Unit II ABNORMAL UTERINE BLEEDING Dr. Shahid Islam, MD, PhD, FRCPC Associate Professor and Director, Residency Program (Anatomical Pathology), University of Ottawa Staff Physician, Ottawa Hospital Presenters Dr. Nadine Doris, MD, FRCSC University of Ottawa Obstetrics and Gynecology PGY5

Dr. Sony Singh, MD, FRCSC Director of Minimally Invasive Gynecology, The Ottawa Hospital Dr. Mina Wesa, MD, FRCSC Minimally Invasive Gynecology Vancouver Disclosure: You may only access and use this PowerPoint presentation for educational purposes. You may not post this presentation online or distribute it without the permission of the author. Presentation Credits:

Objectives Describe menorrhagia, oligomenorrhea, menometrorrhagia, metrorrhagia. Classify abnormal uterine bleeding in ovulatory and anovulatory bleeding. Categorize abnormal uterine bleeding into anatomical, medical/pharmacological, and biochemical hormonal causes.

Objectives Formulate a differential diagnosis of vaginal bleeding with respect to pre‐menarchal, pre‐menopausal and postmenopausal causes Elaborate a clinical approach to abnormal uterine bleeding in perimenarchal, reproductive, peri and post‐menopausal women.

Objectives List investigations to evaluate abnormal uterine bleeding and briefly discuss available treatment options. Compare the normal menstrual cycle with anovulatory conditions such as polycystic ovarian syndrome, premature ovarian failure and menopause. Discuss pharmacologic and surgical management of menorrhagia Describe the etiology and presenting signs and symptoms of anovulatory causes of vaginal bleeding, (including menopause, PCOS and ovarian tumours).

What is AUB? any variation from the normal menstrual cycle, and includes changes in regularity and frequency of menses, in duration of flow, or in amount of blood loss.

So what is a normal menstrual cycle? Occurs every 28 day ±7 days Lasting 3-8 days < 80cc of blood loss

Definitions: Menorrhagia (heavy menstrual bleeding): excessive menstrual blood loss that interferes with quality of life Oligomenorrhea (frequency): cycle length >35 days TRADITONAL TERMINOLOGY NEW TERMINOLOGY

Menometrorrhagia: Irregular intervals and excessive volume and duration of flow Metrorrhagia: irregular intervals with normal or reduced volume and duration of flow

How can we classify AUB? 1.Reproductive Age 2.Structural vs. Non Structural 3.Ovulatory vs. Non Ovulatory

AUB PREGNANTNON PREGNANT Non IntrauterineIntrauterine ADOLESCENT REPRODUCTIVE PHASE PERIMENOPAUSAL MENOPAUSAL

Perimenarche Perimenopause Postmenopause Menarche Menopause Reproductive Early Late 60 - Death Birth - 10 Premenarche Reproductive Cycle

In Adolescents the Hypothalmic-pituitary-ovarian ( HPA) axis immature ANOVULATION is seen disproportionately in this group

Adolescence COMMON CAUSES IN ADOLESCENTS – Anovulatory – Coagulation defects – Exogenous hormone use – STI – Trauma ALWAYS RULE OUT PREGNANCY!!!

Reproductive Age Anovulatory Fibroids Polyps – endometrial or endocervical Exogenous hormones Trauma Thyroid Disorder ALWAYS RULE OUT PREGNANCY!!!

Perimenopausal Anovulatory – insensitive ovarian follicles Fibroids Polyps Endometrial Cancer Endometrial Hyperplasia ALWAYS RULE OUT PREGNANCY!!!

Menopausal RULE OUT ENDOMETRIAL CANCER = MOST IMPORTANT!! ATROPHY ATROPHY ATROPHY Endometrial hyperplasia Polyps – cervical or endometrial DUB Atrophic vaginitis Exogenous hormones

No structural abnormality Structural abnormality

Endometrial or Endocervical Polyps Common cause of abnormal genital bleeding in pre- and postmenopausal women Hyperplastic overgrowths of endometrial glands and stroma around a vascular core, sessile or pedunclulated Single, multiple, variable size and location, may be asymptomatic Risk factors: Tamoxifen, obesity, HRT 95% benign

Adenomyosis  Ectopic endometrial glands and stroma within the uterine musculature  Hypertrophy and hyperplasia of surrounding myometrium, diffusely enlarged uterus “globular”  True incidence unknown as definitive diagnosis based on histopathology (following hysterectomy)  Pathogenesis – endometrial invagination versus mullerian rests.  Pathology:  Uniformly enlarged, boggy uterus  Thickened myometrium ADENOMYOSIS: AUB-A PATHOGNOMONIC on microscopy: Presence of endometrial tissue within the myometrium

Adenomyosis Clinical Manifestations: Heavy menstrual bleeding Painful menstruation Chronic pelvic pain Enlarged, globular uterus on exam, may be tender Hysterectomy – definitive treatment Clinical Diagnosis!

