Abnormal Uterine Bleeding

Educational Objectives

The goal of this program is to improve management of abnormal uterine bleeding (AUB). After hearing and assimilating this program, the clinician will be better able to:

1. Predict causes of AUB in reproductive-aged women.
2. Perform an appropriate workup for women with AUB.
3. Weigh risks and benefits of various therapies for AUB.
4. Counsel patients about treatment options for fibroids.
5. Select appropriate management of AUB for perimenopausal patients and patients with polycystic ovary syndrome.

Summary

Introduction: abnormal uterine bleeding (AUB) affects ≈10 million women in United States; more common in obese women and women with polycystic ovary syndrome (PCOS); associated with iron-deficiency anemia and fatigue; affects quality of life; in postmenopausal patients with AUB, cancer usually suspected until proven otherwise; in premenarchal patients with AUB, consider precocious puberty or abuse

Normal uterine bleeding: average menstrual flow 30 to 40 mL in 28 days; when menstrual bleeding is outside normal range, consider anovulation (common etiology); correlation between perceived amount of blood loss and actual amount of blood loss poor; quantify blood loss by frequency of changing pads or tampons (eg, patients who completely soak pad or tampon in <1 hr considered to have heavy bleeding)

Classification of AUB: heavy menstrual bleeding; intermenstrual bleeding (bleeding in between menstrual periods); classified by PALM-COEIN system based on whether cause of AUB anatomic (eg, fibroids) or hormonal (eg, ovulatory dysfunction)

Pathophysiology: patients with normal function of hypothalamic-pituitary-ovarian (HPO) axis should have regular menstrual cycles (ie, patients are ovulatory); patients with irregular menstrual cycles are anovulatory; menarchal patients — ≈25% of patients who have AUB within 1 yr of menarche have some underlying bleeding diathesis (eg, von Willebrand disease); bleeding usually related to immature HPO axis (ie, anovulation with regular estrogen exposure and irregular progesterone exposure); endogenous estrogen exposure in postmenopausal obese women — patients may report episodes of spotting; biopsy may show weakly proliferative endometrium with no signs of cancer; ultrasonography may be normal with absence of polyps; bleeding caused by endogenous estrogen exposure due to estrogen production by fatty tissue; management includes cyclic progesterone therapy

Workup of AUB: patient history — history of monthly menstrual cycles; pregnancy; testing — Papanicolaou testing to rule out cervical cancer and dysplasia; endometrial biopsy if indicated; imaging studies — vaginal probe ultrasonography; laboratory studies — complete blood cell count; thyroid function testing; prolactin level; pregnancy testing; candidates for biopsy — American College of Obstetricians and Gynecologists recommends biopsy for women >45 yr of age with AUB, regardless of risk factors, and for women <45 yr of age with AUB and positive history of unopposed estrogen (eg, obese patients, patients with PCOS); also recommended for patients unresponsive to medical management and those with persistent bleeding or postmenopausal bleeding; vaginal ultrasonography in postmenopausal bleeding — reasonable for women with endometrial thickness <4 mm; consider risk factors and bleeding history (eg, reasonable to perform ultrasonography instead of biopsy in patient with spotting for only 2 days and thin endometrial lining)

Heavy menstrual bleeding: regular cycles — patients usually ovulatory; consider anatomic cause (eg, fibroids, polyps); endometrial source of AUB — classified as AUB-E on PALM-COEIN system; heavy AUB caused by prostaglandin imbalance in endometrium; consider in patients with anatomically normal uterus and regular heavy menses; treatment includes medications that address prostaglandin synthesis and clotting; irregular cycles — patients usually anovulatory or oligo-ovulatory; consider hormonal problem (eg, PCOS, obesity); AUB caused by endogenous hormonal signal that shuts down HPO axis; AUB tends to occur in recently menarchal patients and perimenopausal patients, and in patients with hypothyroidism or hyperprolactinemia

Common causes and presentations: perimenopause — woman, 48 yr of age, reports that over past 2 yr, menstrual cycles have become irregular (occurring every 24-26 days, or twice monthly) and unpredictable; symptoms include hot flashes, night sweats, irritability, and mood changes; physical examination and test findings normal; von Willebrand disease — girl, 14 yr of age, with recent menarche presents with irregular menstrual cycles (every 24-45 days); menses lasts 10 to 14 days; symptoms include cramping, bloating, fatigue, and frequent nosebleeds; mother had same condition; fibroids — woman, 42 yr of age, presents with regular heavy menstrual bleeding; older family members have undergone hysterectomy; findings on physical examination include palpable mass 3 to 4 cm below umbilicus; PCOS — woman, 30 yr of age, presents with long-standing history of irregular cycles and persistent bleeding for 3 wk; woman has central obesity (body mass index 40), acne, and terminal hair growth

