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2/3/2016 Perimenopausal Bleeding Anna Witt, MD February 3, 2016 Disclosures/Affiliations • Financial • None Objectives • Review the clinical course of perimenopause • Review the standardized terminology, definitions, and classification of abnormal uterine bleeding • Differentiate normal and abnormal bleeding during perimenopause • Learn current recommendations to evaluate abnormal uterine bleeding that occurs during perimenopause • Learn current recommendations to treat abnormal uterine bleeding associated with perimenopause Objective #1 • Review the clinical course of perimenopause • Pharmaceutical • None Perimenopause Perimenopause • Perimenopause (a.k.a. menopausal transition) • The period around the onset of menopause that is often marked by various physical signs (as hot flashes and menstrual irregularity) • Merriam-Webster Dictionary • Time period during which a woman’s body makes its natural transition toward permanent infertility • Mayo Clinic 1 2/3/2016 Perimenopause • Onset • On average, 4 years before the final menstrual period (FMP) • Median age is 47 years • May occur as early as the mid-30’s and as late as the early-50’s • Duration • May last 2-10 years • End • 12 consecutive months without a menstrual period • This retrospectively determines when menopause has occurred. The median age of menopause is 51.4 years < Age 40 Age 40-45 Primary ovarian insufficiency 5% Age 45-55 > Age 55 90% 5% Perimenopause Manifestations • Progressive decline in ovarian function • Irregular menstrual cycles • Hormonal fluctuations • • • • • • • • • • Hot flashes Sleep disturbances Mood changes Vaginal dryness Bladder problems Decreasing fertility Sexual dysfunction Joint pain Breast pain Menstrual Migraines The Stages of Reproductive Aging Workshop (STRAW) +10 Staging System for Reproductive Aging in Women Perimenopause Manifestations • Progressive decline in ovarian function • Irregular menstrual cycles • Hormonal fluctuations • • • • • • • • • • Hot flashes Sleep disturbances Mood changes Vaginal dryness Bladder problems Decreasing fertility Sexual dysfunction Joint pain Breast pain Menstrual Migraines Data • Information about perimenopause comes from a number of longitudinal, cohort studies of midlife women • Study of Women’s Health Across the Nation (SWAN) • Multiethnic, community-based, cohort of >3000 women ages 42-52 for 15 years • A staging system was developed based on these cohort studies to characterize reproductive aging • Stage of Reproductive Aging Workshop (STRAW) staging system Objective #2 • Review the standardized terminology, definitions, and classification of abnormal uterine bleeding 2 2/3/2016 Normal Menses • Normal menstrual flow is 3-7 days (average 5) • Normal menstrual cycle length is 21-35 days (average 28) A normal cycle starts when pituitary follicle stimulating hormone induces ovarian follicles to produce estrogen Estrogen stimulates proliferation of the endometrium A leutinizing hormone surge prompts ovulation the resultant corpus luteum produces progesterone, inducing a secretory endometrium in the absence of pregnancy, estrogen and progesterone levels decline, and withdrawal bleeding occurs 13-15 days post-ovulation Abnormal Uterine Bleeding • Menstrual flow outside the normal volume, duration, regularity, or frequency is considered abnormal uterine bleeding (AUB). • It accounts for > 70% of all gynecologic consults in the perimenopausal and postmenopausal years AUB Terminology to Forget • Menorrhagia/Hypermenorrhea • Heavy menstrual bleeding • Hypomenorrhea • Light menstrual bleeding • Metrorrhagia • Bleeding between periods • Menometrorrhagia • Excessive or prolonged bleeding at and between menstrual periods • Polymenorrhea/Polymenorrhagia/Epimenorrhea/Epimenorrhagia • Bleeding that occurs more frequently than every 21 days • Oligomenorrhea • Bleeding that occurs less frequently than every 35 days • Metropathia hemorrhagica • Abnormal, excessive, often continuous uterine bleeding due to persistence and exaggeration of the follicular phase of the menstrual cycle • Dysfunctional uterine bleeding • Irregular uterine bleeding in the absence of pathology or medical illness • Functional uterine bleeding • Bleeding in the absence of gross lesions, at unexpected times, or in abnormal amounts AUB Terminology that is Currently Acceptable • • • • • • • • • • • • • • • Irregular menstrual bleeding (IrregMB) Absent menstrual bleeding (Amenorrhea) Infrequent menstrual bleeding Frequent menstrual bleeding Heavy menstrual bleeding (HMB) Heavy and prolonged menstrual bleeding (HPMB) Light menstrual bleeding Prolonged menstrual bleeding Shortened menstrual bleeding Intermenstrual bleeding (IMB) Irregular nonmenstrual bleeding Postmenopausal bleeding (PMB) Precocious menstruation Acute AUB Chronic AUB AUB Classification System • In 2011, the International Federation of Gynecology and Obstetrics (FIGO) introduced a new classification system to describe uterine bleeding abnormalities in reproductive-aged women • In 2012, the American College of Obstetricians and Gynecologists (ACOG) said it supports adoption of this nomenclature system to standardize the terminology used to describe AUB 3 2/3/2016 PALM-COEIN • Classifies abnormal uterine bleeding by pattern and etiology • Pattern • Menorrhagia Heavy Menstrual Bleeding • Metrorrhagia Intermenstrual Bleeding • Etiology • Structural Causes (PALM) • Polyp • Adenomyosis • Leiomyoma • • Submucosal Other myoma • Malignancy and hyperplasia • Nonstructural Causes (COEIN) • • • • • Coagulopathy Ovulatory dysfunction Endometrial Iatrogenic Not yet classified (AUB/HMB) (AUB/IMB) (AUB-P) (AUB-A) (AUB-L) Components of PALM-COEIN • Polyp (AUB-P) • Intracavitary and composed of endometrial tissue. • Accounts for 39% of AUB in premenopausal women and 21-28% o f AUB in postmenopausal women. • Diagnosed by transvaginal ultrasound (TVUS), saline infusion sonohysterography (SIS), and hysteroscopy • Adenomyosis (AUB-A) • Endometrial tissue that grows into the muscular tissue of the uterus • 70% of women with adenomyosis have AUB • Diagnosed by TVUS and magnetic resonance imaging (MRI) (AUB-LS) (AUB-LO) • Leiomyoma (AUB-L) (AUB-C) (AUB-O) (AUB-E) (AUB-I) (AUB-N) • Malignancy and hyperplasia (AUB-M) (AUB-M) Components of PALM-COEIN • Coagulopathy (AUB-C) • 13% of women with HMB have a disorder of hemostasis, which is often overlooked in the differential diagnosis • • • • Submucosal, Intramural, or Subserosal. Composed of muscle tissue. Age is most common risk factor with lifetime risk of 60% in women > 45 years. Submucosal lesions more likely to be associated with AUB May be diagnosed by TVUS, SIS, MRI or hysteroscopy, but depends on location • 15% of postmenopausal women with AUB will have endometrial carcinoma • 15% of postmenopausal women with AUB will have endometrial hyperplasia Objective #3 • Differentiate normal and abnormal bleeding during perimenopause • Ovulatory dysfunction (AUB-O) • Unpredictable menses and variable flow that is usually associated with endocrinopathies • Endometrial (AUB-E) • Usually present with HMB, which may be a disorder of endometrial hemostasis, or IMB, which may be secondary to inflammation or infection • Iatrogenic (AUB-I) • Causes include medications that affect blood coagulation or ovulation, chemotherapy, or radiation. Typical Menstrual Cycle Changes during Perimenopause • Overall, there is a general decrease in menstrual bleeding • First, there is a lengthening of the intermenstrual interval. • Persistent ≥ 7 day difference in length of consecutive cycles • Then there are more dramatic changes with episodes of skipped cycles and periods of amenorrhea. • ≥ 60 days of amenorrhea • And finally, there is persistent amenorrhea • 365 consecutive days of amenorrhea 4 2/3/2016 Atypical Menstrual