LEIOMYOMA (Fibroids)  Most common pelvic tumors in women  Benign, originate from myometrial smooth muscle  Women of reproductive age  Symptoms:  AUB  Pelvic pain or pressure  Infertility or adverse pregnancy outcomes  Clinically apparent in 12-25% women, noted on pathological exam in approximately 80% of uteri LEIOMYOMA (Fibroids or Myomas): AUB-L

PHYSICAL EXAMINATION:  Bimanual pelvic examination – enlarged uterus  Speculum examination – prolapsed submucous fibroid, cervical contour LEIOMYOMA Diagnosis

Leiomyoma Fibroid in 53 yo woman who presented with PMB Joizzo, JR et al., AJR Am J Roentgenol 2001 TVSSIS IMAGING: Transvaginal Ultrasound (TVS) % sensitive Most widely used modality – accessible, cost- effective Saline Infusion Sonography (Sonohysterography) Improved assessment of intracavitary fibroids

Leiomyomas Treatment choice based on: Type, severity of symptoms Size Location Patient age Reproductive plans Options: Expectant Medical management Surgical management

Leiomyoma Medical Management - Oral contraceptives pill - Levonorgestrel - releasing intrauterine system (“Mirena IUD”) - Progestin injections (Depot Medroxy Progesterone Acetate - DMPA) - Gonadotropin-releasing hormone (GnRH) agonists, antagonists - Selective progesterone receptor modulators (“SPRMs” - Ulipristal acetate) Surgical Management: - Uterine Artery Embolization - Myomectomy Hysteroscopy Laparoscopy/Laparotomy - Hysterectomy Vaginal Laparoscopic Abdominal

Endometrial Hyperplasia  Proliferation of endometrial glands that may progress to or coexist with endometrial cancer  Result of chronic UNOPPOSED estrogen stimulation without balancing effects of progesterone  Women present with abnormal uterine bleeding  Histologic diagnosis – ENDOMETRIAL BIOPSY

MALIGNANCY / HYPERPLASIA: AUB-M HISTOLOGY% RISK OF COEXISTING CA Simple hyperplasia without atypia1 Complex hyperplasia without atypia3 Simple hyperplasia with atypia8 Complex hyperplasia with atypia29 Normal endometrium Complex hyperplasia without atypia Complex hyperplasia with atypia

Atypical hyperplasia (often complex) Pre-menopausalFertility desired High dose Progestin therapy Childbearing completed Total HysterectomyPost-menopausal Total Hysterectomy Bilateral salpingo- oophorectomy ATYPICAL HYPERPLASIA

No structural abnormality Structural abnormality

Coagulopathy Initial screening for an underlying disorder of hemostasis in patients with excessive menstrual bleeding should be structured by medical history.  Positive screen comprises any of the following: Screening for bledding disorders in women with HMB Heavy menstrual bleeding (HMB) since menarche One of the following: Postpartum hemorrhage Surgery-related bleeding Bleeding associated with dental work Two or more of the following symptoms: Bruising one to two times per month Epistaxis one to two times per month Frequent gum bleeding Family history of bleeding symptoms Von Willebrand disease identified in 13% of women with HMB. Minimum laboratory evaluation: CBC Peripheral blood smear Ferritin Coagulation panel (aPTT, PT)

Ovulatory Dysfunction  Unpredictable bleeding pattern  Variable amount of flow  Absence of cyclic production of progesterone OVULATORY DYSFUNCTION: AUB-O Causes of Ovulatory Dysfunction Obesity Low body weight Weight change Psychological stress Elite Athletes Endocrinopathy  Thyroid dysfunction (hypo)  PCOS / Hyperandrogenic disorders  Hyperprolactinemia  Luteal out of pahse cycles (LOOP) Idiopathic

 Predictable cyclic menses, normal ovulation  No other causes of AUB identified Possible mechanism(s):  Disorder of endometrial hemostasis – deficient vasoconstrictors (PGF2α, endothelin-1), accelerated fibrinolysis  Endometrial inflammation, infection  Abnormal local inflammatory response  Abnormal vasculogenesis  DIAGNOSIS OF EXCLUSION! ENDOMETRIAL: AUB-E

