Normal & Abnormal Uterine Bleeding Syamel Muhammad

Objectives Recognize the characteristics of Normal Menstrual Bleeding (The LMP as the fourth vital sign!) Describe the etiologies of Abnormal Uterine Bleeding (AUB.) Understand etiologies of AUB with respect to the life stages of women. Understand the diagnostic tools to identify the etiology of the AUB. State the medical & surgical options available in primary care and gynecology settings.

Normal Menstruation The Menstrual Cycle In the normal menstrual cycle, orderly cyclic hormone production and parallel proliferation of the uterine lining prepare for implantation of the embryo. Berek & Novak’s Gynecology, 2012, p.145 A sound understanding of the female reproductive cycle is the first step in becoming a women’s health specialist. Starting with a definition is a good start, but as we read a text book definition we know that we also need a lay person definition for counseling our patients.

Normal Menstruation “The menstrual cycle starts with the first day of bleeding of one period and ends with the first day of the next. In most women, the cycle last about 28 days. Cycles that are shorter or longer by 7 days are normal.” ACOG Website: FAQ095 Online sources are good. I like to know a few that I can refer patients for education. “Menstruation, or period, is normal vaginal bleeding that occurs as part of a woman's monthly cycle. Every month, your body prepares for pregnancy. If no pregnancy occurs, the uterus, or womb, sheds its lining. The menstrual blood is partly blood and partly tissue from inside the uterus. It passes out of the body through the vagina." MedlinePlus: A service of the U.S. National Library of Medicine National Institutes of Health

The Normal Menstrual Period Blood loss < 80 ml (average 30-35 ml) Duration of flow 2-7 days (average 4 days) Cycle length 21 - 35 days (average 29 days) (28 days +/- 7 days}

Phases of the Menstrual Cycle Reproductive Cycle Follicular Begins with Menses ends with luteinizing (LH) hormone surge Ovulation (30-36 hours) Begins with LH surge and ends with ovulation Luteal (14 days) Begins with the end of the LH surge and ends with onset of menses The duration of the Luteal Phase is relatively constant @14 day length. Both Follicular and Luteal phases are approximately 14 days. Therefore, the fluctuation in cycle length vary on the length of the follicular phase. Menstrual irregularities are more common at the extremes of reproductive age women. Beckman, et al., Obstetrics & Gynecology, 7th ed., p. 337

The Normal Menstrual Cycle Another Way of looking at it Visually, one can see the ebb and rise of gonadotropins as well as the ovarian steroid hormones. Also remember that the endometrium is going through changes due to these ovarian hormones. The phases of endometrial changes are menstrual, proliferative and secretory. M. Manting; DUB LECTURE 2008

Phases of the Menstrual Cycle Endometrium Proliferative Begins with menses and ends at ovulation Secretory Begins at ovulation and ends with menses

The Normal Menstrual Cycle Another Way of looking at it Visually, one can see the ebb and rise of gonadotropins as well as the ovarian steroid hormones. Also remember that the endometrium is going through changes due to these ovarian hormones. The phases of endometrial changes are menstrual, proliferative and secretory. M. Manting; DUB LECTURE 2008

Regulation: Hypothalamic Pituitary Axis Hypothalamus is the pulse generator mediated through GnRH GnRH cannot be directly measured Negative Feedback The negative feedback loop could have its own hour of lecture, but there are some basic principals that need to be basic knowledge. With the Hypothalamus secreting GnRH, the anterior pituitary. The anterior pituitary produces LH & FSH. These two gonadotropins act respectively on the theca cells and granulosa cells to produce estrogen. Most progesterone comes from peripheral conversion, but some comes from the graafian follicle. The E2 & P along with inhibin increase to inhibit GnRH, creating the negative feedback loop.

Abnormal Uterine Bleeding (AUB) Definition: Any change in menstrual period Flow Duration Frequency Bleeding between cycles Prevalence: 20 million office visits/year 25% of visits to gynecologists

Old Terminology Dysmenorrhea: Pelvic pain with menses Menorrhagia Metrorrhagia Menometrorrhagia Polymenorrhea Dysmenorrhea Amenorrhea Oligomenorrhea Hypomenorrhea Menorrhagia – bleeding at normal intervals but with heavy flow (> 80 cc) and/or long duration (> 7 days) Metrorrhagia – irregular bleeding between menstrual periods Menometrorrhagia – bleeding at irregular intervals with heavy flow and/or long duration Polymenorrhea – bleeding at intervals < 21 days Oligomenorrhea: > 35 day cyles Hypomenorrhea: scanty flow Dysmenorrhea: Pelvic pain with menses Amenorrhea: 3 months without menses if previously regular or 6 months if irregular Oligomenorrhea: >35 days between menses Hypomenorrhea: <2 days light menses

