Anovulatory Uterine Bleeding – Introduction
- Anovulation is a spectrum of disorders most commonly associated with a bleeding pattern that is noncyclic, irregular, and inconsistent in volume due to a disruption of ovulatory dysfunction.
Synonyms
- Oligo-ovulation
- Anovulation
- Oligomenorrhea
- Abnormal uterine bleeding associated with ovulatory dysfunction (AUB-O)
ICD-10 CM CODES | |
N92 | Excessive, frequent, and irregular menstruation |
N93 | Abnormal uterine and vaginal bleeding |
N94 | Pain and other conditions associated with female genital organs and menstrual cycle |
N95 | Menopausal and other perimenopausal disorders |
N97 | Female infertility associated with anovulation |
EPIDEMIOLOGY AND DEMOGRAPHICS
Prevalence
- Estimated 53/1000 reproductive-age women in the U.S., estimated 3% to 30% reproductive-age women internationally 1
Predominant Age
- •Puberty: Immature hypothalamic-pituitary-ovarian (HPO) axis results in inadequate hormonal feedback to achieve regular ovulation and a stable endometrium. Anovulation is common, especially for the first 2 to 3 yr after menarche.
- •Perimenopausal: Diminishing ovarian reserve can result in abnormal follicular recruitment and anovulatory cycles.
- •Pregnancy/lactation.
RISK FACTORS
- •Any disruptions in the HPO axis as described below
- •Extremes of weight
PHYSICAL FINDINGS AND CLINICAL PRESENTATION
- •Underweight (e.g., low body mass index [BMI]), anorexia, or female athlete triad could indicate hypogonadotropic hypogonadism.
- •Hyperandrogenic symptoms including excessive or male-type hair patterns and/or acne could indicate polycystic ovary syndrome (PCOS), nonclassical congenital adrenal hyperplasia, Cushing syndrome, or androgen-secreting tumor.
- •Obesity may result in excessive estrogen production.
- •Women with anovulatory uterine bleeding may not present with classic premenstrual signs including breast tenderness, vaginal discharge, cramping, or bloating.
- •The average menstrual cycle lasts between 21 and 35 days. These patients are likely to have different lengths of cycle or increased variability between cycles.
ETIOLOGY
- Anovulatory uterine bleeding arises from a breakdown in the relationship between the HPO axis and the endometrium.
- An understanding of the menstrual cycle is crucial to recognizing causes of anovulatory bleeding. In the normal menstrual cycle, during the follicular phase, the endometrium is exposed to increasing levels of estrogen as the dominant follicle grows; thus this is termed the proliferative phase of the endometrium.
- Near the end of the follicular phase, estradiol levels increase dramatically, and the endometrium reaches its greatest thickness around approximately 12 mm.
- Rising estrogen levels trigger the luteinizing hormone (LH) surge and subsequent ovulation.
- The endometrium then enters its secretory or luteal phase. The remaining follicular cells differentiate into the corpus luteum. If pregnancy fails to occur, the corpus luteum regresses and progesterone secretion diminishes substantially.
- With this progesterone withdrawal, the spiral arteries constrict and the endometrial functionalis layer sloughs, resulting in menstruation. 2
Abnormalities in the HPO axis:
- •Hypogonadotropic hypogonadism
- 1.Genetic defects include Kallmann syndrome or inherited idiopathic deficiencies
- 2.Functional etiologies include eating disorders, high levels of exercise or stress
- 3.Neoplasm and inflammatory disorders of hypothalamic-pituitary axis
- •Hypergonadotropic hypogonadism
- 1.Turner syndrome
- 2.Prior chemotherapy
- 3.Pure gonadal dysgenesis
- 4.Autoimmune oophoritis
- •Hyperprolactinemia
- 1.Iatrogenic induced (e.g., antipsychotic medications that inhibit dopamine; MAO-I)
- 2.Prolactinoma
- 3.Malignancy, infiltrative disease, radiation
- 4.Hypothyroidism resulting in elevated prolactin levels
- •Polycystic ovarian syndrome
- 1.Without ovulation, there is a paucity of progesterone resulting in the absence of the progesterone withdrawal bleed and triggering of normal endometrial sloughing and menstruation.
- 2.This process also results in unopposed estrogen exposure, resulting in a proliferative endometrium that can have unpredictable episodes of breakdown and shedding.
