Abnormal uterine bleeding

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Farman Khan, MD, MRCP [2]

Causes

Common Causes

• Dysfunctional uterine bleeding
• Leiomyomas (fibroids)
• Endometrial hyperplasia
• Abortion
• Cervicitis
• Endometrial Carcinoma
• Endometritis
• Pelvic Inflammatory Disease
• Vaginitis

Causes by Organ System

Cardiovascular	No underlying causes
Chemical / poisoning	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	Blood thinners, breakthrough bleeding in women using hormonal birth control, copper intrauterine device , depo-Provera hormone replacement therapy, tamoxifen, corticosteroids, chemotherapy, clomiphene, dilantin, antipsychotic drugs , antibiotics ( due to toxic epidermal necrolysis or Stevens-Johnson syndrome )
Ear Nose Throat	No underlying causes
Endocrine	Diabetes, hyperthyroidism, hypothyroidism, Cushing's syndrome, Hormone secreting adrenal and ovarian tumors
Environmental	No underlying causes
Gastroenterologic	Liver disease
Genetic	No underlying causes
Hematologic	Clotting disorders, Von Willebrand disease, thrombocytopenia or platelet dysfunction, acute leukemia ,Some factor deficiencies, Advanced liver disease
Iatrogenic	Radiation therapy
Infectious Disease	Chlamydia, gonorrhea, uterine infection, genitourinary tract infection, bacterial vaginosis sexually transmitted diseases, atrophic vaginitis
Musculoskeletal / Ortho	No underlying causes
Neurologic	No underlying causes
Nutritional / Metabolic	No underlying causes
Obstetric/Gynecologic	Adenomyosis, atrophy of the tissue lining the vagina and uterus, cervicitis, ectopic pregnancy, endometrial hyperplasia, endometritis, uterine sarcoma, first few months after the first menstrual period, first few weeks after abortion, first few weeks after delivery, intrauterine device, miscarriage, ovarian cysts, placenta previa, polycystic ovarian syndrome, retained products of conception, uterine fibroids, uterine polyps, diseases involving the vulva for example Crohn's disease, Behcet's syndrome , pemphigoid , pemphigus , erosive lichen planus , lymphoma, skin tags, sebaceous cysts, condylomata, angiokerataoma
Oncologic	Cancer or precancer of the cervix , cancer or precancer of the endometrium, ovarian cancer, uterine cancer, uterine sarcoma
Opthalmologic	No underlying causes
Overdose / Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal / Electrolyte	Chronic renal disease
Rheum / Immune / Allergy	No underlying causes
Sexual	Sexual abuse
Trauma	Sexual intercourse , sexual abuse , foreign bodies (including IUD) , pelvic trauma, Straddle injuries
Urologic	Genitourinary tract infection
Dental	No underlying causes
Miscellaneous	Foreign body, irritation of the genital area due to bubble baths, soaps, lotions or infection, smoking, Excessive exercise

Causes in Alphabetical Order

Adenomyosis Anticoagulants Atrophy of the tissue lining the vagina and uterus Blood thinners Breakthrough bleeding in women using hormonal birth control Cancer or precancer of the cervix Cancer or precancer of the endometrium Cervicitis Chlamydia Chronic renal disease Clotting disorders Diabetes Ectopic pregnancy Endometrial hyperplasia Endometritis First few months after the first menstrual period First few weeks after abortion First few weeks after delivery Foreign body Genitourinary tract infection Gonorrhea Hyperthyroidism

Hypothyroidism Intrauterine device Irritation of the genital area due to bubble baths, soaps, lotions or infection Liver disease Miscarriage Ovarian cancer Ovarian cysts Placenta previa Polycystic ovarian syndrome Radiation therapy Retained products of conception Sexual abuse Trauma Uterine cancer Uterine fibroids Uterine infection Uterine polyps Uterine sarcoma Von Willebrand disease

Treatment

Contraindicated medications

• Choriogonadotropin alfa

Template:Abnormal uterine bleeding Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3] Associate Editor(s)-in-Chief: Nima Nasiri, M.D.[4]

