10/23/2013

Too much, too little, too The Questions early, too late, too fast:

Abnormal Uterine  Too much (& too early or too late)…Menometrorrhagia Bleeding 1. Differential and approach to work-up. 2. Does she need an EMB? Rebecca Jackson, MD 3. Does she need an ultrasound? Professor 4. How do I stop peri-menopausal bleeding? Obstetrics & Gynecology 5. Isn’t it due to the fibroids? University of California,  Too fast: She’s hemorrhaging—what do I do? San Francisco  Too little: A quick review of 2°

 Too late: pregnant and bleeding

Case 1 Q1: In addition to a and TSH, which of the A 46 yo G3P2T1 reports her periods have become following is the most appropriate increasingly irregular and test to order at this time? heavy over the last 6-8 1. months. Sometimes they come 1. What term describes FSH her symptoms? 2 times per month and 2. Testosterone & DHEAS sometimes there are 2 months 2. Physiologically, what between. LMP 2 months ago. causes this type of 3. Serum beta-HCG bleeding pattern and She bleeds 10 days with clots why? 4. Transvaginal Ultrasound and frequently bleeds through 3. What is the 5. pads to her clothes. She differential? occasionally has hot flashes. She also has diabetes and is obese.

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Pathophysiology: Anovulatory Bleeding Terminology: What is abnormal? Bricks & Mortar Estrogen=Bricks, build  Normal: Cycle= 28 days +- 7 d (21-35); Length=2-7 days; Heaviness=self-defined Progesterone (P) =Mortar,  Too little bleeding: amenorrhea or stabilize it, only have P if ovulate  Too much bleeding: Menorrhagia (regular timing but heavy or long flow (>7 days) Normal menses: withdrawal of P causes wall to fall down,  Metrorrhagia, intermenstrual Irregular bleeding: all at once (orderly bleed) or post-coital bleeding : No P so when  Irregular and Excessive: Menometrorrhagia wall grows too tall, it falls.  Preferred term for non-pregnant bleeding Bleed is heavy because wall is issues= Abnormal Uterine Bleeding (AUB) tall. Bricks can also fall Avoid “DUB” - dysfunctional uterine bleeding. intermittently & incompletely ie irregularly irregular

Differential: AUB Causes of anovulation Step 1: Pregnant vs Not Physiologic Hyperandrogenic CNS Iatrogenic Pregnant * Not Pregnant  Ectopic  Anovulation ***  Spontaneous  Anatomic/structural ** Abortion  Neoplastic *  Threatened Abortion  Infectious  Molar Pregnancy  Iatrogenic Peri-/Peri- PCOS  Trauma  Non-gynecologic Hypo/Hyper Thyroid  Some non-pregnant causes

* = Most likely for this patient Obesity Anorexia/Over-exercise

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Reference: Causes of anovulation Reference: AUB Differential Physiologic Hyperandrogenic CNS Iatrogenic : Myoma, polyp, , atrophy Pregnancy PCOS Pituitary adenoma Levonorgestrel (prolactin- IUD (Mirena) Not Pregnant : polyp, atrophy, trauma Peri-menarche Adult-onset secreting) Depo-provera Vagina: atrophy, trauma Peri-menopause congenital adrenal hyperplasia Neuroleptic agents Nexplanon, AnovulationHormonal Breast-feeding (via increased Implanon prolactin ) Uterus: Hyperplasia, Obesity (via OCP Anatomic Hypo or hyper Cervix: Dysplasia, cancer insulin effect in thyroid Neoplastic Ovary: hormone producing tumor ovary) Hypothalamic (stress, anorexia) Uterus: , PID Infectious Cervix:

Non-Gynecologic Vagina: (eg Trich)

Coagulopathy (vWD), severe renal or liver dz, GI or GU source

Reference: New Schema for AUB Initial Work-up: diagnosis and terminology menometrorrhagia What about heavy  Always: Urine pregnancy AND irregular?  Usually: TSH  Maybe: Hct, r/o coagulopathy  Maybe: EMB  Maybe but later: Transvaginal Ultrasound  Usually not necessary: FSH, LH, “PALM-COEIN” Testosterone, Estradiol

FIGO (Federation International Gyn & Ob)