DIFFERENTIAL DIAGNOSIS
- •Pregnancy
- •Thyroid dysfunction
- •Hyperandrogenic disorders (PCOS, congenital adrenal hyperplasia, Cushing syndrome, androgen-producing tumors)
- •Hyperprolactinemia
- •Premature ovarian insufficiency
- •Anorexia
- •Excessive exercise
- •Stress
- •Medications
WORKUP
Laboratory evaluation and imaging studies
LABORATORY TESTING
- •Human chorionic gonadotrophin
- •Thyroid-stimulating hormone
- •Prolactin
- •Testosterone
- •17-hydroxyprogesterone
- •Follicle-stimulating hormone
- •Estradiol
- •Luteinizing hormone
IMAGING STUDIES
- •Pelvic ultrasound if suspect PCOS or ovarian tumor
- •Brain MRI if elevated prolactin levels or hypothalamic amenorrhea without known cause
- •Computed tomography scan of abdomen if suspect adrenal tumor
TREATMENT
NONPHARMACOLOGIC THERAPY
- •If obese—weight loss and increased exercise
- •If low BMI and/or excessive exercise—improved nutrition and decrease intensity of exercise
GENERAL Treatment
- •If not pregnant, can induce withdrawal bleed with 5 to 10 mg of medroxyprogesterone for 7 to 10 days.
- •Treatment is focused on cause of anovulation ( Box E1 ).
- 1.Thyroid dysfunction: Thyroid replacement or treatment of hyperthyroidism
- 2.Hyperprolactinemia: Dopamine agonist such as cabergoline or bromocriptine or discontinue medication causing hyperprolactinemia
- 3.PCOS: Cycle regulation with combined oral contraceptive or progestin-only hormonal treatment (Note: Combined oral contraceptive is more effective in decreasing androgen levels due to estradiol increasing production of sex-hormone binding globulin, which binds to free androgens. Both combined and progestin-only contraceptives are helpful for endometrial protection. Metformin improves insulin sensitivity, induces ovulation, and reduces androgen levels.)
- 4.Hypothalamic dysfunction: Improved nutrition, treatment of eating disorders, decreased exercise, estrogen replacement
- 5.Premature ovarian insufficiency: Estrogen replacement
- •Ovulation induction for fertility treatment 3 :
- 1.Hypogonadotropic hypogonadism: Injectable gonadotropins are typically necessary to induce ovulation.
- 2.PCOS: Aromatase inhibitor such as letrozole or selective estrogen receptor modulator such as clomiphene citrate. Metformin is also used for ovulation induction but is less effective than clomiphene or letrozole. 4
- 3.Nonclassical congenital adrenal hyperplasia: Glucocorticoids and clomiphene citrate or letrozole.
- 4.Premature ovarian insufficiency: Less than 5% chance over lifetime for unassisted conception. Most patients will require donor oocyte or embryo.
BOX E1
Causes of Anovulation 5
Physiologic
- •Adolescence
- •Perimenopause
- •Lactation
- •Pregnancy
Pathologic
- •Hyperandrogenic anovulation (e.g., polycystic ovary syndrome, congenital adrenal hyperplasia, or androgen-producing tumors)
- •Hypothalamic dysfunction (e.g., anorexia nervosa, excessive exercise)
- •Hyperprolactinemia
- •Thyroid disease
- •Primary pituitary disease
- •Premature ovarian failure
- •Iatrogenic (e.g., secondary to radiation or chemotherapy)
- •Medications
PEARLS AND CONSIDERATIONS
COMMENTS
- •Polycystic ovarian syndrome is the most common cause of anovulation in women, approximately 6% to 10%.
- •In patients with PCOS, metabolic complications such as impaired glucose tolerance, obesity, metabolic syndrome, hypertension, hyperlipidemia, cardiovascular disease, and nonalcoholic fatty liver disease are common and patients should be screened for these. Additionally, unopposed estrogen levels due to anovulation lead to endometrial hyperplasia/carcinoma; thus cycle regulation with either hormonal contraceptive or regular progestin withdrawal is essential for endometrial protection.
- •In patients with hypothalamic dysfunction or premature ovarian insufficiency requiring estrogen replacement, either cyclic or continuous progestin is required for endometrial protection if uterus is present.
PATIENT AND FAMILY EDUCATION
- •Nutrition and optimal weight should be discussed.
- •In patients with hypothalamic cause, bone protection should be emphasized due to low estrogen.
- •In patients with PCOS, counsel regarding risks of metabolic syndrome and endometrial hyperplasia/cancer.
- •Future fertility options should be discussed with all patients.
References
1.Jones K, Sung S: Anovulatory bleeding. In StatPearls, Treasure Island, FL, 2022, StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK549773/ .
2.Corton M., et al.: Williams gynecology . ed 4 2020 . McGraw-Hill Education , New York
3.Davis E, Sparzak PB: Abnormal uterine bleeding. In StatPearls, Treasure Island, FL, 2022, StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK532913/ .
4.Strauss J., Barbieri R.: Female infertility . Yen and Jaffe’s reproductive endocrinology . 2019. Elsevier , Philadelphia, PA
5.Practice bulletin no. 136: management of abnormal uterine bleeding associated with ovulatory dysfunction . Obstet Gynecol 2013; 122: pp. 176-185.