Dysfunctional uterine bleeding 

• A normal menstrual cycle has a frequency of 24 to 38 days and lasts 2 to 7, with 5 to 80 milliliters of blood loss. 
• Variations in any of these 4 parameters constitute abnormal uterine bleeding
• Definitions

Term	Abnormal uterine bleeding pattern
Oligomenorrhea	Bleeding occurs at intervals of > 35 days and usually is caused by a prolonged follicular phase.
Polymenorrhea	Bleeding occurs at intervals of < 21 days and may be caused by a lutealphase defect.
Menorrhagia	Bleeding occurs at normal intervals (21 to 35 days) but with heavy flow (80 mL) or duration (7 days).
Menometrorrhagia	Bleeding occurs at irregular, noncyclic intervals and with heavy flow (80 mL) or duration (7 days).
Amenorrhea	Bleeding is absent for 6 months or more in a nonmenopausal woman.
Metrorrhagia or bleeding intermenstrual	Irregular bleeding occurs between ovulatory cycles; causes to consider include cervical disease, intrauterine device, endometritis, polyps, submucous myomas, endometrial hyperplasia, and cancer.
Midcycle spotting	Spotting occurs just before ovulation, usually because of a decline in the estrogen level.
Postmenopausal bleeding	Bleeding recurs in a menopausal woman at least 1 year after cessation of cycles.
Acute emergent abnormal uterine bleeding	Bleeding is characterized by significant blood loss that results in hypovolemia (hypotension or tachycardia) or shock.
Dysfunctional uterine bleeding	This ovulatory or anovulatory bleeding is diagnosed after the exclusion of pregnancy or pregnancy-related disorders, medications, iatrogenic causes, obvious genital tract pathology, and systemic conditions.

• The differential diagnosis for genital tract bleeding based on anatomic location or system:
  • infections
    • Cervicitis
    • Endometritis
    • Myometritis
    • salpingitis 
  • Benign anatomic abnormalities:
    • Adenomyosis
    • Leiomyomata
    • polyps of the cervix or endometrium
  • Premalignant lesions:
    • cervical dysplasia
    • endometrial hyperplasia
  • Malignant lesions:
    • cervical squamous cell carcinoma
    • endometrial adenocarcinoma
    • estrogen-producing ovarian tumors
    • testosterone-producing ovarian tumors
    • leiomyosarcoma
  • Trauma:
    • foreign body
    • abrasions
    • lacerations
    • sexual abuse or assault
  • Gastrointestinal tract:
    • Inflammatory bowel disease
    • Behçet syndrome
  • Pregnancy complications:
    • Spontaneous abortion
    • ectopic pregnancy
    • placenta previa
  • Medications and iatrogenic causes
    • Anticoagulants
    • Antipsychotics
    • Corticosteroids
    • Herbal and other supplements: ginseng, ginkgo, soy
    • Hormone replacement
    • Intrauterine devices
    • Oral contraceptive pills, including progestin-only pills
    • Selective serotonin reuptake inhibitors
    • Tamoxifen (Nolvadex)
  • Systemic conditions
    • Adrenal hyperplasia and Cushing’s disease
    • Blood dyscrasias, including leukemia and thrombocytopenia
    • Coagulopathies
    • Hepatic disease
    • Hypothalamic suppression (from stress, weight loss, excessive exercise)
    • Pituitary adenoma or hyperprolactinemia
    • Polycystic ovary syndrome
    • Renal disease
    • Thyroid disease

• Once pregnancy and iatrogenic causes have been excluded, patients should be evaluated for systemic disorders, particularly thyroid, hematologic, hepatic, adrenal, pituitary, and hypothalamic conditions
• Menstrual irregularities are associated with both hypothyroidism (23.4%) and hyperthyroidism (21.5%)
• Inherited coagulopathy
• Initial screening for an underlying disorder of hemostasis screening questions – positive screening result comprises the following circumstances:
  • Heavy menstrual bleeding since menarche
  • One of the following conditions:
    • Postpartum hemorrhage
    • Surgery-related bleeding
    • Bleeding associated with dental work
  • Two or more of the following conditions:
    • Bruising, one to two times per month
    • Epistaxis, one to two times per month
    • Frequent gum bleeding
    • Family history of bleeding symptoms

• Anovulatory dysfunctional uterine bleeding is a disturbance of the hypothalamic-pituitary-ovarian axis that results in irregular, prolonged, and sometimes heavy menstrual bleeding. 

• It may occur immediately after menarche but before maturation of the hypothalamic-pituitary-ovarian axis, or it may occur during perimenopause, when declining estrogen levels fail to regularly stimulate the LH surge and resulting ovulation.
• Unopposed estrogen stimulation may lead to endometrial proliferation and hyperplasia. 
• Without sufficient progesterone to stabilize and differentiate the endometrium, this mucous membrane becomes fragile and sloughs irregularly. 
• Estrogen also affects uterine vascular tone, angiogenesis, prostaglandin formation, and endometrial nitric oxide production.

Evaluation of Abnormal Uterine Bleeding

Diagnostic step	Pertinent signs, symptoms, and tests	Conditions
History	Pelvic pain	Miscarriage, ectopic pregnancy, PID, trauma, sexual abuse or assault
	Nausea, weight gain, urinary frequency, fatigue	Pregnancy
	Weight gain, cold intolerance, constipation, fatigue	Hypothyroidism
	Weight loss, sweating, palpitations	Hyperthyroidism
	Easy bruising, tendency to bleed	Coagulopathy
	Jaundice, history of hepatitis	Liver disease
	Hirsutism, acne, acanthosis nigricans, obesity	Polycystic ovary syndrome
	Postcoital bleeding	Cervical dysplasia, endocervical polyps
	Galactorrhea, headache, visual-field disturbance	Pituitary adenoma
	Weight loss, excessive exercise, stress	Hypothalamic suppression
Physical examination	Thyromegaly, weight gain, edema	Hypothyroidism
	Thyroid tenderness, tachycardia, weight loss, velvety skin	Hyperthyroidism
	Bruising, jaundice, hepatomegaly	Liver disease
	Enlarged uterus	Pregnancy, leiomyoma, uterine cancer
	Firm, fixed uterus	Uterine cancer
	Adnexal mass	Ovarian tumor, ectopic pregnancy, cyst
	Uterine tenderness, cervical motion tenderness	PID, endometritis
Laboratory tests	Beta-subunit human chorionic gonadotropin	Pregnancy
	Complete blood count with platelet count and coagulation studies	Coagulopathy
	Liver function tests, prothrombin time	Liver disease
	Thyroid-stimulating hormone	Hypothyroidism, hyperthyroidism
	Prolactin	Pituitary adenoma
	Blood glucose	Diabetes mellitus
	DHEA-S, free testosterone, 173-hydroxyprogesterone if hyperandrogenic	Ovarian or adrenal tumor
	Papanicolaou smear	Cervical dysplasia
	Cervical testing for infection	Cervicitis, PID
Imaging and tissue sampling	Endometrial biopsy or dilatation and curettage	Hyperplasia, atypia, or adenocarcinoma
	Transvaginal ultrasonography	Pregnancy, ovarian or uterine tumors
	Saline-infusion sonohysterography	Intracavitary lesions, polyps, submucous fibroids
	Hysteroscopy	Intracavitary lesions, polyps, submucous fibroids

Treatment

• The goal in the treatment of DUB is to halt the acute bleeding episode and prevent recurrence. 
• If the patient wishes to become pregnant, the secondary goal would be to restore ovulation. 
• If a hormone deficiency or systemic illness is detected in the patient’s workup, then the appropriate treatment for that ailment would be administered. 
• Hormone therapy is the first-line treatment for DUB.
  • Combination oral contraceptives (cocs) 
    • Suppress endometrial development by reducing LH and FSH secretion and by reestablishing predictable bleeding patterns and resulting in a lighter flow. 
    • CI:
      • Arteriothromboembolic disease (myocardial infarction, stroke)
      • History of or active deep vein thrombosis (DVT) or pulmonary embolus (PE)
      • Untreated hypertension
      • Diabetes mellitus with vascular complications
      • Breast cancer, estrogen-dependent neoplasia
      • Undiagnosed abnormal genital bleeding
      • Active liver disease.
  • Oral progestogens
    • Cyclical oral progestogens are less effective for heavy menstrual bleeding than the LNG-IUD and tranexamic acid. 
    • Long-term use of progestogens is associated with a risk of hypoestrogenism (affecting bone and possibly cardiovascular health).
    • The progestogen-only contraceptive pill is not recommended for heavy menstrual bleeding.
    • Oral progestogens provide only short-term treatment of abnormal menstrual bleeding due to limited efficacy and adverse effects.
    • Regular cycles in heavy menstrual bleeding
      • Medroxyprogesterone 5 to 10 mg orally, 1 to 3 times daily (depending on heaviness of bleeding) on days 1 to 21 of a 28-day cycle. Review choice of therapy at 6 months    OR
      • Norethisterone 5 mg orally, 2 to 3 times daily on days 5 to 26 of a 28-day cycle. Review choice of therapy at 6 months.   
    • Irregular menstrual bleeding  
      • Medroxyprogesterone 5 to 10 mg orally, once daily for the same 12 days of each calendar month.   
      • Norethisterone 5 mg orally, once or twice daily for the same 12 days of each calendar month. 
      • Progesterone (micronised) 200 to 300 mg orally, once daily at night for the same 12 days of each calendar month 
  • Levonorgestrel-releasing intrauterine device (IUD) (Mirena)
    • Controls the endometrium with low dose (20 mcg/day) local release of progestin.
    •  80% decrease in menstrual blood loss after 3 months 
    • 90% decrease after 6 months of the insertion of this IUD
  • Depot medroxyprogesterone
    • Induces amenorrhoea after a year in 50 to 70% of individuals using it for contraception.
      • Medroxyprogesterone 150 mg by deep intramuscular injection, every 12 weeks.   
  • Tranexamic acid 
    • Slows bleeding quickly (within 2 to 3 hours) because it helps stabilize and preserve the fibrin matrix by moderating plasmin activity.
      • Tranexamic acid 1-1.5 g orally, 6- to 8-hourly for the first 3 to 5 days of each cycle.
    • Caution is suggested in individuals predisposed to thromboembolic effects, although studies have not shown an increased risk of venous thromboembolism.. 
  • Nonsteroidal anti-inflammatory drugs 
    • Inhibit blood prostacyclin formation, and can effectively decrease uterine blood flow
      • Ibuprofen 200 to 400 mg orally, 3 times daily. Start just before or at onset of menstrual bleeding and continue for up to 5 days   
      • Mefenamic acid 500 mg orally, 3 times daily. Start just before or at onset of menstrual bleeding and continue for up to 5 days  
      • Naproxen 500 mg orally initially, then 250 mg every 6 to 8 hours. Maximum daily dose 1250 mg. Start just before or at onset of menstrual bleeding and continue for up to 5 days.
  • Gnrh agonist (leuprolide acetate)
    • Suppresses gonadotropin, induces a medical castration, and breaks the ongoing cycle of abnormal bleeding in many anovulatory patients.
    • Long term use: associated with osteoporosis and other postmenopausal adverse reactions\

Acute severe heavy uterine bleeding

• Acute severe heavy uterine bleeding is an episode in a patient of reproductive age who is not pregnant, in which the quantity of bleeding requires immediate intervention to prevent further blood loss.

• Exclude
  • Pregnancy-related bleeding.
  • Coagulation disorders in adolescents, especially if it occurs from menarche
  • Underlying cause (once haemodynamically stable)

• Hormonal treatments include:
  • Medroxyprogesterone 10 mg orally, every 4 to 8 hours until bleeding stops   
  • Norethisterone 5 to 10 mg orally, every 4 to 8 hours until bleeding stops.   
  • Tapering the dose over a few weeks is suggested. 
  • This may reduce the volume of withdrawal bleeding when progestogen is stopped, although evidence is lacking. 
  • Advise that a withdrawal bleed is likely to occur once therapy is stopped.

Early referral (before 6 months) in heavy menstrual bleeding is indicated for:

• Concurrent severe dysmenorrhoea at baseline
• Concurrent dysmenorrhoea that does not settle after 3 months of pharmacotherapy
• Individuals who wish to conceive in whom fertility may be at risk (eg if endometriosis or adenomyosis is suspected)
• Fibroids greater than 3 cm
• Endometrial polyps
• Increased risk of endometrial cancer due to risk factors such as:
• Oligomenorrhoea
• Polycystic ovary syndrome
• A personal or family history of endometrial or colon cancer 
• Use of unopposed estrogen or tamoxifen
• Obesity (particularly with diabetes or hypertension)
• Age older than 45 years
• Radiological findings (such as endometrial thickness greater than 12 mm in premenopausal individuals or 5 mm or greater in perimenopausal individuals, when measured in the first half of the menstrual cycle).