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Does she need an EMB? The Problem Endometrial Cancer Facts  Irregular bleeding is common  4th most common cancer in women  Endometrial cancer is relatively common  Average age 61 but 25% occur pre-menopausally  Risk prediction models are not useful  10% of post-menopausal women with bleeding have cancer  Little evidence to guide us regarding when  Presents at early stage with bleeding; rare in the to do EMB absence of bleeding. Vast majority effectively treated with simple hyst  ACOG guidelines (expert opinion) recommend biopsy in MANY women  Risk Factor = Increased estrogen (long h/o anovulation eg PCOS, obesity). Protective = smoking, OCP’s

ACOG, July 2012 Perimenopause

 Averages 4 years

12% suddenly stop menstruating

18% have longer, heavier menses

70% have short, irregular menses

Should we therefore perform EMB on all but 12% of women? ACOG Practice Bulletin 128, Diagnosis of AUB in Reproductive-Aged Women

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The evidence… A rational approach to EMB

 Natural history: Endometrial cancer takes many  One prospective cohort study of 1000 women years to develop progressing from no atypia to to test less aggressive EMB Clinical Pathway atypia prior to invasion. We have time to detect  All eligible for biopsy using ACOG guidelines. it. Only biopsied those that were post-  Bleeding pattern cues: Cancer & hyperplasia menopausal or had at least 1 risk factor present most commonly with (n=570) menometrorrhagia, sometimes with  No /hyperplasia in 2 yrs f/u in those . Rarely with regularly that weren’t biopsied. (under-powered to timed menses as they are not under hormonal answer this question) control.  Progestins (IUD, progestin-only pill) have been Dunn, J Reprod Med. 2001 Sep;46(9):831-4 shown to treat hyperplasia and cancer

A Rational Approach to EMB A Rational Approach to EMB (cont’d) Post-Menopause: ALL women WITH ANY Other reasons: Pap with atypical BLEEDING (except 4-6 months after starting HRT) glandular cells or endometrial cells (ie if Recent onset irreg blding: Consider treating first and pap not done at time of menses). if blding normalizes, no need EMB >50: All women with recurrent irregular bleeding EMB is not perfectly sensitive so further (consider not doing if periods light and spacing out) evaluation mandatory if: 45-50: Recurrent irregular bleeding plus >1 risk 1. Persistent AUB after negative EMB factor OR > 6 mos menometrorrhagia 2. Persistent AUB after 3-6 months of <45: Long history (>2 yr? >5yr?) of untreated medical therapy anovulatory bleeding (eg PCOS)

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Do all women with AUB need an What about U/S instead of EMB ultrasound? for post-meno blding? Although TVUS is the best imaging choice Transvaginal Ultrasound for pelvic pathology (ie better than MRI, CT)….  Measure endometrial stripe  80% with have no anatomic pathology  Abnormal= >4 mm (or 5)  Incidental findings such as functional  Non-specific: myomas, polyps and ovarian cysts and small fibroids (~50%) hyperplasia all cause thick EM are often found leading to anxiety and  Operator skill mandatory unnecessary treatments  NOT USEFUL PRE-MENOPAUSE  SO….treat first, TVUS if treatment fails

TVUS vs EMB to detect cancer EMB=“B9 Proliferative”. How do I (in post-menopausal women) stop the bleeding?

TVUS EMB Medical Surgical NSAID’s Endometrial ablation Sensitivity 96% 94% Transexamic Acid (D&C/) Oral E+P (OCP) Specificity 61% 99% Hysterectomy (failed medical E+P patch, ring (Evra, Nuvaring) management) NPV 99% 99% HRT (lower dose E+P) HRT patch (Combi-patch) Further w/u 40-50% ? <5% Oral Progestin necessary

Progestin IUD (Mirena) IM Progestin (DMPA) Can offer patient choice as long as either is quickly GnRH agonist (Lupron) available and patient understands she may need EMB B9 Proliferative= Anovulation after U/S

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Non-hormonal treatment: Transexamic Acid (Lysteda) NSAID’s  Anti-fibrinolytic; available in Europe for many years- available in US (Lysteda) 2011  5 days around the clock  Expensive $170 per cycle

 Many dosages and types  In RCT’s, more effective than NSAID, cyclic proven effective in multiple provera. Less effective than Mirena. RCT’s to decrease blding Improves QOL for 80% by 3rd cycle by ~40%  Dose: 2 tabs tid for 5 days (3900mg)  Risks: Theoretic risk of VTE. No increase in  Use alone or with other large studies. Contraindicated in those with therapies history or risk factors for VTE. Unknown if safe in conjunction with OCP. DON’T FORGET NSAID’s!  Side effects: Minimal

First Line Hormonal treatments Second Line Hormonal Options  First choice: Levonorgestrel IUD  HRT (ie post-meno dosing): – >80% reduction in blood loss, decreased – More difficult to gain cycle control cramping, prevents/treats hyperplasia, highly compared with OCP effective birth control – Options with higher dose progestin may be – Great option when want to avoid estrogen more effective (FemHRT) – Blood loss and satisfaction comparable to  Cyclic Progestins: ablation, satisfaction comparable to hyst. – Less effective than NSAID’s and Levo IUD.  2nd choice: combined contraceptives (OCP, patch, ring) or DMPA – 21 day therapy more effective than 10 day but poorly tolerated – Proven to decrease irregular peri-menopausal bleeding (20 & 35 mcg); – Any type ok, 20 mcg preferred for women >40

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Perimenopausal/Anovulatory Surgical Treatments Bleeding: Summary  D&C, Hysteroscopy: Not really a treatment. Temporary reduction in bleeding. Diagnostic, not curative R/o pregnancy, thyroid dz (except if polyp removed). EMB if meets criteria  Endometrial Ablation – Reduces but doesn’t eliminate Treat first as if anovulatory bleeding: menses – NSAID’s + – ~25% repeat ablation or hyst in 5 – Hormones (Levo IUD or OCP’s, DMPA) years – Must rule out cancer first If persists: – Can’t be done in >12 week uteri – get U/S to check for anatomic causes (and EMB if or for women who want future not already done) fertility – Discuss surgical options for bleeding refractory to medical management.

Case 2: Is it the fibroids? Fibroids…... Same history as Case 1 except she has fibroids…. A 46 yo G2P2 woman presents stating that her  Very common 80% of fibroids are causing irregular bleeding. hysterectomy specimens (done She has a known fibroid uterus and complains of for any reason) and ~75% increasingly irregular and heavy periods. have on U/S at age 50. Sometimes they come 2 times per month and  2-3 fold higher incidence in sometimes there are 2 months between. LMP 2 months ago. She bleeds 10 days with clots black women and frequently bleeds through pads to her  About 50% are asymptomatic clothes. She occasionally has hot flashes. She  Grow slowly until also has diabetes and is obese. menopause and then On exam, her uterus is 16 weeks size and irregular. decrease by ~50%

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Is the bleeding due to the Fibroid Symptoms fibroids?  Bleeding:  Fibroids are common in later 40s – Usually normal or menorrhagia (heavy  Anovulation is common in later 40s but regular)  The increased bleeding seen with – Occasionally fibroids is typically due to increased menometrorrhagia if volume or distortion of the endometrium submucous or intracavitary  Therefore: Decrease the amount of endometrium by treating as anovulatory  Pressure Symptoms bleeding. This often works. 

AUB with known fibroids: Work- up and Treatment Hysterectomy

 R/o cancer and pregnancy (don’t blame fibroids for the bleeding)  Very high patient satisfaction (90%)  NSAID’s and hormones (higher than ablation)

 Improved quality of life, sexual  If no better, blame the fibroids! satisfaction and decreased pain  +/- Lupron--as a bridge to menopause or pre- op to shrink to obtain vag hyst  Increased long term risks of prolapse, incontinence  Surgical therapies (hysteroscopic resection if <3 cm, myomectomy, hysterectomy, UAE)

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Uterine Artery Embolization Case 3… Too Fast  40% decrease in size, 75-90% improved bleeding 41 year old woman presents with  Most studies have short term follow-up only (5 yrs max). Will dizziness and heavy they re-grow? In 5yr f/u of RCT, for 2 weeks straight. 25% had hysterectomy Prior to this, occasional irregular periods  Not recommended for women who but nothing like this! want future fertility  Requires hospitalization for pain Hemoglobin by hemocue=9 control, ~2 weeks to return to full activities (due to pain and fever)  Risks: emergent hyst (1-2%), 5% expel myoma through cervix, 40% have fever

