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Women’s Health - Menstrual and Bleeding Disorders - Fast Facts | NEJM Resident 360

Fibroids

Fibroids (uterine leiomyomas) are common benign tumors of the uterus, made of smooth muscle cells and fibroblasts.

• Risk factors include a family history of fibroids, early menarche, black or Asian race, and obesity.

• Timing: Fibroids are controlled by estrogen and progesterone. Therefore, they are almost never seen prior to menarche and typically regress with improvement of symptoms after menopause.

• • Submucosal and intramural fibroids are more likely to decrease pregnancy rates, although evidence is inconclusive.

• Clinical presentation: Fibroids vary in size and clinical presentation, with many being asymptomatic. Clinical presentation can include heavy menstrual bleeding, pelvic pain, and infertility.

• Diagnosis: Fibroids can be suspected clinically and on physical exam with confirmation by ultrasound; occasionally MRI is needed to further characterize inconclusive lesions.

• **Referral:**Red flag symptoms that should prompt specialty referral include:

• • intermenstrual or postcoital bleeding

  • sudden onset of pain

  • increase in fibroid size in postmenopausal women

Treatment

Symptomatic patients may desire treatment. Treatment options depend on the number, size, and location of fibroids; desired outcome; and desire for preservation of fertility. The evidence comparing these options is relatively limited. Treatment options include:

• medical therapy:

• to reduce active symptoms (bleeding and cramping): levonorgestrel intrauterine device, subdermal implant, or other hormonal contraceptives; in addition to reducing bleeding and fibroid size, the progesterone receptor modulator ulipristal acetate also improved quality-of-life measures in a pooled analysis.

• to decrease fibroid size: ulipristal acetate, gonadotropin-releasing hormone agonists

• surgery: hysterectomy, myomectomy

• Preoperative medical therapy with gonadotropin-releasing hormone agonists or ulipristal acetate before surgery for fibroids has been found to improve surgical outcomes.

• interventional therapies: uterine artery embolization

Algorithm for the Management of Symptomatic Uterine Fibroids

Menstrual and Bleeding Disorders

Common menstrual and bleeding abnormalities include the following:

• menorrhagia: excessively heavy flow

• metrorrhagia: uterine bleeding at irregular intervals

• oligomenorrhea: infrequent menstrual periods

• amenorrhea: absence of a menstrual period

Menorrhagia and Abnormal Uterine Bleeding in Premenopausal Women

• The PALM-COEIN classification system: Etiologies of abnormal uterine bleeding can be summarized with the acronym PALM-COEIN, divided into structural causes and nonstructural causes. Remember that, along with pregnancy, infections like chlamydia can also cause bleeding.

The PALM-COEIN Classification System for Abnormal Uterine Bleeding

• Clinical classification of uterine bleeding: This alternative classification categorizes uterine bleeding clinically as ovulatory and anovulatory bleeding:

  • normal menses with longer cycles (causing increased estrogen exposure)

  • coagulopathy

  • structural causes (fibroids, malignancy)

  • thyroid disease

  • endometriosis

• • Ovulatory bleeding: Differential diagnosis includes:

    • normal menses with longer cycles (causing increased estrogen exposure)

    • coagulopathy

    • structural causes (fibroids, malignancy)

    • thyroid disease

    • endometriosis

Evaluation and Management of Abnormal Uterine Bleeding

*The likelihood of a bleeding disorder increases if any of the following historical clues are present: heavy menstrual bleeding since menarche; history of postpartum hemorrhage, surgical bleeding, or bleeding with dental procedures; or two or more of the following: frequent gum bleeding, bruising > 5 cm at least monthly, epistaxis at least monthly, or family history of abnormal bleeding.
†—Risk factors include a history of exposure to unopposed estrogen, failed medical management, and persistent bleeding.
‡—Initial screening tests may be normal in the setting of some coagulopathies, with diagnosis requiring further testing and possibly hematology consultation.
(Source: Abnormal Uterine Bleeding in Premenopausal Women. Am Fam Physician 2019.)

• Anovulatory bleeding: Differential diagnosis is the same for oligo/amenorrhea, including pregnancy, thyroid disease, premature ovarian failure, perimenopause, and use of hormonal contraception.

  • Up to 13% of women with heavy menstrual bleeding have some variant of von Willebrand’s syndrome, and up to 20% have underlying coagulation disorder. Initial workup includes a thorough history, including heavy bleeding since menarche, postpartum hemorrhage, surgery-related bleeding, bleeding with dental work, easy bruising, and epistaxis.

  • All women older than 45, or women younger than 45 with history of obesity or unopposed estrogen exposure with abnormal uterine bleeding, should be referred for endometrial tissue sampling.