Abnormal uterine bleeding differential diagnosis

• Abnormal uterine bleeding differential diagnosis include:

• Endometrial hyperplasia
• Cervical polyp
• Cervical leiomyoma
• Cervical lymphoma
• Cervical sarcoma
• Metastases to the cervix
• Cervical ectopic pregnancy
• Cervicitis
• Cervical erosion ( Ectropion )
• IUD use
• Pelvic inflammatory disease
• Endometriosis
• Adenomyosis
• Postcoital bleeding
• Clear cell adenocarcinoma
• Hematologic causes:
  • Von willebrand disease
  • Thrombocytopenia
  • Clotting disorder
  • Platelet dysfunction
  • Factors deficiency

Abnormal Uterine bleeidng differential diagnosis
Ob-Gyn neoplasm and diseases	Clinical manifestations							Para-clinical findings					Gold standard
	Symptoms					Physical exam		Lab Findings		Imaging		Histopathology
	Abnormal vaginal bleeding	Other Genitourinary/ Gastrointestinal symptoms	Abdominal pain	Pelvic pain	B symptoms	Gynecological examinations	Abdominal mass	HPV Pap smear STI panel	Other labs	Ultrasound	Other imagings
Cervical cancer	Postmenopausal Intermenstrual Postcoital Bleeding after pelvic exam	Dysuria Urinary hesitancy Dyspareunia Vaginal discharge Itching or burning of the vulva	+	+	+	Cervical mass on exam	+	± HPV Atypical cells on Pap smear STI: ±Chlamydia	↑ CA-125 Leukomoid reaction	Large cervical cancer Angiogenesis on Doppler sonography Bladder involvement Lymph node involvement	T2-weighted MRI : Ovoid, heterogeneous tumor distending the cervical canal with stromal involvement. PET/CT scan: Detect tumor size Lymph node involvement, Metastases to bladder or rectum	CIN1: mild dysplasia CIN2: moderate dysplasia CIN3: high degree of dysplasia/metastases	Colposcopy/biopsy
Cervical polyp	Postcoital Intermenstrual Postmenopausal Bleeding after exam	Vaginal discharge Dyspareunia	−	−	−	Mass on exam	−	−	↓ RBC count ↓ Hb, ↓ Hct ↓ Serum Iron	Hyper/hypoechogenic masses with or without cysts Filling the endocervical or vaginal canal		Epithelial cells with no nuclear atypia/mitoses	Hysteroscopy /Biopsy
Cervical leiomyoma	Heavy/prolonged menstrual bleeding Intermenstrual bleeding	Urinary retention Constipation Infertility Bowel obstruction Increase in pregnancy/labor complications Vaginal discharge	+	+	−	Large,irregular pelvic mass	±	−	Erythrocytosis	Well circumscribed hyperechoic mass	T2-weighted MRI: Hypointense masses Homogeneous enhancement Red degeneration	Spindle shaped smooth muscle cells Mature adipocytes Extracellular matrix consist of collagen,fibronectin.	Clinical diagnosis/ and Ultrasound
Cervical lymphoma	Postmenopausal bleeding	Difficulty urinating Post-coital pain	+	+	+	Larrge uterine/cervix mass Irregularity	+	Pap smear: Small round blue cells High nuclear/cytoplasm ratio, Scant cytoplasm	Immunohistochemistry markers: CD19, CD20, CD79a, PAX5	Well-defined, solid, concentric, hypoechoic mass	MRI: Intramyometrial infiltrative nodules	Small tumor cells with large nuclei High mitoses and proliferation	Biopsy diffuse large B-Cell lymphoma (DLBCL) most frequent type.
Cervical sarcoma	Intermentrual Postmenopausal	Post-coital pain Fullness in pelvic Vaginal discharge	+	+	±	Cervical mass Lump protruding from vagina/vulva	+	−	Leiomyosarcoma markers: Positive for for S-100 and vimentin and are negative for desmin, myoglobin and actin.	Endometrial mass with heterogeneous echogenicity	MRI: Endometrial polypoid mass Hypointense hypervascular solid components	Poorly circumscribed bulky mass protruding from cervical canal Different subtypes: Leiomyosarcoma Endocervical sarcoma Embryonal rhabdomyosarcoma( Sarcoma botryoides)	Biopsy
Cervical erosion(Ectropion)	Light bleeding after pelvic exam Spotting	Post-coital pain Painful cramps Dyspareunia Vaginal discharge Itching of vulvovaginal area	+	+	−	Red, glandular area around os of cervix	−	−	N/A	N/A	N/A	Squamous metaplasia Vascular ectasia Lymphocytic infiltration	Colposcopy and biopsy
Cervicitis	Intermenstrual bleeding Postcoital Bleeding after pelvic exam	Pain during urination Pain during sex Painful menstruation Purulent vaginal discharge Itching of vulva	+	+	May have fever only	Red,inflammed swollen cervix Inflammation/irritation of vulva/vagina	−	STI panel: Chlamydia Gonorrhea Herpes simplex Trichomonas vaginalis	↑ WBC + NAAT for chlamydia, gonorrhea		MRI: May be detected as retention cysts in cervix.	Non-specific, lymphocytic infiltration may be seen in microscopic histology. Koilocytic changes in case of HPV as cause of chronic cervicitis.	Nucleic acid amplification tests (NAATs)
Endometrial carcinoma	Postmenopausal bleeding Intermesntrual bleeding	Vaginal discharge Pain during urination Pain during sex Fulness in pelvic Difficulty emptying bladder	+	+	±	Often normal Vaginal lump Pelvic mass	+	−	↑ CA-125	Thickened endometrium Myometrial invasion	T1-weighted MRI: Hypo-to-isointense T2-weighted MRI: Intermediate signal intensity lower than the normal endometrium	Type I endometrioid endometrial carcinomas (EECs): Moderately differentiated Superficial invasion into the myometrium Type II non-endometrioid endometrial carcinomas (NEECs): Deep invasion of the myometrium Poorly differentiated Highly metastatic Not related to endometrial hyperplasia	Hysterectomy and biopsy
Endometrial hyperplasia	Postmenopausal bleeding Intermenstrual bleeding Amenorrhea	Dysmenorrhea Amenorrhea Dyspareunia Heavy menstrual bleeding	+	+	N/A	Normal or thickened endometrium	±	−		Thickened endometrium	T1-weighted MRI: Hypo-to-isointense	Simple(cystic) hyperplasia Complex hyperplasia Simple hyperplasia with atypia Complex hyperplasia with atypia (glands are highly irregular in size and shape)	Biopsy
Endometriosis	Heavy mentrual bleeding	Painful menstruation Burning/painful urination Painful bowel movement Pain during or after sex Infertility Watery vaginal discharge	+	Pelvic pain Back pain	−	Tender uterosacral nodularity Immobile uterus Cervical motion tenderness Retroverted uterus	+	−	↑ IL-6 ↑ TNF-α ↑ CA-125 (limited value)	Ground glass echogenicity of the cyst fluid (Endonetrioma) Cysts are unilocular	MRI findings is variable, depending upon the sites of endometriosis such as peritoneal implants, ovarian endometrioma, pelvic endometriosis.	Endometrial type glands and stroma presence is charracteristic histology findings, suggestive for endometriosis.	Visual inspection by laparoscopy