Medical management: iron transfusion — particularly for patients who do not tolerate oral iron; tranexamic acid (Lysteda) — useful for management of prostaglandin imbalance in endometrium; associated with low compliance because of dosing regimen (must be taken 3 times daily) and high cost; tranexamic acid is plasminogen inhibitor (prevents breakdown of clots in endometrium); European data show no increased risk for deep venous thrombosis (DVT) or pulmonary embolism (PE); contraindicated in patients with DVT or PE; scheduled nonsteroidal anti-inflammatory drugs (NSAIDs) — used for menstrual cramps and endometrial prostaglandin imbalance; in ovulatory patients, starting NSAID 1 day before menses and continuing treatment through cycle can decrease blood loss

Oral progestins: used to control active bleeding or manage ongoing bleeding; anovulatory patients — most effective in patients with, eg, period every 6 to 12 mo; regular monthly withdrawal bleeding prevents heavy prolonged bleeding and protects endometrium from hyperplasia or cancer; oligo-ovulatory patients — may be used for monthly withdrawal bleeding; may be used continuously; norethindrone (eg, Aygestin, Camila, Ortho Micronor) more likely to inhibit HPO axis than medroxyprogesterone (Provera); norethindrone 2.5 mg/day or 5 mg/day inhibits ovulation in ≈50% of patients; ovulatory patients with regular cycles — continuous use of progestins may not be effective

Medroxyprogesterone injection (Depo-Provera, depo-subQ provera 104): highly effective for inhibiting HPO axis; can be used to treat pain in patients with endometriosis; initially causes heavy bleeding, but most patients become amenorrhoeic after 3 injections; long-term risks and side effects include changes in bone mineral density and mood, and weight gain

Levonorgestrel-releasing intrauterine system (eg, Liletta, Mirena, Skyla): delivers high dose of progestin directly to uterus; efficacy comparable to or higher than that of hysterectomy, ablation, high-dose progestins, or oral contraceptive pills (OCPs); particularly effective for perimenopausal patients

Oral contraceptive pills: contraindications include DVT and PE

Case presentation: patient history — woman, 40 yr of age, presents with heavy menstrual bleeding; patient not on contraception; positive history of hypertension and peptic ulcer disease; current tobacco smoker; clinical findings — vital signs, blood pressure (BP), and endometrial biopsy normal; management — levonorgestrel-releasing intrauterine system good option; OCPs not best choice because of risks associated with tobacco smoking and age ≥40 yr; cyclic perimenstrual NSAIDs not best long-term choice for smokers or patients with peptic ulcer disease who need contraception; medroxyprogesterone injections increase risk for changes in bone mineral density; norethindrone not highly contraceptive

Management options for perimenopausal patients: OCPs — average age of menopause 51 yr of age (OCPs can be continued until 52-53 yr of age); discontinuing OCP can increase follicle-stimulating hormone level (important to look for symptoms and absence of menses to determine whether patient in menopause); levonorgestrel-releasing intrauterine system — can be placed for 5 yr; use add-back estrogen therapy; daily oral progestin — norethindrone (2.5 or 5 mg/day) reasonable for patients with no symptoms of estrogen deficiency (patients become anovulatory and amenorrhoeic 50% of time); patients can be transitioned to menopause with hormone therapy (eg, estradiol and norethindrone [Activella, Mimvey]); if patient becomes amenorrhoeic on norethindrone and develops hot flashes, then adding estradiol (1 mg/day) helpful; less favorable choices — direct use of hormone therapy causes irregular bleeding; etonogestrel implant (Nexplanon) primarily indicated for contraception; etonogestrel implant and medroxyprogesterone injection associated with bone mineral density changes, and do not provide estrogen

Options for adolescents with von Willebrand disease and immature HPO axis: OCPs standard treatment; no strong data that OCPs cause harm in patients with immature HPO axis; progestin intrauterine device reasonable; tranexamic acid useful for patients who do not respond well to OCPs, and is more effective in patients with regular cycles; long-term use of medroxyprogesterone injection challenging; 40% of patients with etonogestrel implant develop abnormal bleeding

Options for patient with fibroid uterus: refer to gynecologist if patient considering hysterectomy; leuprolide (eg, Eligard, Lupron, Viadur) — gonadotropin-releasing hormone (GnRH) agonist; highly effective at inducing menopause; after 6 mo of use, must be stopped or add-back hormone therapy added to prevent bone loss; medroxyprogesterone injection — effective at suppressing HPO axis, but initially causes irregular bleeding; elagolix (Orilissa) — oral GnRH antagonist; used once or twice daily; used for treatment of pain and dyspareunia associated with endometriosis; no data about use in patients with fibroids; requires prior authorization and at least 3 mo of alternative therapy with no improvement; costs $1000 for 3 mo of therapy, compared with $1700 for 3-mo injection of leuprolide; uterine artery embolization — highly effective; does not maintain fertility; newer ablative options include magnetic resonance imaging (MRI)-guided ultrasonography and laparoscopy-guided cryoablation of fibroids