New Terminology Heavy Menstrual Bleeding Intermenstrual Bleeding Acute Chronic Intermenstrual Bleeding

History for AUB Onset Quantity : Spotting or heavy daily or intermittent Duration

History for AUB Associated Symptoms Pain Fever/chills Dysmenorrhea Menstrual Changes Timing Flow (clots) Frequency Fever/chills Changes in hair/ body Bruising/bleeding Rectal/urethral bleeding Nausea/vomiting

Gender Specific History Menstrual Contraception Gynecologic Obstetric Sexual Genital Infections

Other Important Details Family History Anyone else? Von Willebrand's PCOS Nutrition and exercise Weight changes Exercise habits diet Chronic conditions Liver disease Kidney disease Anemia Drugs /medications Psychiatric medications Thyroid Disorders Blood thinners

Differential Diagnosis Of AUB Structural: PALM-COEIN (Non Gravid Women) Life Cycles: Pre-menarche Menarche Reproductive Post-Menopause Anatomic: “Bottoms Up” This is an introduction into how to organize your medical information. Once the organization of the differential is determined, apply it clinically in an organized fashion. PALM-COEIN was published in FIGO 2011 and adopted by ACOG. Sometimes more than one strategy is used to develop a differential diagnosis.

Pregnancy P PROVE IT! Never Forget Pregnancy Age is Not An Issue! Assumptions can lead to death

PALM-COEIN FIGO Classification System (PALM-COEIN) for causes of AUB in non gravid women of reproductive age Structural vs. Non-Structural Developed to create a universally accepted nomenclature

PALM Structural Causes P- Polyp (AUB-P) A- Adenomyosis (AUB-A) L- Leiomyoma (AUB-L) Submucosal myoma (AUB-LSM) Other myoma (AUB-LO) M- Malignancy & hyperplasia (AUB-M)

COEIN Non-Structural Causes C- Coagulopathy (AUB-C) O-Ovulatory dysfunction (AUB-O) E- Endometrial (AUB-E) I- Iatrogenic (AUB-I) N- Not yet classified (AUB-N

AUB-O Abnormal Uterine Bleeding with ovulatory dysfunction Heavy, irregular bleeding

Causes of Anovulation: Physiologic Adolescence Menopause Transition Lactation Pregnancy

Causes of Anovulation Pathologic Hyperandrogenic anovulation (e.g., PCOS, CAH, or androgen-producing tumors) Hypothalamic dysfunction Hyperprolactinemia Thyroid disease Pituitary disease Premature ovarian failure Iatrogenic (Chemo) Medications

Iatrogenic I IUD related Post-instrumentation Post medical abortion Infection Endometritis Cervicitis Ascending/PID Hematogenously (TB) Clinical findings may be very subtle. Very thorough, gender specific history is absolutely necessary to find the clues that illuminate the diagnosis. Think about how differently a clinical vs. sub-clinical infection might present.

Liver Disease Patients known to have liver disease manifest additional symptomatology because of abnormal hepatic function. Evaluate patients for spider angioma, palmar erythema, splenomegaly, ascites, jaundice, and asterixis.

Coagulation Disorders Rule out von Willebrand's in any girl who requires transfusion for excessive bleeding when first starting periods

Bleeding from ther Sites GI Neoplasia or hemorrhoids GU Urethral caruncle or diverticulum Renal lithiasis or hemorrhagic cystitis GYN Labia, cervix, or vagina Trauma, infection, or neoplasia Remember Hemoccult & Urinalysis

Differential Diagnosis of AUB: Life Cycles Pre-Menarche Menarche Reproductive Postmenopausal

Etiology of AUB Life Cycles Approach E2 withdrawal @birth Foreign Body Sarcoma Ovarian Tumor Trauma Coagulation Defects Hypothalamic Immaturity Psychogenic Pregnancy Anovulation Endogenous Exogenous Anatomic Carcinoma Vaginal Atrophy E2 Replacement Post-Menopausal Menarche Reproductive Premenarchal In all ages one must consider foreign body. Anatomic = uterine lyomas, polyps, muellerian anomalies, etc. Sarcoma Botryoides is a very aggressive almost uniformly fatal pediatric cancer.