Pelvic inflammatory diseases	Bleeding after sex Intermenstrual bleeding	Fever Pelvic pain Dyspareunia Dysmenorrhea Dysuria Dyschezia Smelly grey/white/yellow vaginal discharge Itching and burning of vulvovaginal area	±	+	Oral temperature >101F	Vaginal/vulvar tender lesion depending on microbial causes	−	STI panel: Chlamydia Gonorrhea	Non-specific lab values: ↑ CRP ↑ ESR ↑ WBC Oral temperature >101F	Ultrasound: Thickened, fluid-filled tubes with or without free pelvic or tuboovarian complex	MRI findings: Inflammation in pelvic soft tissue Hydrosalpinx Tubo-ovarian abscess in chronic PID.		Clinical diagnosis is gold standard for diagnosing PID Laparoscopy is confirmatory in acute salpengitis
Adenemyosis	Abnormal uterine bleeding	Painful menstruation	+	+	−	Polypoid mass protruding into the endocervical canal.	Enlarged uterus may present as abdominal mass	−	↑ CA-125	Subendometrial striations Myometrial cysts Asymetrical thickness in myometrium walls Heterogenous exhotexture of myometrum	MRI: Thickened junctional zone	Presence of ectopic endometrial glands into the myometrium.	Histology findings post hysterectomy
Cervical ectopic pregnancy	Amenorrhea Bleeding after pelvic exam	Pelvic pain	+	−	−	Soft and disporportionally enlarged uterus.	±	−	↑ β-HCG	Empty uterine Thickened endometrium	T2-weighted MRI: Hypointense large mass T1-weighted MRI: Partially hyperintense mass	Necrotic hemorrhagic mass with chorionic villus	Hysterectomy and biopsy
Vaginal cancer	Postcoital bleeding	Tenesmus Dysuria Urinary frequency Constipation Pelvic pain Vaginal discharge	+	+	±	Ill-defined vaginal ulcer Vaginal lump Inguinal lymphadenopathy Edema and ulceration of vaginal wall Foul-odor blood tinged vaginal discharge Vaginal prolapse Cystocele	In case of metastases to internal organs	Pap smear can be normal ± HPV	↓ RBC count	Ultrasound: Hydronephrosis in case of pelvic metastases Multiple liver metastases	MRI: Isointense on T1-weighted images Soft-tissue mass with intermediate-to-high signal intensity on T2-weighted images	Biopsy findings: Squamous cell carcinoma of vagina	Biopsy
Paget's disease of vulva to cervix	Bleeding from lesion Oozing	±Vaginal discharge Pain in vulva Itching or burning sensation in vulva	−	−	−	Scaly eczematoid lesion in vulva. Erythematous plaques with white scaling. Inguinal lymphadenopathy in case of metastases.	−	−	Positive for cytokeratins(CK7) Negative for S-100 and Melan-A	N/A	MRI: Hyperintense on diffusion weighted imaging	Thick vulvar skin "Cake-icing effect", pathognomic for vulvar paget's disease Intraepidermal adenocarcinoma which involves epidermis	Biopsy of lesion
Nabothian cyst	Postcoital bleeding	Pain during sex Vaginal discharge	In very rare cases depending upon the size of cyst it can cause abdominal pain and amenorhea	−	−	Majority of them are asymptomatic due to their small size( few milimeters) Cystic mass on exam	−	−	N/A	Anechoic well defined cystic lesions	T1-weighted Intermediate or slightly high signal intensity T2-weighted High signal intensity on T2-weighted images Benign cystic lesion	Multiple benign cystic masses, usually few milimieters in diameter.	Histopathological exam if large cystic masses
IUD use	Heavy bleeidng	Painful menstruation ±Vaginal discharge	+ In cases of uterine rupture and far migration of IUD, it can cause adhesion, bowel obstruction, perforation.	+	−	Normal	−	−