Options for patient with PCOS: weight loss — multiple studies have shown that ovulation resumes in >50% of patients who lose 10% of body weight (regardless of initial weight); OCPs — regulate cycle and affect liver synthesis of sex hormone-binding globulin; results in greater binding of androgens; useful for treating acne and hirsutism; other therapies — levonorgestrel-releasing intrauterine system, medroxyprogesterone injection, and oral progestins address bleeding, but not hirsutism or acne; patients who are trying to become pregnant likely need induction of ovulation; NSAIDs, tranexamic acid, and etonogestrel implant not good options for anovulatory patients

Management of heavy menstrual bleeding: high-dose estrogen — no data show that intravenous (IV) conjugated estrogens (Premarin) are more effective than oral estrogen; OCPs — eg, medroxyprogesterone (20 mg) 3 times/day for 1 wk; progestin — consider in patients who do not tolerate OCPs; start with, eg, norethindrone (5-10 mg twice daily) until bleeding slows or stops, then reduce dosage to once daily for 3 to 4 wk, then stop therapy; inform patient that withdrawal bleeding occurs when therapy stopped

Selection of OCP: avoid ultra-low-dose pill; 20-μg OCPs may be insufficient for inhibiting HPO axis or stabilizing lining; choose 30- to 35-μg OCP with first-generation progestin; first-generation progestins more androgen-dominant and tend to inhibit endometrium more effectively; ethinyl estradiol — levonorgestrel (eg, Amethyst, Orsythia, Nordette) useful; for PCOS — OCPs with fourth-generation progestins (eg, drospirenone–ethinyl estradiol [eg, Gianvi, Loryna, Yasmin], ethinyl estradiol–norgestimate [eg, Estarylla, Mononessa, Ortho Tri-Cyclen]) have stronger effect on liver synthesis of sex hormone-binding globulin, and are more effective for reducing androgen and effects (acne, hirsutism); associated with slightly higher risk for DVT and PE (2 in 10,000, compared with 1 in 10,000 with other OCPs)

Questions and answers: weight gain with levonorgestrel-releasing intrauterine system — not commonly seen in clinical practice; circulating level of progestin low (≈50 picograms/day); gastrointestinal (GI) side effects of using OCPs 3 times/day — nausea (consider prescribing ondansetron [eg, Zofran, Zuplenz]); side effects of oral progestins — bloating; mood changes; management of breakthrough bleeding in patients with levonorgestrel-releasing intrauterine system — important to counsel and educate patients about expected bleeding; start daily use of oral norethindrone 3 wk before placement of intrauterine system; most bleeding during first 3 to 6 mo occurs because of progesterone withdrawal; consider oral progestins or temporary use of OCPs; patients who develop bleeding 3 to 4 yr after placement of intrauterine system because of atrophy of lining may benefit from estrogen therapy (eg, 1 mg of estradiol for 1-2 mo)

Readings

Ashraf MN et al: Clinical efficacy of levonorgestrel and norethisterone for the treatment of chronic abnormal uterine bleeding. J Pak Med Assoc. 2017 Sep;67(9):1331-1338; Bacon JL: Abnormal uterine bleeding: current classification and clinical management. Obstet Gynecol Clin North Am. 2017 Jun;44(2):179-193; Bradley LD, Gueye NA: The medical management of abnormal uterine bleeding in reproductive-aged women. Am J Obstet Gynecol. 2016 Jan;214(1):31-44; Deligeoroglou E et al: Dysfunctional uterine bleeding as an early sign of polycystic ovary syndrome during adolescence: an update. Minerva Ginecol. 2017 Feb;69(1):68-74; Laberge P et al: Endometrial ablation in the management of abnormal uterine bleeding. J Obstet Gynaecol Can. 2015 Apr;37(4):362-79; Mullins TL et al: Evaluation and management of adolescents with abnormal uterine bleeding. Pediatr Ann. 2015 Sep;44(9):e218-22; Pinkerton JV: Pharmacological therapy for abnormal uterine bleeding. Menopause. 2011 Apr;18(4):453-61; Sarkar P et al: Optimal order of successive office hysteroscopy and endometrial biopsy for the evaluation of abnormal uterine bleeding: a randomized controlled trial. Obstet Gynecol. 2017 Sep;130(3):565-572; Sweet MG et al: Evaluation and management of abnormal uterine bleeding in premenopausal women. Am Fam Physician. 2012 Jan 1;85(1):35-43.

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Fothergill spoke in Austin, TX, at Family Medicine Review, presented April 24-27, 2019, by Baylor Scott & White Health. For more information about this sponsor, please visit www.bswhealth.med/cme. The Audio-Digest Foundation thanks Dr. Fothergill and Baylor Scott & White Health for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

FP680301

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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