Differential Diagnosis of AUB: Structural “Bottoms Up” Vulva Vagina Cervix Ovary Brain Contiguous Anatomy GU GI Non-Pelvic Etiology Endogenous Iatrogenic

PHYSICAL EXAM: INSPECTION IS IMPORTANT Vulvar Infections HPV Atrophy Benign Lesions Cancerous lesions Dermatologic Causes PHYSICAL EXAM: INSPECTION IS IMPORTANT

Vagina Malignancy : Infections Foreign bodies Laceration/trauma Carcinoma Sarcoma Infections Foreign bodies Diaphragm, Pessary Tampon other Laceration/trauma Atrophic changes Granulomatous tissue formed after surgery post hysterectomy Physical Exam: Inspection is important

Cervix Neoplasia Cervical Eversion (Ectropion) Infection Cancer Polyps Myomas Cervical Eversion (Ectropion) Infection Cervicitis Condyloma Acuminata IMPORTANT: Visualize the Cervix!

until proven otherwise PHYSICAL EXAM: Bimanual Exam checks enlargement Postmenopausal Bleeding is considered endometrial cancer until proven otherwise Uterus Myomas Polyps Endometrial Hyperplasia Endometrial Carcinoma Atrophy Postmenopausal bleeding is evaluated by an Endometrial biopsy Most PMB Is due to Atrophy PHYSICAL EXAM: Bimanual Exam checks enlargement

Ovary Anovulation PCOS Menopause Transition

Pathophysiology Etiologies Of AUB Estrogen Withdrawal Estrogen Breakthrough Progesterone Withdrawal Pathophysiology: Estrogen Withdrawal: Sudden withdrawal of estrogen will cause the uterus to bleed, either iatrogenic (bilateral oophorectomy) or endogenous (natural drop of estradiol at mid cycle ovulation). Estrogen Breakthrough: During an anovulatory cycle, the corpus luteum fails to form, which causes failure of normal cyclical progesterone secretion. This results in continuous unopposed production of estradiol, stimulating overgrowth of the endometrium. Without progesterone, the endometrium proliferates and eventually outgrows its blood supply, leading to necrosis. The end result is overproduction of uterine blood flow. There is not universal simultaneous change with and orderly progression of cyclic events involving formation of rigid, compact glandular structure, vasomotor rhythmicity, vasoconstriction, structural collapse and clotting. Progesterone Withdrawal: Sudden decrease in the progesterone levels in a female which is iatrogenic (a progesterone only oral contraceptive). The endometrium Atrophies and ulcerates due to lack of estrogen and is prone to bleeding Clinical Management of Abnormal Uterine Bleeding: APGO Educational Series, May 2002, p. 8.

Initial Assessment of AUB Acute Sub-Acute Chronic Initial evaluation should be directed at assessing patient's volume status and degree of anemia.

Initial Assessment of AUB History & Physical Vital Signs Shock Signs Laboratory Pregnancy Test Complete Blood Count General impression of the patient is your first clue. Is she pale, tachycardic, Hypotensive? Is there a positive sock sign?

EVALUATION OF AUB Pregnant? Evaluate for complications IUP, SAB, Ectopic Structural (PALM) VS. Non-Structural (COEIN) YES NO

Evaluation of AUB Evaluation of the Endometrium Endometrial Biopsy Pregnancy test Endometrial Biopsy Transvaginal &/or abdominal Ultrasound (TVS/AUS) Saline Sono-hysterocopy (SIS) Hysteroscopy Evaluation of the Uterus TVS SIS

Endometrial Biopsy (EMB) Evaluation of the Endometrium Pipelle Endometrial Biopsy is sensitive 98-99% in diagnosing cancer, but it misses 50% of benign diagnosis (i.e., polyps, fibroids, endometritis).

Transvaginal Ultrasound To assess for thickened endometrium In 92% of abnormal endometrial biopsies, ultrasound showed >5mm endometrium In 96% of endometrial cancer by biopsy result, ultrasound showed >5mm endometrium Therefore, ultrasound measured endometrium <5mm is likely benign uterine condition

TVS & SIS SIS is superior to TVS alone fo evaluating the uterine cavity. Sterile saline is infused into the endometrial cavity during real-time ultrasound. The saline provides contrast to clearly define endometrial abnormalities. TVS SIS

Hysteroscopy Hysteroscopy, which may been done as an office procedure, allows for direct visualization of the endometrial cavity. For many years it was considered the gold standard for evaluation of the endometrial cavity. More recently, studies have shown hysteroscopy is less sensitive in detecting endometrial hyperplasia.

