Ovulatory AUB may occur in
- Polycystic ovary syndrome (because progesterone secretion is prolonged)
- Endometriosis, which does not affect ovulation
Other causes are a short follicular phase and luteal phase dysfunction (due to inadequate progesterone stimulation of the endometrium); a rapid decrease in estrogen before ovulation can cause spotting.
- 1. Munro MG, Critchley HOD, Fraser IS, FIGO (International Federation of Gynecology and Obstetrics) Menstrual Disorders Committee: The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions. Int J Gynaecol Obstet 143 (3):393–408, 2018. doi: 10.1002/ijgo.12666
Symptoms and Signs of AUB-O
Compared with typical menses, abnormal uterine bleeding may
- Occur more frequently (menses < 21 days apart—polymenorrhea)
- Involve more blood loss (> 7 days or > 80 mL) during menses (menorrhagia, or hypermenorrhea)
- Occur frequently and irregularly between menses (metrorrhagia)
- Involve more blood loss during menses and frequent and irregular bleeding between menses (menometrorrhagia)
Ovulatory AUB tends to cause excessive bleeding during regular menstrual cycles. Women may have other symptoms of ovulation, such as premenstrual symptoms, breast tenderness, midcycle cramping pain (mittelschmerz), a change in basal body temperature after ovulation (see Ovulatory Dysfunction), and sometimes dysmenorrhea.
Anovulatory AUB occurs at unpredictable times and in unpredictable patterns and is not accompanied by cyclic changes in basal body temperature.
Diagnosis of AUB-O
- Exclusion of other potential causes
- Complete blood count (CBC), pregnancy test, and hormone measurement (eg, thyroid-stimulating hormone [TSH], prolactin)
- Usually transvaginal ultrasonography and endometrial sampling
- Often sonohysterography and/or hysteroscopy
Women should be evaluated for abnormal uterine bleeding when the amount or timing of vaginal bleeding is inconsistent with normal menses.
Abnormal uterine bleeding due to ovulatory dysfunction is a diagnosis of exclusion; other conditions that can cause similar vaginal bleeding must be excluded. Pregnancy should be excluded, even in young adolescents and perimenopausal women. Coagulation disorders should be considered, particularly in adolescents who have anemia or require hospitalization for bleeding. Regular cycles with prolonged or excessive bleeding (possible ovulatory abnormal uterine bleeding) suggest structural abnormalities.
Several tests are typically done:
- A urine or blood pregnancy test
- Complete blood count (CBC)
- Thyroid-stimulating hormone (TSH), prolactin, and sometimes progesterone levels
All women of reproductive age should have a pregnancy test.
CBC is routinely done. However, hematocrit may be normal in women who report heavy bleeding, or anemia may be severe in women who regularly have heavy periods. The serum ferritin level, which reflects body iron stores, is measured if women have chronic, heavy bleeding.
TSH levels are usually measured, and prolactin levels are measured, even when galactorrhea is absent, because thyroid disorders and hyperprolactinemia are common causes of vaginal bleeding.
To determine whether bleeding is anovulatory or ovulatory, some clinicians measure serum progesterone levels during the luteal phase (after day 14 of a normal menstrual cycle or after basal body temperature increases, as occurs during this phase). A level of ≥ 3 ng/mL (≥ 9.75 nmol/L) suggests that ovulation has occurred.
Other tests are done depending on results of the history and physical examination and include the following:
- Coagulation tests if women have risk factors for coagulation disorders, bruising, or hemorrhage
- Liver function tests if a liver disorder is suspected
- Testosterone and dehydroepiandrosterone sulfate (DHEAS) levels if polycystic ovary syndrome is suspected
- Serum glucose and lipid levels, blood pressure, and body mass index if polycystic ovary syndrome is suspected
- Follicle-stimulating hormone (FSH) and estradiol levels if primary ovarian insufficiency is possible
- Serum ferritin to check iron stores if anemia is present
- A cervical cancer screening test (eg, Papanicolaou [Pap] test, human papillomavirus [HPV] test) if results are out-of-date
- Testing for Neisseria gonorrhea and Chlamydia species if pelvic inflammatory disease or cervicitis is suspected
- Electrolytes (particularly potassium and magnesium) if anorexia nervosa is suspected
If all clinically indicated tests are normal, the diagnosis is abnormal uterine bleeding due to ovulatory dysfunction.
Transvaginal ultrasonography is done if women have any of the following:
- Risk factors for endometrial cancer (eg, obesity, diabetes, hypertension, polycystic ovary syndrome, chronic eugonadal anovulation, hirsutism, other conditions associated with prolonged unopposed estrogen exposure)
- Age ≥ 35 (earlier if women have risk factors)
- Bleeding that continues despite use of empiric hormone therapy
- Pelvic organs that cannot be examined adequately during the physical examination
- Clinical evidence that suggests abnormalities in the ovaries or uterus
These criteria include almost all women with abnormal uterine bleeding.