Acute menorrhagia treatment OCP Taper ABC’s and Stop the bleeding!  Estrogen—2-4 OCPs (30-35 mcg E2) – Increases fibrinogen, factors V, IX, platelet  Don’t want to give 2-4 OCP’s per day aggregation. “Covers” denuded areas in and then stop suddenly b/c will have uterus large withdrawal bleed – Oral as effective as IV (so use oral).  Taper: 4 ocp’s X 4 days, 3 ocps x 4  Give with anti-emetic days, 2 ocp X 4days then 1 ocp per day  Transfusion prn for 1-2 months (66-96 pills required).  If not effective, consider D&C, Foley bulb  Must instruct no placebos and give at tamponade, emergency hyst least 3 packs of pills at once.  Small RCT suggests high dose provera may be effective as well, 20mg tid

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What about too little bleeding? WORK-UP: Amenorrhea

Seven questions in evaluation of 2° amenorrhea  Always: Urine pregnancy test. If Neg: TSH 1. Pregnant? & PLN 2. Excessive hair growth or acne?  PCOS 3. Overweight?  Obesity induced anovulation  If hot flashes: FSH 4. Breast secretions?  Hyperprolactinemia  If hirsute/obese: Usually no further testing 5. Very thin, over-exercise, stress?  Functional hypothalamic amenorrhea needed. If deep voice or cliteromegaly: testosterone. If family history hirsutism or onset at puberty: 17 OH-P 6. Hot flashes?  Premature ovarian failure 7. Pregnant recently complicated with infection or uterine surgery (D&C)?  Asherman’s syndrome

Role of progestin challenge Amenorrhea Treatment test 1. PCOS--Protect the endometrium! (from  Progestin challenge test (10 mg Provera x 10days) hyperplasia due to unopposed E2) combined determines if endogenous estrogen is present contraceptives, dmpa, Mirena

– Distinguishes hypothalamic amenorrhea (no bleeding or just 2. Obesity induced anovulation same spots) from PCOS (full withdrawal bleed) 3. Hyperprolactinemia due to microadenoma OCP’s or nothing, Bromocriptine if desires pregnancy or  Estrogen challenge test (Premarin 2.5 mg qd x 3 wks then Sx bothersome Provera x 10 days) distinguishes hypothalamic 4. Functional hypothalamic amenorrhea-- protect amenorrhea (full withdrawal bleed) from Asherman’s (no the bones! (from lack of E2) estrogen containing bleeding or just spots) contraceptives 5. Premature ovarian failure same 6. Asherman’s syndrome Hysteroscopy

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Patient #4 Patient #4

A 45 yo G1P0S1 presents with irregular menses. Most likely diagnosis? Anovulatory bleeding She has had irregular menses off and on for 2 years with occasional hot flashes. More recently, she has had nearly daily light bleeding and Must first rule out…..? cramping for almost 2 months straight. She has a long history of , had laparoscopic adhesiolysis many years ago and Pregnancy had a hysterosalpingram that showed non- patent tubes

Ectopic Pregnancy First trimester bleeding GOAL: Early Diagnosis . Occurs in 20 to 40% of pregnancies  Decreased chance of rupture (rupture can occur . Up to ½ end in spontaneous abortion or ectopic at any level of beta HCG and whether rising, falling or . Ectopic Pregnancy (2% of pregnancies): plateauing) – Incidence has increased but death rate  Rupture associated with decreased fertility, decreased due to early diagnosis and increased morbidity and mortality treatment. Nonetheless: • Leading cause of 1st trimester maternal death (6%  More treatment options (eg methotrexate, of all maternal deaths in US) conservative surgical treatment) if diagnose earlier • Disparity: Deaths more likely in AA  Methotrexate more likely to be effective if – 2/3 of women dying of EP had recently seen a diagnose earlier clinician but had incorrect or delayed diagnosis .