MEDICAL TREATMENT OPTIONS Non-Hormonal Iron NSAIDs Antifibrinolytics Hormonal Combined Hormonal Contraceptive Progestins GnRH agonists Danazol SPRM’s

Pharmacologic and surgical management of menorrhagia

NSAIDS Mechanism – COX converts AA (arachidonic acid) – NSAIDS inhibit COX2>COX1 – shifts balance between PGs and thromboxanes = promote vasoconstriction Effectiveness: –  blood loss by 33-55% vs. placebo

NSAIDS Additional benefits: -improves dysmenorrhea up to 70% -Low cost, only during menses, acceptable side effects and reduced dysmenorrhoea Dosing: -Start before menses and continue 3-5 days Comparison: -Less effective than tranexamic acid, cOCP, danazol or LNG-IUS

Tranexamic Acid – Antifibrinolytic Reversibly binds to plasminogen to reduce local fibrin degradation without changing blood coagulation parameters an overall reduction in menstrual blood loss between 40% and 59% from baseline

Hormonal Options CHC Progestins Progestin IUS GnRH agonists

Hormonal Options - CHC Most prescribed treatment Mechanism – Progestin: ovulation suppression  &  ovarian steroidogenesis = endometrial atrophy – Estrogen: supports endometrium to  breakthrough bleeding Responsible for most Contraindications

CHC Effectiveness:  blood loss by 40-50% if taken cyclically -Extended cycle (continuous) has many advantages over cyclic -Very few studies exist for HMB Additional: -Regulate cycles, contraception, prevent hyperplasia and treat dysmenorrhoea Contraindications: - Smokers > 35 (> 15 cigarettes/day) -history of DVT, stroke, uncontrolled HTN, migraine with neurological symptoms, breast CA, CAD and liver disease

Progestins Mechanism: – Endometrial atrophy by inhibition of ovarian steroidogenesis How you give it matters: – Cyclic (luteal phase): MPA or NETA for days q mo for anovulatory bleeding – Helps 50% of women with irregular cycles achieve regular cycles – NOT effective for regular HMB – LESS EFFECTIVE THAN NSAIDS, tranexamic acid Inhibits endometrial growt

LNG-IUS: The Pro’s Effectiveness:  menstrual blood loss by 86% at 3 months, 97% at 1 year% 20-80% amenorrhea or at 1 year More effective than: – OCP’s, oral P, NSAIDS and tranexamic acid

LNG-IUS: The Pro’s Mechanism – Releases 20µg levonorgestrel per day locally – Induces atrophy of endometrium – Reduces mean uterine vascular density – Minimal systemic absorption ( nmol/L) Does not inhibit ovulation Additional: – improves dysmenorrhea and pelvic pain

LNG – IUS versus surgery Cochrane meta-analysis (8 trials) – Hysterectomy is better at reducing menstrual blood loss BUT – LNG-IUS provides equivalent improvement in QOL If awaiting hysterectomy, > 2/3 cancelled surgery at 1 yr (vs. 14% in control group)

GNRH Agonists Mechanism: -Induces reversible menopausal state -Endometrial atrophy and amenorrhea within 3-4 wks Effectiveness: -Very effective -Relieves dysmenorrhoea Dosing: -Dependent on type of GnRH agonist -Daily, monthly, q3 months

GNRH Agonists Limited by side effects – Hot flashes – Vaginal dryness – Mood fluctuation – Bone effects – Cost Consider add-back therapy for menopausal symptoms and bones

51 GnRH-Agonist Benefits Pre-Hysterectomy √ √ √ Menorrhagia / Anemia Fibroid Shrinkage Pelvic Pain/Pressure Symptoms

Surgical Management Surgical options include: Dilation and Uterine curettage Hysteroscopic polypectomy Endometrial ablation Myomectomy Hysterectomy

CASE 72 yo nulliparous woman Menopausal x 20 years Complains of vaginal bleeding x 3 months She denies HRT PMHx: DM2 Meds: Metformin O/E: vitals stable, bmi=35, abdo soft non tender no masses, external genitalia normal, speculum and bimanual exam normal

What do investigations do you want to do next? What is your concern for this patient? What must be ruled out?

External Genitalia: -Hemorrhoids, Vular Disease ex. Lichen Sclerois, UTI, Trauma Vaginal Cervical UterineOvarian Systemic Causes: