Anovulatory Bleeding

Etiology

The etiology of AUB-O is believed to stem from a disturbance in the hypothalamic-pituitary-ovarian (HPO) axis.[2] Physiological anovulation is common at the beginning of reproductive life when the HPO axis is not fully mature. Near menopause, follicular recruitment may occur prematurely in the luteal phase, followed by precocious maturation of the follicle.[4] This "luteal out-of-phase event" then results in high levels of circulating estradiol and increased menstrual volume.[4] Physiological anovulation can also occur during lactation. Pathological anovulation is often secondary to endocrine dyscrasia, with polycystic ovary syndrome (PCOS) being the most commonly implicated process.[5]

Additional common etiologies of AUB-O include:

• Hyperandrogenism (eg, PCOS, congenital adrenal hyperplasia, and androgen-producing tumors)
• Hyperprolactinemia
• Anorexia
• Excessive exercise
• Psychological stress
• Thyroid dysfunction
• Primary pituitary dysfunction
• Premature ovarian failure
• Medications [3][6]

Medications associated with ovulatory dysfunction include antiepileptics such as valproate and lamotrigine, as well as antipsychotics such as haloperidol, chlorpromazine, and risperidone.[7][8][9] Typical antipsychotics, more than atypical antipsychotics, are more likely to cause hyperprolactinemia and subsequent AUB-O.

Epidemiology

AUB is a common problem. In the United States, the annual rate of AUB has been reported to be 53 per 1000 reproductive-aged women.[10] AUB-O can occur at any stage of a patient’s reproductive life. Once regular menstruation is established, AUB-O becomes the leading cause of AUB.[11] In a particular study, anovulation was identified in 3.4% to 18.6% of menstruating women, depending on the diagnostic criteria used.[12] 

The condition is most prevalent in patients who fall into the following categories:

• Perimenarchal
• Perimenopausal
• Obese (a possible independent risk factor for anovulation)
• Of extremely low body mass index (individuals with anorexia or athletes with relative energy deficiency) [2][3][5][13][14]

Pathophysiology

The follicle is the primary functional unit of the ovary, which is responsible for germ cell development and steroid production. Follicular maturation reaches its peak at the midpoint of the ovulatory cycle. At this stage, elevated estrogen levels trigger a surge in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland, which leads to ovulation. After ovulation, follicular cells reorganize to form the corpus luteum, which produces the hormone progesterone and stabilizes the endometrium in preparation for implantation. In the absence of ovulation, the corpus luteum does not form, resulting in lower progestin levels. This leads to the persistence of proliferative endometrium, which becomes unstable and is prone to irregular, heavy shedding.

Additionally, the presence of high estrogen levels unopposed by progesterone is believed to contribute to increased vascular fragility and decreased vascular tone in the endometrium, resulting in an increased volume of blood loss. Abnormal prostaglandin synthesis and prostaglandin receptor upregulation, increased fibrinolytic activity locally, and an increase in the activity of tissue plasminogen activator have all been implicated as mechanisms of AUB-O.[11] The most common clinical features include heavy menstrual bleeding, irregular menses, and intermenstrual bleeding.[2][3][15]

History and Physical

A detailed history and physical examination can significantly narrow the differential diagnosis of AUB and guide the selection of appropriate testing and imaging for further evaluation. For adolescent patients, it is important to take the history both with the patient's parents present and again in their absence, as adolescent patients may be hesitant to discuss symptoms and sexual practices openly in front of a parent.

Irregular bleeding associated with AUB-O typically includes phases of amenorrhea lasting for months, along with periods of heavy bleeding or spotting. Typical premenstrual symptoms are generally absent. AUB-O should be suspected in women, particularly those at the extremes of reproductive age, who present with an irregular bleeding pattern.

Understanding what constitutes a normal menstrual cycle is essential. Typically, the interval between cycles ranges from 21 to 45 days, with bleeding lasting 7 days or less. Menstrual product use generally averages 3 to 6 pads or tampons per day.[16][17] A comprehensive patient history should include the below criteria.

Bleeding History

• Frequency, regularity, and duration of bleeding.
• Volume of blood loss: Studies have shown that patients' perceptions of blood loss during menstruation are often unreliable.[18][19] Menstrual volume is best assessed by asking questions such as:
  • Have you passed any blood clots?
  • How frequently do you change pads or tampons?
  • Are the products fully or partially saturated with each change?
  • Do you have to change sanitary protection overnight?
• Presence or absence of postcoital bleeding: The presence of postcoital bleeding is more suggestive of an extrauterine cause, such as cervical polyps.
• Bleeding with stools: This symptom suggests a gastrointestinal etiology, possibly confounding the perception of blood loss.

Associated Signs or Symptoms

• Fevers, chills, pelvic pain, vaginal discharge, bowel or bladder dysfunction may be present.
• Breast discomfort, premenstrual bloating or cramping, and increased vaginal discharge are typical of ovulatory bleeding.

Signs or Symptoms Associated With Known Causes of Ovulatory Dysfunction–Related Abnormal Uterine Bleeding

• Polycystic ovary syndrome: Obesity, male-pattern or rapidly worsening hirsutism, acne, and acanthosis nigricans.
• Thyroid dysfunction: Palpitations, tachycardia, hot or cold intolerance, fatigue, and weight gain.
• Hyperprolactinemia: Galactorrhea and spontaneous or expressed lactation on an examination.
• Coagulopathy: Positive family history, easy bruising, and petechiae.

Sexual History

• Date of last intercourse.
• Number of sexual partners.
• Use of contraception.
• History of sexually transmitted infection (STI) exposure.
• History of abnormal cervical cancer screening.

Medical History

• Current medications, including pills, powders, shakes, and supplements.
• Past medications.
• Surgical history.

Family History 

• Menstrual history of mother and siblings.
• Coagulopathies, such as von Willebrand disease and factor VIII deficiency.
• Hormone-sensitive cancers (such as breast or ovarian).[3][20][21][22][23]

Physical Examination

The physical examination for anovulatory bleeding is essential in identifying potential underlying causes and ruling out other etiologies of AUB. A thorough assessment includes the below criteria.

• Vital signs: Measurement of vital signs, including orthostatic blood pressure, especially if hypovolemia or anemia is suspected.
• General: Assessment of BMI and body composition.
• Head and neck: Examination for conjunctival or mucosal pallor and thyroid abnormalities.
• Abdomen: Inspection for tenderness, masses, or distension.
• Pelvic or perineal: Examination of the vulva, vaginal and speculum examination, Pap smear, and cervical cultures if there is a concern for an STI.
• Rectal examination: This is conducted if there is a concern for a rectal source of bleeding.[3][20][21]

Evaluation

The initial evaluation for AUB-O begins with a general assessment of AUB. If the history or physical examination suggests a specific pathology, targeted testing can be conducted promptly. At a minimum, all patients should undergo a blood or urine pregnancy test and a complete blood count (CBC). The CBC is essential, especially if the patient reports heavy menses, shortness of breath, lightheadedness, dizziness, fatigue, or pica, as these could indicate anemia or thrombocytopenia.[21] For patients with a recent pregnancy or miscarriage, a quantitative beta-human chorionic gonadotropin (β-hCG) level may be helpful in excluding trophoblastic disease.

Once pregnancy is ruled out and anemia is either excluded or diagnosed and treated, attention should shift to the patient's history, including family history, and physical examination to identify potential clues regarding the underlying cause of the bleeding. Appropriate testing based on specific aspects of the history includes the below conditions.

• Thyroid dysfunction: Serum thyroid-stimulating hormone.
• Prolactinemia: Serum prolactin.
• Polycystic ovary syndrome: 17-Hydroxyprogesterone, total and free testosterone, FSH, LH, and pelvic ultrasound.
• Coagulopathies: CBC, prothrombin time, partial thromboplastin time, von Willebrand factor antigen test, factor VIII levels, and platelet aggregation studies.

The treatment of patients with positive findings during workups should target the specific pathology. For patients with no concerning findings or positive tests, it is reasonable to initiate medical management.

Age-Based Considerations

• Menarche to age 18: The concern for endometrial hyperplasia is low in this age group. However, if anovulatory cycles persist for more than 2 years without an identified cause, an evaluation with an endometrial biopsy is recommended.
  • Approximately half of girls with bleeding disorders present with heavy menstrual bleeding. Screening for blood dyscrasias is appropriate in this age group.
  • Other pathologies that may cause platelet dysfunction and result in excessive bleeding should also be considered, including leukemia, idiopathic thrombocytopenic purpura, and hypersplenism.

• Age 19 to 39: Approximately 6% to 10% of women in this age group have hyperandrogenic chronic anovulation, such as in PCOS. Patients who do not respond to medical therapy should undergo an endometrial biopsy performed.

• Age 40 to menopause: Endometrial biopsy is warranted as first-line testing for women older than 45 or in cases with a concerning personal or family history.[3][20][22][24]

Acute Abnormal Uterine Bleeding

In cases of acute AUB, where there is a discrete episode of bleeding requiring immediate medical attention, the clinician should first stabilize the patient. After stabilization, an assessment should be performed using transvaginal ultrasonography to evaluate uterine pathology and sonohysterography to assess endometrial pathology.

Imaging

Imaging may be used as a first-line diagnostic tool if indicated by history or symptoms. Imaging can also be employed secondarily in patients who do not respond to medical management. The most common imaging modalities include hysteroscopy, transvaginal ultrasonography, magnetic resonance imaging, and saline infusion sonohysterography.[3]

Treatment / Management

The approach to treating AUB-O depends on identifying the underlying cause of anovulation and aligning management with the patient's therapeutic goals. Any underlying endocrine abnormalities should be addressed. While challenging, normalization of eating disorders or stress levels can be achieved. If medications are contributing to ovulatory dysfunction, the patient should be counseled on the purpose of the medication, the risks and benefits of alternative options, and strategies to mitigate the effects of the drug. The choice of management often depends on the patient's reproductive goals. Above all, patient safety is a priority, as ovulatory dysfunction can lead to endometrial hyperplasia or malignancy.

Medication management is the cornerstone of treatment for AUB-O. The medical treatment options include progestin-only therapy and combined hormonal contraception. Progestin therapy is available in several forms, including an intrauterine device (IUD), intramuscular injection, and oral progestin-only hormonal pill. Noncontraceptive progestins can be prescribed cyclically (7-10 days each month) to induce regular withdrawal bleeding. The levonorgestrel-releasing IUD is suitable for all age groups. Combined hormonal contraception is available as an oral pill, transdermal patch, or intravaginal ring. These options help protect the endometrium from hyperplasia or malignancy. Cyclic progestins or combined hormonal contraceptives may also improve bleeding regularity if desired.

If the patient desires fertility, contraceptives no longer align with the treatment goals. Brief courses of the aforementioned therapies may be considered until the patient is ready to actively attempt pregnancy. Correcting underlying disorders remains essential. For women with PCOS, weight loss has been shown to lower circulating androgens. A reduction in body weight by as little as 5% may lead to the spontaneous resumption of normal menses.[25] Pharmacological weight loss agents may also improve ovarian function in patients with PCOS.[25] These include orlistat, an inhibitor of intestinal lipid absorption, and sibutramine, an anorexic agent.

Ovulation induction with medications such as letrozole or clomiphene citrate may be an option for anovulatory patients seeking pregnancy.[26] Clomiphene citrate has traditionally been used as the first line for ovulation induction. Clomiphene citrate has traditionally been the first-line treatment for ovulation induction. Studies have shown a 6-month live birth rate of 20% to 40% with clomiphene, depending on the population.[25] Some patients may require higher doses of clomiphene to achieve ovulation.[27] However, recent studies suggest that letrozole may be more effective than clomiphene in patients with PCOS, showing a higher live birth rate (odds ratio 1.64) and clinical pregnancy rate (odds ratio 1.4).[28] Insulin-sensitizing agents, such as metformin, have also been used in women with PCOS. In obese patients, combining metformin with clomiphene may improve pregnancy rates compared to clomiphene alone.[29](A1)

Surgical management for AUB-O is indicated in cases of medication failure or when medications are contraindicated. Laparoscopic ovarian drilling is an option for patients with PCOS who desire fertility but have not responded to medications such as clomiphene citrate. However, there is no conclusive evidence that this procedure significantly improves clinical pregnancy rates, live birth rates, or miscarriage rates in these patients.[30] Additionally, concerns exist regarding the long-term effects of ovarian drilling on ovarian function. Conversely, some studies suggest that ovarian drilling may reduce the rate of multiple pregnancies.[30] For morbidly obese women with PCOS, gastric bypass surgery has been shown to normalize reproductive and metabolic abnormalities in many patients.[31](A1)

Due to the risk of hyperplasia and malignancy, endometrial tissue sampling, such as endometrial biopsy or dilation and curettage, should be performed as a first-line test in women with AUB who are aged 45 or older.[11] Sampling should also be considered for younger women with a history of unopposed estrogen exposure, those who have failed medical management, or those with persistent abnormal bleeding.[11] For patients who have completed childbearing, hysterectomy is the definitive treatment for abnormal bleeding and the treatment or prevention of endometrial hyperplasia.[3] Hysterectomy offers the advantage of being immediately effective and permanent.

Alternatively, endometrial ablation is a surgical procedure that can be beneficial for many patients with AUB. However, it is not recommended for patients with endometrial hyperplasia or malignancy.[32] Cases of patients developing endometrial cancer after an ablation procedure have also been reported, so caution is necessary when recommending this procedure to patients, such as those with AUB-O, who may already have an increased risk of developing an intrauterine malignancy.[33] 

In a study, 1-year treatment success (defined by a Pictorial Blood Assessment Chart score of ≤75) was observed in 88.3% of patients treated with radiofrequency endometrial ablation and 81.7% of those treated with resectoscopic endometrial resection.[34] The amenorrhea rates at 1 year were 41% for radiofrequency ablation and 35% for endometrial ablation with a resectoscope.[34] Regarding treatment failure, a study with a mean follow-up of 39 months found that 13.4% of women who underwent endometrial ablation later required a hysterectomy.[35](A1)

Differential Diagnosis

AUB-O is a diagnosis of exclusion. The differential diagnosis includes all potential causes of AUB. The International Federation of Gynecology and Obstetrics (FIGO) introduced the PALM-COEIN system in 2011 to categorize the common causes of AUB in nonpregnant women. The PALM group includes structural abnormalities that can be measured through imaging or histopathology and often require surgical intervention. The COEIN group represents nonstructural etiologies that generally receive medical management.[36] Extrauterine causes of vaginal bleeding include vaginitis, genital trauma, foreign body, vulvar neoplasia, and vaginal neoplasia.[3][5]

The PALM-COEIN system categorizes the causes of AUB as follows:

P for polyp; A for adenomyosis; L for leiomyoma; M for malignancy; C for coagulopathy; O for ovulatory dysfunction; E for endometrial; I for iatrogenic; and N for not yet classified.

Specific causes of ovulatory dysfunction that should be considered include:

• Pregnancy, including uncomplicated, threatened and incomplete miscarriage, and ectopic.
• Menarche, perimenopause, and premature ovarian failure.
• Lactation.
• Endocrinopathy, including thyroid dysfunction, hyperprolactinemia, and pituitary disorder.
• Medication use, particularly antipsychotics, antidepressants (tricyclic antidepressants and selective serotonin reuptake inhibitors), verapamil, and antiemetics.

Prognosis

The overall prognosis for patients with AUB-O is generally favorable. Symptoms can typically be managed medically, leading to significant improvements in patient quality of life.[20] Identification and management of AUB-O may help prevent complications such as hyperplasia or malignancy. Even in the worst-case scenario, the prognosis for endometrial cancer is relatively favorable compared to other gynecological malignancies.

Ovulation induction can also be highly successful in patients seeking fertility. A review found that letrozole achieved live birth rates of 27.5%, whereas clomiphene citrate resulted in live birth rates of 19.1%.[37]

Complications

The most common complications of anovulation include infertility and irregular menses. Irregular menses can improve with hormonal contraception; however, if fertility is a goal, ovulatory induction agents such as clomiphene or letrozole may be appropriate. Depending on the primary clinician's comfort level, referral to an obstetrician-gynecologist or reproductive endocrinologist may be necessary. Chronic anovulation and unopposed estrogen can lead to endometrial hyperplasia and malignancy. Patients with AUB-O should be counseled about this severe complication of irregular menses when discussing treatment options.

The most common complication of irregular heavy menses is iron-deficiency anemia, which can be treated with oral or intravenous iron therapy. For patients with symptomatic anemia who are taking oral contraceptives, clinicians may recommend skipping the placebo week to prevent menstrual blood loss.

Sheehan syndrome (pituitary infarction) is a potential complication of endometrial ablation. Patients should receive educational counseling about this risk before being offered the treatment.[3]