Pregnancy and pregnancy related conditions	Clinical manifestations			Para-clinical findings					Gold standard	Additional findings
	Symptoms		Physical examination
				Lab Findings	Imaging			Histopathology
	Abnormal uterine bleeding	Other symptoms
Miscarriage	+	Pelvic/back pain Spotting Nausea Vomiting	Enlarged uterus Blood clot in cervical os.	↑ β-HCG ↓ RBC	Ultrasound: ‘Sliding sign’ on transvaginal ultrasound Embryo with increase in crown-rump length without visible embryo heart activity Absence of embryo heart activity			Abnormal villi in chromosomal abnormalities Hydropic changes in cases of molar pregnancy	Transvaginal ultrasound
Abruptio placenta	+	Pelvic/back pain Abdominal pain Vaginal bleeding Painful uterine contractions	Uterine tenderness ↓ Fetal heart rate ↓ Fetal movement	↑ β-HCG	Ultrasound: Uterine hypertonicity Non-reassuring fetal heart			Hematoma, Fibrin deposition Compressed villi Hemosiderin-laden histiocytes Villous infarctions Decidual destruction, hemorrhage	Transvaginal ultrasound
Placenta previa	+	Abdominal pain Pelvic pain	Dilated cervix ↑ Uterine contraction Blood clot or spotting	↑ β-HCG	Ultrasound: Low lying placenta, less than 1cm from cervical os.			Trophoblastic giant cell migration into decidua Hemorrhage into decidua and myometrium	Transvaginal sonography
Ectopic pregnancy	+	Pelvic pain which is worse on one side Abdominal pain	Abdominal or pelvic tenderness Hemorrhagic shock	↑ β-HCG	Ultrasound: Empty uterus Adnexal mass Absence of "Sliding sign" on gentle pressure of cervix Tubal rupture				Diagnostic laparascopy
Molar pregnancy	+	Heavy vaginal bleeding Nausea Vomiting	Uterine size larger than date Sign of hyperthyroidism Sign of Anemia	↑↑ β-HCG ↑ Inhibin-A ↑ Activin-A ↓ RBC	Ultrasound: Complex and echogenic intrauterine mass Containing many small cystic spaces Classical "snow storm" appearance			Hydropic villi Empty uterus Fetal tissue in partial hydatiform mole.	Histological confirmation post-curettage
Hematologic conditions	Clinical manifestations			Para-clinical findings					Gold standard	Additional findings
	Symptoms		Physical examination
				Lab findings		Imaging		Histopathology
	Abnormal uterine bleeding	Other symptoms
Von willebrand disease	+	Epistaxis Easy bruising Gum/dental bleeding Heavy menses Fatigue Blood in stool Blood in urine GI bleeding in rare cases	Bruises on skin Menorrhagia Hematuria Melena	↓ RBC count ↓ Serum Iron + FOBT RBC in Urinalysis ↓ VWF Normal PT, Normal or ↑ PTT, Normal or ↑ Bleeding time Normal or low platelet Normal Fibrinogen		N/A		N/A	Current gold standard diagnostic testing includes: VWF Activity(via Ristocetin cofactor) VWF Antigen Factor VIII Activity (FVIII)
Factors deficiencies	+ Heavy bleeding since the menarche	Easy bleeding Epistaxis Easy bruising Gum/dental bleeding Heavy menses Fatigue Blood in stool Blood in urine	Petechia on skin Intramuscular hematoma Hematemesis Melena Hematuria Abdominal pain Intracranial bleeding signs: Headache Neck stiffness Vomiting Lethargy	`↓ Factors VIII, IX, XI ↑ PTT , Normal PT Normal VWF ↓ RBC count		N/A		N/A	Factor VIII , IX, XI assay
Platelet dysfunction	±	Skin bruises Epistaxis Excessive bleeding after surgery Menorrhagia	Bruises on skin	Thrombocytopenia Normal PT , Normal PTT ↓ RBC count Platelet secretion and dense granules abnormalities		N/A
Metabolic conditions	Clinical manifestations			Para-clinical findings					Gold standard	Additional findings
	Symptoms		Physical examination
				Lab findings			Imaging	Histopathology
	Abnormal uterine bleeding	Other symptoms
Hyperthyroidism	+	Wet skin/hair thinning Palpitation Insomnia Anxiety Weight loss Heat intolerance Diarrhea	Enlarged thyroid (Goiter) Exophthalmos	High T3,T4 Low TSH TSH receptor antibodies (TRAb)			Ultrasound: Homogenous hypo-echogenicity	Microscopic histology: Lymphocytic infiltration in follicles Enlarged colloids	Total T4 For Grave's disease: TSH receptor antibody	Associated conditions: Osteoprosis Atrial fibrillation
Hypothyroidism	+	Fatigue Cold intolerance Decreased sweating Hypothermia Coarse skin Weight gain Constipation Dry skin/hair loss	Dry skin Bradycardia Hair loss Myxedema Delayed relaxation phase of deep tendon reflexes	Low T3,T4 Normal/ low TSH ↑ Total cholesterol ↑ LDL ↑ VLDL			Ultrasound: Homogenous hypo-echogenicity	Microscopic histology: Follicular atrophy Chronic lymphocytic infiltration Hyperplastic change in the follicles Presence of Hurthle cell metaplasia	TSH	Associated conditions with Hashimoto thyroiditis: Sjögren disease Pernicious anemia Diabetes mellitus type 2 Rheumatoid arthritis
Adrenal hyperplasia	+	Acne Virilization Irregular menses Percocious puberty Muscle weakness Fatigue	Depending upon deficient enzyme: Ambiguous genitalia in male or female Hypertension/ Hypotension Primary amenorrhea Absence of secondary sexual characteristics Minimal body hair	Depending upon enzyme deficiencies may include the following: Androstenedione Testosterone 11-deoxycortisol Dehydroepiandrosterone sulfate (DHEAS) 17-hydroxypregnenolone Pregnenolone Renin/Aldosterone			CT-Scan: Enlargement of glands	Diffuse cortical hyperplasia	Cosyntropin stimulation test (250 μg cosyntropin intravenously): measuring levels of 17-OHP and androstenedione at baseline and 60 min	Ovarian torsion may be seen due to bleeding in 21-Hydroxilase deficiency infants
Cushing's disease	+	Acne Hirsutism/hair loss Weight gain Moon facies Skin bruising Abdominal striae Insomnia, Amenorrhea Decrease libido	Facial plethora Acanthosis nigricans Ecchymosis Violacious striae Muscle weakness Kyphosis Hypertension Edema Slow deep tendon reflex relaxation Emotional lability Depression Lipodystrophy Glucose intolerance or diabetes mellitus	Low/Normal ACTH High cortisol			T1-weighted MRI: Pituitary macroadenoma	Pituitary macro/micro adenoma	Testing urinary free cortisol over 24 hours (UFC) Overnight Dexamethasone 8 mg, distinguishes Cushing’s syndrome from the ectopic ACTH secretion
Polycystic ovarian syndrome	+	Pelvic pain Acne Hair thinning Mood swings Irregular mens Amenorrhea Oligomenorrhea Infertility	Enlarged ovaries Hirsutism Weight gain Acanthosis nigricans	↑ DHEAS and androstenedione, testosterone ↓ HDL, ↑ Total cholesterol, LDL, TG ↑ Prolactin in some women ↑ LH/ Normal or ↓ FSH ↑ Serum Anti-mullerian hormone			Ultrasound: ↑ Number of follicles Large ovaries ↑ Ovarian volume Fluid filled ovaries	Multiple cysts in ovaries bilaterally.	Clinical,biochemical and ultrasound	Associated conditions: Increased risk of cardiovascular disease Insulin resistance Diabetes mellitus type 2 Metabolic syndrome
Medication side effects/ Iatrogenic	Clinical manifestations			Para-clinical findings					Gold standard	Additional findings
	Symptoms		Physical examination
				Lab Findings			Imaging	Histopathology
	Abnormal uterine bleeding	Other symptoms
Anticoagulants	+	Heavy menstrual bleeding	Pallor Heavy menstrual bleeding	↑ PT or ↑ PTT , ↑ bleeding time ↓ RBC count ↓ Hemoglobin, ↓ Hematocrit ↓ Serum Iron ↓ Ferritin			N/A	N/A	Complete medication history	History of venous thromboembolism or pulmonary embolism
Antipsychotics	+	Amenorrhea Sexual dysfunction	Galactorrhea Gynecomastia	↑ Prolactin level			N/A	N/A	Complete medication history Serum prolactin test
Oral contraceptive pills	Break through bleeding	Amenorrhea Menstrual irregularity Mood swings	Heavy bleeding Depressed mood				N/A	N/A	Ruling out organic cause, complete history of medication use
Herbal supplements	+	Heavy menstrual bleeding Menstrual irregularity Amenorrhea	Menorrhagia	↓ RBC count ↓ Hemoglobin, ↓ Hematocrit ↓ Serum Iron ↓ Ferritin			Ultrasound: Thickened endometrium	N/A