Transvaginal ultrasonography, which does not expose patients to radiation, can detect structural abnormalities, including most polyps, fibroids, other masses, ovarian abnormalities, adenomyosis, endometrial cancer, and any areas of focal thickening in the endometrium. If focal thickening is detected, further testing may be needed to identify smaller intrauterine masses (eg, small endometrial polyps, submucous myomas). Sonohysterography (ultrasonography after saline is infused into the uterus) is useful in evaluating such abnormalities; it can be used to determine whether hysteroscopy, a more invasive test, is indicated and to plan resection of intrauterine masses. Or hysteroscopy may be done without sonohysterography. Both can be done in the office. MRI provides detailed images that are useful in planning surgery but is expensive and is not the first-line imaging test for patients with AUB.
In endometrial sampling, only about 25% of the endometrium is analyzed, but sensitivity for detecting abnormal cells is about 97%. This test is usually recommended to rule out hyperplasia or cancer in women with any of the following:
- Age ≥ 35 years with one or more risk factors for endometrial cancer (see above)
- Age < 35 years with multiple risk factors for endometrial cancer (see above)
- Bleeding that is persistent, irregular, or heavy or recurs in an abnormal pattern despite treatment
- Endometrial thickness that is > 4 mm, focal, or irregular, detected during transvaginal ultrasongraphy
- Inconclusive ultrasonography findings
Directed biopsy (with hysteroscopy) may be done to visualize the endometrial cavity directly and target the abnormal tissue. Most endometrial biopsy specimens contain proliferative or dyssynchronous endometrium, which confirms anovulation because no secretory endometrium is found.
Electrocardiography is done if anorexia nervosa is suspected to check for arrhythmias, particularly bradycardia, or if patients report palpitations.
Treatment of AUB-O
- Control of bleeding, usually with a nonsteroidal anti-inflammatory drug (NSAID), tranexamic acid, or hormone therapy
- In women with endometrial hyperplasia, prevention of endometrial cancer
Iron deficiency anemia should be treated with oral or parenteral iron.
Nonhormonal treatments for abnormal uterine bleeding due to ovulatory dysfunction have fewer risks and adverse effects than hormone therapy and can be given intermittently, when bleeding occurs. They are used mainly to treat women who desire pregnancy, who wish to avoid hormone therapy, or who have heavy regular bleeding (menorrhagia). Choices include
- Nonsteroidal anti-inflammatory drugs (NSAIDs), which reduce bleeding by 25 to 35% and relieve dysmenorrhea by reducing prostaglandin levels
- Tranexamic acid, which inhibits plasminogen activator, reducing menstrual blood loss by 40 to 60%
Hormone therapy (eg, oral contraceptives, progestogens, a long-acting progestin-releasing intrauterine device [IUD]) is often tried first in women who want contraception or who are perimenopausal. This therapy does the following:
- Suppresses endometrial development
- Reestablishes predictable bleeding patterns
- Decreases menstrual flow
Hormone therapy is usually given until bleeding has been controlled for a few months.
Oral contraceptives (OCs) are commonly given. OCs, used cyclically or continuously, can control abnormal uterine bleeding due to ovulatory dysfunction. Limited data suggest that they do the following:
- Decrease menstrual blood loss by 40 to 50%
- Decrease breast tenderness and dysmenorrhea
- Decrease risk of uterine and ovarian cancer
Combination formulations consisting of an estrogen and a progestin or a progestin alone may be used. Risks of an OC depend on the type of OC, dose, duration of use, and patient factors.
A progestogen can be used alone in the following cases:
- Estrogen is contraindicated (eg, for patients with cardiovascular risk factors or prior deep vein thrombosis).
- Estrogen is declined by the patient.
- Combination OCs are ineffective after about 3 months of use.
Withdrawal bleeding may be more predictable with cyclic progestin therapy (medroxyprogesterone acetate 10 mg/day orally or norethindrone acetate 2.5 to 5 mg/day orally) given for 21 days a month than with a combination OC. Cyclic natural (micronized) progesterone 200 mg/day for 21 days a month may be used, particularly if pregnancy is possible; however, it may cause drowsiness and does not decrease blood loss as much as a progestin.
If patients using cyclic progestins or progesterone wish to prevent pregnancy, contraception should be used. Contraceptive options include
- A levonorgestrel-releasing IUD: It is effective in up to 97% by 6 months, provides contraception, and relieves dysmenorrhea.
- Depot medroxyprogesterone acetate injections: They cause amenorrhea and provide contraception but may cause irregular spotting and reversible bone loss.
Other treatments that are occasionally used to treat abnormal uterine bleeding due to ovulatory dysfunction include
- Danazol: It reduces menstrual blood loss (by causing endometrial atrophy) but has many androgenic adverse effects, which may be lessened by using lower doses or a vaginal formulation. To be effective, danazol must be taken continuously, usually for about 3 months. It is usually used only when other forms of therapy are contraindicated.
- Gonadotropin-releasing hormone (GnRH) agonists: These drugs suppress ovarian hormone production and cause amenorrhea; they are used to shrink fibroids or the endometrium preoperatively. However, their hypoestrogenic adverse effects (eg, osteoporosis) limit their use to 6 months; they are often used concurrently with low-dose hormone therapy.
Ergot derivatives are not recommended for treatment of abnormal uterine bleeding due to ovulatory dysfunction because they are rarely effective.
If pregnancy is desired and bleeding is not heavy, ovulation induction with clomiphene (50 mg orally on days 5 through 9 of the menstrual cycle) can be tried.
Hysteroscopy with dilation and curettage (D & C) may be therapeutic as well as diagnostic; it may be the treatment of choice when anovulatory bleeding is severe or when hormone therapy is ineffective. Structural causes such as polyps or fibroids may be identified or removed during hysteroscopy. This procedure may decrease bleeding but, in some women, causes amenorrhea due to endometrial scarring (Asherman syndrome).
Endometrial ablation (eg, laser, rollerball, resectoscopic, thermal, or freezing) may help control bleeding in 60 to 80%. Ablation is less invasive than hysterectomy, and the recovery time is shorter. Ablation may be repeated if heavy bleeding recurs after ablation is initially effective. If this treatment does not control bleeding or if bleeding continues to recur, the cause may be adenomyosis and thus is not abnormal uterine bleeding due to ovulatory dysfunction. Endometrial ablation does not prevent pregnancy. Pregnancy rates may be as high as 5% after ablation. Ablation causes scarring which may make sampling the endometrium difficult later.
Hysterectomy, abdominal or vaginal, may be recommended for patients who decline hormone therapy or who, despite other treatments, have symptomatic anemia or poor quality of life caused by persistent, irregular bleeding.
Emergency measures are needed only rarely, when bleeding is very heavy. Patients are stabilized hemodynamically with IV crystalloid fluid, blood products, and other measures as needed. If bleeding persists, a bladder catheter is inserted into the uterus and inflated with 30 to 60 mL of water to tamponade the bleeding. Once patients are stable, hormone therapy is used to control bleeding.
Very rarely, in patients with very heavy bleeding due to anovulatory AUB, conjugated estrogens 25 mg IV every 4 to 6 hours for a total of 4 doses may be used. This therapy stops bleeding in about 70% of patients but increases risk of thrombosis. Immediately afterward, patients are given a combination OC, which may be continued until bleeding has been controlled for a few months.
In postmenopausal women, atypical adenomatous endometrial hyperplasia is usually treated with hysterectomy.
In premenopausal women, atypical adenomatous endometrial hyperplasia may be treated with medroxyprogesterone acetate 40 mg orally once a day for 3 to 6 months or a levonorgestrel-releasing IUD (1). After 3 to 6 months of treatment, endometrial sampling is repeated. If repeat endometrial sampling indicates resolution of hyperplasia, women may be given cyclic medroxyprogesterone acetate (5 to 10 mg orally once a day for 10 to 14 days each month) or, if pregnancy is desired, clomiphene. This treatment is given for 3 months, then response is assessed, usually by endometrial biopsy. If repeat endometrial sampling shows persistent or progressive atypical hyperplasia, hysterectomy may be necessary.
More benign cystic or adenomatous hyperplasia can usually be treated with high-dose cyclic progestin therapy (eg, cyclic medroxyprogesterone acetate) or a progestin- or levonorgestrel-releasing IUD; sampling is repeated after about 3 months.
- 1. Mentrikoski MJ, Shah AA, Hanley KZ, et al: Assessing endometrial hyperplasia and carcinoma treated with progestin therapy. Am J Clin Pathol 38 (4):524–534, 2012. doi: 10.1309/AJCPM2TSDDF1MHBZ
- Abnormal uterine bleeding due to ovulatory dysfunction is the most common cause of abnormal uterine bleeding.
- Test for treatable causes of bleeding; tests may include a pregnancy test, CBC, ferritin to check iron stores if anemia is present, measurement of hormone levels (TSH, prolactin, progesterone), and often ultrasonography or office hysteroscopy and endometrial sampling.
- In women at risk, check for and treat endometrial hyperplasia.
- If drugs are needed to control bleeding, treat with NSAIDs, tranexamic acid, OCs, levonorgestrel-releasing IUDs, or other hormones, which are usually effective.
Drugs Mentioned In This Article
|Drug Name||Select Trade|
|levonorgestrel||MIRENA, PLAN B|
|Danazol||No US brand name|