  • Treatment depends on the etiology of the bleeding.

  • For acute bleeding, only one treatment (IV conjugated estrogen) is approved by the FDA.

  • For chronic treatment for menorrhagia, medical options include combined hormonal contraceptive (pill, patch, or ring), oral or injectable (subcutaneous or intramuscular) progestins, a subdermal implant or levonorgestrel IUD, and/or tranexamic acid.

  • See the ACOG guidelines for additional information on treatment options.

Algorithm for Evaluation and Treatment of Anovulatory Bleeding

Postmenopausal Bleeding

Any woman with vaginal bleeding after menopause requires evaluation to exclude malignancy. All women should be referred to an OB/GYN or clinician capable of performing endometrial biopsy.

ACOG recommendations for postmenopausal bleeding are as follows:

• Perform initial assessment with endometrial biopsy or transvaginal ultrasonography.

• Endometrial sampling is not recommended for endometrial thickness ≤4 mm.

• Further evaluation is required for endometrial thickness ≥4 mm.

Secondary Amenorrhea

• Secondary amenorrhea is defined as the cessation of regular menses for 3 months or of irregular menses for 6 months.

• Pregnancy is the most common cause of secondary amenorrhea and should be excluded in all cases. Polycystic ovary syndrome and hypothalamic amenorrhea are other common causes to be considered. Workup may include serum levels of luteinizing hormone, FSH, prolactin, and TSH.

Diagnosis of Secondary Amenorrhea

*Abbreviations: DHEA-S = dehydroepiandrosterone sulfate; FSH = follicle-stimulating hormone; LH = luteinizing hormone; MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone.
—May be repeated in one month if needed to clarify diagnosis
(Source: Amenorrhea: A Systematic Approach to Diagnosis and Management. Am Fam Physician 2019.)

Endometriosis

• Endometriosis is the presence of endometrial-like tissue outside the uterus. Endometrial implants appear almost anywhere, although they are primarily found in the peritoneum, on the ovaries, and occasionally on and above the diaphragm.

• The exact mechanisms underlying the development of endometriosis remain unclear but are likely to involve a number of processes.

• Common clinical presentation includes pelvic pain, dyspareunia, bladder and bowel symptoms, dysmenorrhea, and infertility.

• The diagnosis and staging of endometriosis are best achieved with laparoscopic visualization and biopsy with histological confirmation. Transvaginal ultrasound and MRI can both detect ovarian endometriomas but are less sensitive at finding peritoneal or ovarian implants.

Treatment:

• First-line treatment for endometriosis is traditionally medical management; oral contraceptive pill hormonal therapy is widely used.

• Second-line treatments include systemic estrogen suppression with gonadotrophin-releasing hormone (GnRH) agonists; however, the hypoestrogenic adverse effects of bone loss made these less desirable.

• Elagolix, a GnRH antagonist, has been approved for treatment of endometriosis; studies have associated it with reduced dysmenorrhea and nonmenstrual-related pelvic pain in women with endometriosis-associated pain.

• Ovarian suppression with lactation has recently been found to decrease the risk of incident endometriosis

The following tables describe medical and surgical treatment options for endometriosis:

Currently Available Hormonal Therapies for Endometriosis

Type of Hormonal Medication	Application	Possible Adverse Effects*
Short-acting progestins	Daily oral pill	Changes in bleeding pattern, skin changes, bloating, nausea, changes in appetite, mood disturbances, breast tenderness, headaches
Delayed-release progestins	Subcutaneous implant, intramuscular injection, intrauterine contraceptive device	Changes in bleeding pattern, skin changes, bloating, mood disturbances, weight gain, headaches, loss of bone density†
Progestin-only oral contraceptive pill	Daily oral pill	Changes in bleeding pattern, skin changes, bloating, changes in appetite, mood disturbances, headaches, breast tenderness
Combined oral contraceptives	Daily oral pill for 28 days with 4- to 7-day break or continuous daily intake	Changes in bleeding pattern‡, skin changes, bloating, mood disturbances, migraines, thromboembolic events, stroke
Gonadotropin-releasing hormone agonists§	Monthly or trimonthly subcutaneous injection	Menopausal symptoms, bone loss, headaches, mood change
Gonadotropin-releasing hormone antagonist§	Daily oral pill	Menopausal symptoms, bone loss, headaches, mood change
Aromatase inhibitors§	Daily oral pill	Development of ovarian cysts, multiple pregnancy, menopausal symptoms, bone loss

*Not an inclusive list

†Medroxyprogesterone acetate injections
‡Breakthrough bleeding with continuous use
§Longterm use combined with hormone replacement therapy
(Reference: Endometriosis. N Engl J Med 2020.)

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