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Ectopic Diagnosis: Back to the patient: Simplified  Pregnancy is strongly desired Patient pregnant & bleeding or pain:  Office U/S: No IUP is seen (thin 1. Where is the pregnancy?  U/S (same day) endometrial stripe with fluid collection, could be early gestational sac). No adnexal 2. If we can’t tell where it is, is it normal or masses. Trace free fluid. abnormal?  serial quantitative Beta-HCG – If Beta above threshold and no IUP = Abnormal  Beta-HCG=4000 – If Beta drops or rises very little = Abnormal  Rh- Rhogam given (always give for any 3. Once pregnancy determined to be abnormal amount of first tri bleeding. Can give mini-dose if or if undesired uterine aspiration to available) determine if IUP. Ectopic treatment if not.

Role of ultrasound in ectopic No adnexal masses, no IUP diagnosis  Only 2% of u/s are diagnostic for EP  Given no adnexal masses, does that – “diagnostic” = Gestational Sac with yolk sac or fetal rule out ectopic? pole visualized outside uterus  Normal adnexal exam does not exclude ectopic  Given no IUP, does that rule out normal pregnancy?  Suggestive of ectopic • Empty uterus + hCG above discriminatory zone (86% are EP) • Complex mass + fluid in cul-de-sac (94% are EP)

Main role of U/S is to rule in IUP

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Ectopic Treatment: MTX vs surgery Spontaneous Abortion & Early

 If hemodynamically unstable straight to OR Pregnancy Failure  If hemodynamically stable, depending on patient  15-20% of clinically recognized pregnancies characteristics, choice of MTX vs surgery end in miscarriage – No difference in future IUP rate (both groups decreased) – 600,000-800,000 annually – No difference in future ectopic rate (10-15%) – 1 in 4 women experience EPF in lifetime  MTX:  Early Pregnancy Failure replaces – Less effective than salpingostomy (OR=0.38). “missed abortion” and “blighted ovum” – Efficacy related to b-hcg level (ranges from 98% for beta<1000 to 68% at >15,000) (terms from a pre-U/s era) – 15% require a second dose  Includes: anembryonic gestation and – 5% have rupture despite MTX embryonic demise – Requires pt compliance and follow-up

Early Pregnancy Failure: Reference: Helping your patient Counseling to choose treatment for EPF

 Women blame themselves (“was it the stress?”) Expectant: 66% at 2wks (higher if incomplete ab) Advantages: Privacy, some can avoid surg trtment, ? Decr infx  Wonder if will happen again Disadvantages: up to 6 wks to complete, more bleeding & more Patient counseling should include: visits, less patient satisfaction

 How common it is (encourage to talk to friends) Misoprostol (800 PV): 80% (higher if incomplete ab)  Reassurance that it is beyond her control and Advantages: Privacy, availability, most can avoid surgical unlikely to recur. (“Nothing could have been done to trtment, ? Decr infx, similar satisfaction as surgical prevent it.”) Disadvantages: multiple visits, 30% require 2nd dose, more pain, N/V & bleeding than surgical  Acknowledge/validate grieving Surgical Aspiration: 97-100%  No need to wait to attempt another pregnancy. Advantages: 2-4 hrs, high success rate, less blding & pain Ok to try after resumption of menses (when Disadvantages: less available, rare surgical complications, emotionally ready) ? Inc infx

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Conclusions: Non-pregnant Conclusions: Pregnant and AUB bleeding

 Diagnosis: consider anovulation even in  Maintain high index of suspicion for ectopic until women with fibroids IUP is definitively ruled in. Diagnose as quickly as possible to avoid rupture.  Work-up: Always rule out pregnancy. Usually: TSH, PLN, ?HCT, ?EMB, TVUS if initial  2 step ectopic diagnostic process: Where is the treatment fails. pregnancy (U/S), If can’t see the pregnancy, is it normal or abnormal (serial B-HCG).  Treatment: all bleeding treated similarly; NSAID’s plus hormones. Consider other  Methotrexate is not for everyone, is associated with causes and treatments if this doesn’t work 5% rupture and may not improve future fertility  Persistent abnormal bleeding requires  SAB and early pregnancy failure very difficult for continued work-up even if EMB and/or women—repetitive reassurance is necessary ultrasound are negative

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