MRI Precisely localizes sub-mucosal fibroids MRI is not superior to TVS & SIS in overall diagnostic potential MRI is used primarily to determine whether a patient is a candidate for Selective Uterine Artery Embolization (EUA). Dueholm M, et al. Fertil Steril. 2001;76(2):350357

Treatment of AUB Observation Medical Minimally invasive surgery Major surgery

Medical Management Iron Parenteral estrogens Anti-fibrinolytics Progestins Estrogen + progestins (OCP) Parenteral estrogens Androgens GnRH agonists Anti-progestational agents For older, stable (hematocrit 25-35%) patients with a known history of DUB, iron deficiency anemia, and moderate amount of prolonged bleeding, administer a combination of high-doses estrogen and synthetic progesterone oral contraceptives (e.g., Ortho-Novum 1/50 qid 7 d) to arrest bleeding. Oral contraceptives may aggravate an already suppressed hypothalamic-ovarian axis in young postmenarcheal patients; therefore, use it in patients with an established menstrual history. Exclude pregnancy prior to initiating therapy. Modicon 21 (ethinyl estradiol, norethindrone) Ortho-Novum 1/35 (ethinyl estradiol, norethindrone) Ortho-Novum 1/50 (mestranol, norethindrone) Levlen 21,28 (ethinyl estradiol, levonorgestrel) Lo/Ovral (ethinyl estradiol, norgestrel) Ortho-Cept 21 (ethinyl estradiol, desogestrel) Demulen 1/30,50 (ethinyl estradiol, ethynodiol diacetate) These can be started safely in the ED after the severe acute bleeding episode is curtailed with IV estrogen and pregnancy has been ruled out.

Minimally Invasive Surgery Intrauterine Device (IUD) with progesterone Dilation & Curettage Endometrial Ablation Progesterone containing IUD reduces bleeding in most women with the added benefit of providing contraception as well. 95% are satisfied with the reduction in bleeding. D & C is only 70% effective in controlling bleeding. Endometrial Ablation is comparable to progesterone IUD in controlling AUB. The smaller the uterus the better the result.

Major Surgery Myomectomy Total Abdominal Hysterectomy (TAH) Total Vaginal Hysterectomy (TVH) Laparoscopic Hysterectomy LSH (laparoscopic supra-cervical) TLH (total laparoscopic) LAVH (laparoscopically assisted vaginal hysterectomy) Robotic (TLH or LSH) Total hysterectomy refers to the removal of the cervix with the uterine fundus. Supra-cervical Hysterectomy may be done abdominally or laparoscopic. Note that a hysterectomy can be done as minimally invasive. All hysterectomies may or may not include removal of the ovaries.

Management of Acute AUB Can be a life-threatening emergency Monitor Vital signs, Start oxygen IV fluids (wide bore IV catheter) Type and Cross 2-4 units of blood IV Estrogen IM Progesterone NSAIDS (Anti-prostaglandins vs. Anti-fibrinolytics) Emergency Dilatation and Curettage (D&C) Start with ABC’s. Use clinical judgment to for the most likely etiology to begin treatment.

Treatment in Chronic, Stable AUB High dose OCP’s to slow the bleeding Anovulatory Bleeding can be treated with progesterone alone Endometrial sampling is indicated prior to starting hormones in older women

Clinical Pearls PROVE IT! Never Forget Pregnancy! Age is Not an Issue! Assumptions Can Lead to Death!

References ACOG Practice Bulletin No. 136, July 2013 Beckmann, et al., Obstetrics & Gynecology, 7th ed., Chapters 37, 39 Clinical Management of Abnormal Uterine Bleeding: APGO Educational Series, May 2002 Dueholm M, et al. Fertil Steril. 2001;76(2):350357 Fritz, MA, Speroff et al, Clinical and Gynecologic Endocrinology and Infertility, 8th ed. 2011. Manting M., AUB Lecture 2008 Munro, MG, et al, FIGO Classification System (PALM-COEIN) for causes of AUB in non gravid women of reproductive age. Int J Gynaecol Obstet 2011; 113:3-13