Cycle Changes during Perimenopause • An overall increase in menstrual bleeding is not normal • Heavy menstrual bleeding • Changing pad or tampon every 1-2 hours for 2 hours or more Objective #4 • Learn current recommendations to evaluate abnormal uterine bleeding that occurs during perimenopause • Prolonged menstrual bleeding • Bleeding lasts longer than 7 days • Intermenstrual bleeding • Bleeding in between cycles • Frequent menstrual bleeding • Menstrual cycles < 21 days apart Clinical Case • J.K. is a 45 yo female who presents to clinic with complaint of irregular menses. Wonders if she is going through menopause. Missed 2 cycles completely. Some months, menses have been lighter and shorter than usual, followed by a few days of no bleeding, but then bleeding returns for another few days. Other months, menses heavier than what she considers normal. She has also noticed breast tenderness in the middle of her cycles rather than with bleeding. Thinks she is starting to have hot flashes because she feels hotter than she is used to when physically active and also occurs out of the blue at rest. No idea about when other female relatives went through menopause. Also complains of urinary frequency and urgency for past week. Denies dysuria or vaginal discharge. Evaluation • Medical conditions • • • • • • Polyp Adenomyosis Leiomyoma Malignancy or hyperplasia (endometrial) Coagulopathy Ovulatory dysfunction • • • Pregnancy Lactation Hyperandrogenism • Hypothalamic dysfunction • • • • • • • • • Polycystic ovarian syndrome, congenital adrenal hyperplasia, etc… Anorexia nervosa Pituitary disease Premature Ovarian Failure Hyperprolactinemia Thyroid disorder Diabetes Endometrial Iatrogenic • • Medications Chemotherapy or radiation • J.K. • • • • • • • • • • • • • • • Bipolar 2 disorder, major depressive Irritable bowel syndrome Morbid obesity Esophageal reflux Hypertension Anemia, iron deficiency Osteoarthritis of right knee Cholecystitis Tibial plateau fracture ASCUS and LSIL on pap smear Sudden cardiac arrest Takotsobu syndrome Cardiomyopathy ICD in place G0P0 Evaluation • Menstrual history • Age of menarche and menopause • Menstrual bleeding patterns • Severity of bleeding (clots or flooding) • Pain (severity and treatment) • J.K. • Onset of menses at age 13. • Typical pattern • Bleeding duration of 6 days • Flow is heavy light • Cycle length is 24-29 days and regular. • Associated symptoms of breast tenderness with bleeding. • Severity is normally without clots or flooding. Also denies clots or flooding recently, just heavier bleeding that usual and recurrent bleeding several days after she thinks her period has ended • Only pain is breast tenderness and does not take medication for it. Evaluation • Surgical history • • • • Brain Endocrine Pelvic Complications • J.K. • Wisdom tooth extraction • Colposcopy with biopsy/curettage • Cholecystectomy • ORIF proximal tibial plateau fracture • Endotracheal intubation • Cardiac catheterization • Cardiac defibrillator placement 5 2/3/2016 Evaluation • Use of medications Antiplatelet Anticoagulant Antiepileptics Antipsychotics Hormonal contraceptives • Herbals • • • • • Evaluation • Physical examination • General • Pelvic • J.K. • • • • • • clonazepam duloxetine ferrous sulfate fluoxetine lamotrigine nadolol Evaluation • Symptoms and signs of possible hemostatic disorder • Heavy menstrual bleeding since menarche • One of the following: • Obese, otherwise normal exam • External genitalia • Speculum • Bimanual • ? Heavy menstrual bleeding • Postpartum hemorrhage • Surgery-related bleeding • Bleeding associated with dental work • Two or more of the following: • • • • • J.K. • J.K. Bruising 1-2 x per month Epistaxis 1-2 x per month Frequent gum bleeding Family history of bleeding symptoms AUB Age Based Common Differential Diagnosis • 13 to 18 years • 19 to 39 years • 40 years to menopause • • • • • • • Anovulatory bleeding Endometrial hyperplasia or carcinoma Endometrial atrophy Leiomyoma Pregnancy Thyroid disease Hyperprolactinemia • Postmenopausal Anovulatory Bleeding In the absence of ovulation, the corpus luteum does not develop and the ovary fails to produce progesterone Endometrial proliferation without progesteronewithdrawal induced shedding and bleeding Endometrium that develops is fragile, vascular, and lacking stromal support As one area of bleeding begins to heal, another area begins to slough. Result is bleeding that is noncyclic, unpredictable, and inconsistent in volume Hormonal Changes of Early Perimenopause 6 2/3/2016 Endometrial Hyperplasia or Malignancy Cancer of the Corpus and Uterus, Age-Specific Rates, 2008-2012 SEER Cancer Statistics Review Age at Diagnosis/Death Incidence/100,000 Mortality/100,000 20-24 0.4 - 25-29 2.0 0.1 30-34 4.5 0.2 35-39 9.0 0.5 40-44 14.2 1.0 45-49 24.5 1.9 50-54 46.2 3.9 55-59 74.6 7.5 60-64 93.1 12.9 65-69 101.6 17.6 70-74 94.8 21.9 75-79 82.4 24.5 80-85 70.6 27.6 85+ 56.3 33.7 Evaluation • Tissue Sampling Methods • Office endometrial biopsy (EMB) • Hysteroscopy directed endometrial sampling (office or hospital) • Dilation and curettage (D&C) • Diagnostic or Imaging Tests • • • • Transvaginal ultrasound (TVUS) Hysteroscopy Saline infusion sonohysterography (SIS) Magnetic resonance imaging (MRI) Evaluation Uterine Evaluation for Abnormal Uterine Bleeding, ACOG Practice Bulletin 128, Figure 2 Evaluation • Laboratory Testing • • • • • • • J.K. Pregnancy test CBC TSH Prolactin Cervical cancer screening Cervicitis screening • HCG Qualitative Urine • Negative • Hgb/Plt • 11.7/395 • TSH • 2.35 • Prolactin • not obtained • Cervical Cancer • Cytology negative for intraepithelial lesion or malignancy • HPV negative for high risk types • Cervicitis • not obtained Evaluation Evaluation and Management of Abnormal Uterine Bleeding in Premenopausal Women. AFP. 2012; 85(1):35-43. Table 2 Test Utility Endometrial Biopsy • • • Readily available Low complication rate Inexpensive • • • • Pregnancy Clotting disorder Acute PID or Cervicitis Not able to diagnose AUBP,A,L Endometrial carcinoma • 91% sen, 98% sp Endometrial hyperplasia w/ atypia • 82.3% sen, 98% sp Hysteroscopy • Direct visualization of the uterine cavity Allows for directed biopsy at time of procedure • • • • Pregnancy Clotting disorder Acute PID or Cervicitis Does not evaluate myometrium or ovaries Intracavitary abnormality • 94% sen, 89% sp Detects endometrial and myometrial abnormalities Assesses ovaries Less sensitive and specific than SIS Intracavitary abnormality • 60-92% sen • 62-96% sp Pregnancy Clotting disorder Acute PID or Cervicitis More expensive than TVUS Limited availability Intracavitary abnormality • 88-99% sen • 72-95% sp • Transvaginal Ultrasound • • Saline Infusion Sonohysterography Has utility of TVUS with improved capacity to diagnose endometrial abnormalities Limitations or Contraindications • • • • • Effectiveness Evaluation • J.K. • Endometrial Biopsy • DIAGNOSIS • Benign endometrium with uneven hormone effect and features consistent with exogenous hormone effect. • GROSS DESCRIPTON • Present are multiple fragments of clear mucoid material as well as pale to pinktan tissue measuring in aggregate 1.3 x 0.8 x 0.5 cm. The specimen is entirely submitted in one cassette. • MICROSCOPIC DESCRIPTION • Sections from the endometrial biopsy show several fragments of endometrial tissue. The endometrium has a variable appearance with some fragments displaying small tubular-like inactive endometrial glands surrounded by pseudodecidualized appearing endometrial stroma. Other fragments of endometrium display irregularly contoured and coiled appearing endometrial glands lined by vacuolated columnar epithelium. The glandular to stromal ratio is not increased. Crush artifact is present. No definitive stromal breakdown is identified. No atypical complex hyperplasia or malignancy is identified. 7 2/3/2016 Evaluation • J.K. • US Pelvic Transvaginal • FINDINGS • The uterus is retroverted. It measures 7.1 x 4.4 x 5 cm. Endometrial stripe is of normal caliber measuring 3 mm. Within the uterine myometrium, there is a solid right-sided myometrial mass measuring up to 4.7 cm in diameter consistent with a uterine fibroid. The right and left adnexa are identified. A 1 cm simple-appearing cyst is noted in the right adnexa. Blood flow is noted to both adnexa. The right and left ovaries measure 2.5 x 2.2 x 2.1 and 2.1 x 1.7 x 1.9 cm. No complex adnexal masses or free pelvic fluid is evident. • IMPRESSION • Retroverted uterus with evidence of right-sided uterine fibroid. Tissue Sampling Considerations • Role of testing is to determine whether endometrial hyperplasia or carcinoma is present • Women 45+ and Women < 45 with history of unopposed estrogen, failed medical treatment, and persistent AUB • First line test • Technique • Office endometrial biopsy (EMB) • Office or hospital hysteroscopy with endometrial sampling • Dilation and curettage (D&C) • If specimen insufficient, non-diagnostic, or cannot be performed, try again with same or different technique. • Only an endpoint if positive for hyperplasia or carcinoma • Persistent bleeding necessitates further evaluation to rule out other pathology Imaging Considerations • Literature is unclear about when evaluation with imaging is indicated. • Reasonable to perform if patient has an abnormal pelvic exam • Polyps, Adenomyosis, Leiomyomas, Imaging Considerations - Polyp • Also if patient has a normal pelvic exam, but persistent AUB symptoms despite medical treatment and benign endometrial tissue sampling • Imaging Choice • Transvaginal Ultrasound (TVUS) is useful as a screening test • Endometrial thickness • Measurement is of limited value in the premenopausal women since thickness varies throughout the cycle in response to hormonal changes • Hysteroscopy • Saline infusion sonohysterography (SIS) • Magnetic resonance imaging (MRI) • Routine use not recommended, but may be useful to guide treatment such as myomectomy or uterine artery embolization Imaging Considerations Adenomyosis Imaging Considerations Leiomyoma 8 2/3/2016 Objective #5 • Learn current recommendations to treat abnormal uterine bleeding associated with perimenopause Treatment of AUB-O during Perimenopause • Initiate treatment after a complete diagnostic workup has been completed • Choice of treatment should be guided by goals of therapy • • • • Stop acute bleeding Avoid future irregular or heavy bleeding Provide contraception Prevent complications such as anemia, unnecessary surgical intervention, or diminished quality of life • Because AUB-O is an endocrinologic abnormality, the underlying disorder should primarily be treated medically • Surgical therapy is rarely indicated unless medical treatment fails, is contraindicated, is not tolerated by the patient, or the patient has concomitant significant intracavitary lesions. Treatment of AUB-O during Perimenopause • Medical Therapy • Hormonal contraceptives are preferred to hormonal therapy unless there is a contraindication • Hormonal contraceptives have the benefit of menstrual control, endometrial protection, contraception, and vasomotor symptom control • Premenopausal use of hormone therapy will not provide contraception, and is +/- on menstrual regularity and vasomotor symptom control • • • • Treatment of AUB-O during Perimenopause • Medical Therapy • Nonhormonal options may relieve symptoms of heavy menstrual bleeding, but do not offer benefit of menstrual control, endometrial protection, or contraception • NSAIDS • Tranexamic acid Combined hormonal contraceptives • Oral pills, transdermal patches, vaginal rings Progestin contraceptives • Levonorgestrel intrauterine device • Depot medroxyprogesterone acetate Cyclical progestins • Oral medroxyprogesterone acetate • Norethindrone acetate Continuous progestins • Megestrol Treatment of AUB-O during Perimenopause • Surgery • Concomitant Intracavitary lesions • Polypectomy • Myomectomy • Uterine artery embolization • Hysterectomy • For women who have completed childbearing and failed medical therapy or have contraindications to medical therapy • Risks of surgical complications, longer recovery time, increased cost Treatment • J.K. • Elected no treatment • 8 month follow-up • Menses are still erratic. Not a regular interval between them. Sometimes flow is very heavy, sometimes light. Sometimes has flow for 2-3 days, nothing for 2-3 days, then flow for another 2-3 days. Other times just has steady flow for 8-10 days. Gets crankier and short tempered or emotional a few days before menses. • Endometrial ablation • Not first line • Risks regarding future ability to detect and diagnose endometrial cancer because methods of endometrial surveillance (EMB, hysteroscopy, TVUS, SIS) may be compromised due to complications of procedure (intrauterine synechiae or adhesions, cervical stenosis, and endometrial contractures, strictures, or distortion) • No contraceptive benefit 9 2/3/2016 Contraception • Perimenopause vs. Menopause • If using a hormonal method • Discontinue when risk remote based on age: 50-55 • Switch to non-hormonal method until able to diagnose menopause • If using a non-hormonal method • Continue to use until able to diagnose menopause Is there an indication for testing serum FSH? • In general, changes in menstrual bleeding patterns are a better predictor of menopausal stage than serum FSH concentrations (SWAN study) due to FSH variability • Special situations • Underlying menstrual cycle disorders • Menstrual cycle changes may not occur and/or are not reliable. If menopausal symptoms develop, measure FSH • Estrogen-progestin contraceptives • Women on these do not experience menstrual cycle changes or menopausal symptoms. Stop the contraception at age 50-55 years and measure FSH 2-4 weeks later • Post-hysterectomy or endometrial ablation • Women do not have bleeding. If menopausal symptoms develop, measure FSH The Stages of Reproductive Aging Workshop (STRAW) +10 Staging System for Reproductive Aging in Women • The STRAW staging system includes supportive criteria for determining reproductive stage. • Serum levels of FSH, inhibin B, AMH • Pelvic ultrasound for antral follicle count (AFC) • These are NOT diagnostic criteria for perimenopause or menopause and have NOT been validated for such use. These have been used to assess ovarian reserve in the setting of assisted reproductive technologies. Questions References • http://www.mayoclinic.org/diseasesconditions/perimenopause/basics/definition/con-20029473 • Harlow SD, Gass M, Hall JE, et al. Executive Summary of the Stages of Reproductive Aging Workshop + 10: Addressing the Unfinished Agenda of Staging Reproductive Aging. J Clin Endocrinol Metab 2012. • Welt CK, McNicholl DJ, Taylor AE, Hall JE. Female reproductive aging is marked by decreased secretion of dimeric inhibin. J Clin Endocrinol Metab 1999; 84:105. • http://www.nature.com/articles/nrdp20154 • ACOG. Practice Bulletin #128. Diagnosis of Abnormal Uterine Bleeding in Reproductive Aged Women. July 2012. • ACOG. Practice Bulletin #136. Management of Abnormal Uterine Bleeding Associated with Ovulatory Dysfunction. July 2013. • ACOG. District 8. Abnormal Uterine Bleeding (AUB) New Standardized Terminology, Definitions, Classification • Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z,Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEER data submission, posted to the SEER web site, April 2015. • http://www.advancedwomensimaging.com.au/saline-sono-hysterogram • Sweet MG, Schmidt-Dalton TA, Weiss PM. Evaluation and Management of Abnormal Uterine Bleeding in Premenopausal Women. American Family Physician. 2012; 85(1):35-43. • http://www.drugs.com/dict/metropathia-hemorrhagica.html 10