DIRECTOR AND CLINICAL ASSOCIATE PROFESSOR OF … · - 2-Third-Generation Endometrial Ablation:...

A Reprint from Surgical Technology International Volume 33

ENDOMETRIAL ABLATION: PAST, PRESENT, AND FUTURE PART II

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MORRIS WORTMAN, M D , F A C O G

DIRECTOR AND CLINICAL ASSOCIATE PROFESSOR OF GYNECOLOGY

11 SURGICAL TECHNOLOGY • . • . , . . . • , - • ' ' - r , •

l'N TERN AT l ON AL

International Deyelopments in Surgery and Surgical Research

Volume 33

Edited by: Zoltan Szabo, PhD, FICS, Harr)· Reich, MD, FACOG, Manabu Yamamoto, MD, PhD

Harold Brem, MD, FACS, Steven F. Harn-in, MD, FACS, Michael T. Manley, PhD, FRSA Michael A. Mont, MD, Prof. Arnaud Watticz, MD

EEndometrial ablation (EA) is the most commonly performed surgical procedure for the management of

abnormal uterine bleeding unresponsive to medical therapy. In well-selected subjects, EA provides a safe,

inexpensive, and convenient alternative to hysterectomy with a rapid return to normal function.

The first generation of EA techniques were introduced in 1886 by Professor Sneguireff of Moscow. He was the

first to apply super-heated steam to the uterine cavity to vaporize the endometrial basalis. This method—

known as atmocausis—was refined by Ludwig Pincus of Danzig in 1895, and he went on to perform over 800

procedures. As the 20th century brought forth other energy sources—electricity, X-ray, radium, and even

cryogenics—they were each used, in turn, to accomplish endometrial ablation.

In 1981, Dr. Milton Goldrath successfully performed EA by co-locating a neodymium-doped yttrium

aluminum garnet (Nd:YAG) laser with a rod-lens hysteroscope to achieve photovaporization of the

endometrium. The accomplishment of EA under direct visualization defined the second generation of EA.

The challenges and risks of second-generation technology, however, were soon apparent, and though this

practice continues today, it appears to be confined to a relatively small number of devoted and highly-skilled

sub-specialists.

The late 1990s saw increasing interest in safe, affordable, and easily-mastered EA technology. The result was a

return to blind technology but modified with a variety of features that brought unprecedented safety to EA,

even permitting its selected in-office application. This third generation of EA techniques and devices has

propelled the growth of EA in the 21st century.

Although much has been accomplished in the quest for safe, affordable, convenient, and easily-mastered EA,

the future requires refinement of patient selection criteria, management strategies for late-onset endometrial

ablation failures (LOEAFs), as well as minimally invasive methods for reducing them.

Endometrial Ablation: Past, Present, and Future

Part IIMORRIS WORTMAN, MD, FACOG

DIRECTOR AND CLINICAL ASSOCIATE PROFESSOR OF GYNECOLOGYCENTER FOR MENSTRUAL DISORDERS

UNIVERSITY OF ROCHESTER MEDICAL CENTERROCHESTER, NEW YORK

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ABSTRACT

GynecologySURGICAL TECHNOLOGY INTERNATIONAL Volume 33

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Third-Generation EndometrialAblation: Non-Resectoscopic or“Global” Endometrial Ablation

The late 1980s were a time of impor-tant innovations in gynecologic surgery.In 1989, the continuous flow gynecolog-ic resectoscope cleared the US Food andDrug Administration1 and soon supplant-ed the neodymium-doped yttrium alu-minum garnet (Nd:YAG) laser foraccomplishing endometrial ablation(EA). The low-cost resectoscope, pow-ered by a standard electrosurgical unit,enabled EA technology to spread to anincreasing number of community andmedium-sized hospitals. That same year,Dr. Harry Reich reported the firstlaparoscopic hysterectomy,2 a minimallyinvasive endoscopic technique to accom-plish hysterectomy. These two modali-ties—advanced laparoscopic andhysteroscopic surgery—would dramati-cally influence gynecologic practice andbring increasingly safe, minimally-inva-sive, and low-cost solutions to commongynecologic maladies.By the early 1990s, despite great

interest in resectoscopic endometrialablation, the complications associatedwith this approach were undeniable. Ari-eff et al.3 and Baggish et al.4 both report-ed numerous cases of fatal hyponatremicencephalopathy resulting from fluid andelectrolyte disturbances. Uterine perfo-ration and visceral injuries5-7—coupledwith the difficulties in mastering a com-

plex surgical technique—limited EA’sgrowth and potential for impacting hys-terectomy rates in the United States.8,9In 1990, recognizing the complexity

of hysteroscopic endometrial ablationtechniques, Phipps et al.10 treated 33subjects utilizing a 10-mm diameterradiofrequency thermal probe (RocketMedical plc, London, United King-dom). The authors employed bothstraight and curved probes of lengthsvarying from 50–70 mm in a techniquereminiscent of the one described byBardenheuer11 in 1937. Despite the rel-ative simplicity of the technique, twoserious complications—vaginal burnsthat resulted in vesico-vaginal fistulae—occurred prompting the authors tomodify their procedure. In 1994,Neuwirth et al.12 introduced a thermalballoon which was intended to conformto the uterine cavity and was “designedto produce endometrial ablation blind-ly.” Neuwirth et al. treated 10 subjectsin a study designed to demonstrate thesafety of the device. These approach-es—the radiofrequency probe and thethermal balloon—are recognized todayas the beginning of non-resectoscopicendometrial ablation (NREA) and areoften referred to as “global” endometri-al ablation or GEA. Some authors havealso referred to these techniques as sec-ond-generation EA which is an unfortu-nate misnomer that fails to recognizethe history of EA. These latest tech-niques are, in fact, third-generation EAprocedures.

Between Phipps’ reports in 1990 and2018, there have been at least 10 differ-ent NREA systems that direct energyinto the uterine cavity in an attempt toselectively destroy the regenerativeendometrial basalis. All of these systemseliminate the use of large volumes ofdistention media and all but one—hydrothermal ablation—are blind tech-niques reminiscent of first-generationEA devices introduced in the late 19thand early 20th centuries. Two of theNREA techniques are iterative andinvolve the blind introduction ofprobes—one is a microwave and theother a cryo-probe—to accomplishendometrial destruction “bit by bit”.The remaining eight techniques seek tocause the near simultaneous destructionof the entire endometrium. With theexception of hydrothermal ablation,described below, the other nine tech-niques and devices represent a return—albeit far more sophisticated—to themethods first employed in the late 19thcentury.

I. Thermal BalloonTHERMACHOICE® Uterine Balloon TherapySystem In 1997, The US Food and Drug

Administration (FDA) issued the firstpremarket approval13 for a non-resecto-scopic endometrial ablation device—theTHERMACHOICE® Uterine BalloonTherapy System (Gynecare, Inc.,Somerville, New Jersey). The THER-MACHOICE® system, first introducedin 1995 in other parts of the world, con-sisted of a disposable 16 cm long x 4.5mm diameter catheter that housed alatex balloon, heating element, and ther-mocouple (Fig. 1). The original catheterwas inflated with 5% dextrose in water,was heated to 87°C, and maintained anintrauterine pressure of 160–180 mmHg for eight minutes. The THERMA-CHOICE® underwent several modifica-tions in 1999 and 2004. In 1999, asilicone balloon with an internal impellerwas approved to provide more uniformdistribution of heat within the uterinecavity. The last version— THERMA-CHOICE® III—incorporated a silasticballoon; a more flexible material withimproved elasticity designed to enhancecontact at the uterine cornua. However,in 2015, the THERMACHOICE® IIIcatheter was recalled by the FDA becauseof an issue related to the catheter’s pur-ported two-year shelf life and has sincebeen permanently withdrawn from

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Endometrial Ablation: Past, Present, and Future Part IIWORTMAN

THIRD-GENERATION ENDOMETRIAL ABLATION: NON-RESECTOSCOPIC OR “GLOBAL” ENDOMETRIAL ABLATION

Figure 1. THERMACHOICE® Balloon.

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worldwide distribution. In a large randomized multicenter

study comparing thermal uterine bal-loon therapy with hysteroscopic roller-ball endometrial ablation, Meyer etal.14 reported 12-month follow-up dataon 239 women and demonstrated simi-lar outcomes. However, while the inci-dence of complications was 3.2% inthe rollerball EA group, there werenone in the THERMACHOICE®group. Another large study of theTHERMACHOICE® system was con-ducted by Kumar et al.15 who followed253 women for up to 11 years. Duringa median follow-up interval of 71months (S. D. 42), 84% percent ofsubjects successfully avoided a hys-terectomy while the vast majority ofwomen reported significant improve-ment in their symptoms.The successful in-office application

of THERMACHOICE® has beenreported by Chapa et al.16 who per-formed THERMACHOICE® III proce-dures on 148 patients under parametrialblock using dilute mepivacaine and oralanxiolysis. Although the THERMA-CHOICE® provided an excellent alter-native to resectoscopic endometrialablation, the system proved unsuitablefor in-office use because of its relativelylong treatment cycle and the require-ment for high intrauterine pressures. However, the advantages of the sys-

tem—minimal cervical dilation, sim-plicity of use, and very low risk ofcomplications—were responsible forpropelling the GEA market. Anotherbenefit of the THERMACHOICE® sys-tem, compared to its resectoscopic pre-decessors, was the elimination ofexpensive medical preparation of theendometrium and substituting a brief

suction curettage just prior to the pro-cedure.

Cavaterm™ and Cavaterm Plus™The Cavaterm™ (Veldana Medical

SA, Morges, Switzerland) thermal bal-loon was first tested on extirpated uteriin 1992, introduced into clinical trialsby Pnn Medical SA (former WallstenMedical SA, Vaud, Switzerland) in1993, and approved for use in 1995.Although the Cavaterm™ is unavailablein the United States, it is used in manyEuropean countries. The system has two components, a

central unit (Fig. 2) and a ballooncatheter (Fig. 3). The catheter is a high-ly-flexible, antiallergenic silicone bal-loon designed to conform to the uterinecavity by adjusting its length from 4–8cm. Subsequent to its introduction, theCavaterm’s™ original 8 mm diametercatheter was reduced to 6 mm and rein-troduced as the Cavaterm™ Plus. TheCavaterm™ Plus balloon is filled with5% dextrose in water heated to 78°C atan intrauterine pressure of 230–240mm Hg for a 10-minute treatmentcycle. A pressure relief valve is auto-matically activated if an overpressure issensed, thus adding an important safetyfeature.Like the THERMACHOICE®,

endometrial preparation may be per-formed with a simple suction curettageand is associated with very low complica-tion rates. Vilos et al.17 notes that “thedevice emphasizes the concept that a sus-tained high intraballoon pressure causesreduction in uterine blood flow, whichin turn enhances deeper penetration ofheat resulting in deeper endomyometri-al necrosis.” The manufacturer recom-mends that if the balloon position is in

doubt, the operator may utilize an intra-operative abdominal ultrasound exami-nation to confirm the proper position ofthe balloon prior to the initiation of thetreatment cycle.18 Although theCavaterm™ system has been utilized inthe presence of leiomyomas less than 2cm in diameter, it is not approved forsuch use.Friberg et al.19 conducted the first

clinical trials in 116 women who werefollowed for 10–46 months. The suc-cess rate—defined as amenorrhea, min-imal or normal bleeding at the time ofthe patient’s worst days of flow—was94% in women whose uteri did notcontain submucous leiomyomas. Thehysterectomy avoidance rate for womenwithout submucous leiomyomas was85% at 49 months.

MenoTreat™ Thermal BalloonThe MenoTreat™ device (Atos, Med-

ical AB, Hörby, Sweden)—a third ther-mal balloon ablation device—isavailable in many European countriesand consists of a controller and dispos-able silicone balloon catheter. During an11-minute treatment cycle, heatedsaline (85°C) is circulated through theinflated balloon at 200 mm Hg. As withother balloon ablation devices, the pro-cedures are most often performed withthe adjuvant use of intravenous sedationor general anesthesia. The efficacy ofthe MenoTreat™ system is comparableto other balloon ablation systems.20

Thermablate Endometrial Ablation System™

The Thermablate EAS™ system (Ido-man Teoranta Ltd., Toronto, Canada) isthe final example in this category ofthermal balloon ablation systems andconsists of a handheld treatment control

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Figure 2. Cavaterm™—central unit. Figure 3. Cavaterm™—balloon catheter.

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unit (TCU; Fig. 4), a disposable siliconeballoon catheter, and a power supply.“The objectives [in designing] the Ther-mablate EAS™ system [was] to shortenprocedure times, provide more uniformand consistent treatment, improve clini-cal outcomes, perform the procedureunder no or minimal analgesia/anesthe-sia outside the operating room, andreduce costs compared to existing [sec-ond] generation endometrial ablationtechniques.”21The balloon is housed in a flexible 12

cm long x 6 mm diameter catheter thatis introduced through the cervix andsubsequently filled with pre-heatedglycerin (173°C) prior to initiating a15-second balloon integrity test. Afterconfirming the balloon’s reliability, thecatheter is deflated and reintroduced fora treatment cycle lasting just over twominutes at an intrauterine pressure of220 mm Hg during which the glycerinis kept at 100–150°C.21-23Karmanidis et al.23 reported the

results of 72 premenopausal womenwith menorrhagia who were treatedwith the Thermablate EST™ device andfollowed for up to two years. The com-bined amenorrhea and hypomenorrhearates at three, six, 12, and 24 monthswere 39%, 73%, 77%, and 70% respec-tively.Some of the manufacturer’s con-

traindications are listed in Table I22 andare representative of those reported fornearly all thermal balloon EA devices.The manufacturer notes that

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Table IContraindications to the use of the Thermablate™ system

Uterus sounds to <8 cm or >12 cm

Uterine cavity with significant distortion

Intramural leiomyomas >3.0 cm

Intracavitary lesions (Type 0 or 1 submucous myoma or polyp of any size)

Septate uterus

Previous classical cesarean section or transmural myomectomy

A history of 3 or more lower segment cesarean sections

Linear scar (from cesarean Section) thickness <8 mm

A previous endometrial ablation

Desire to retain fertility

Figure 5. NovaSure® controller unit. Figure 6. NovaSure® disposable probe.

Figure 4. Thermablate Endometrial Ablation System™.

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“patients requiring further treatmentafter thermal balloon ablation shouldbe treated medically, by resectoscopicendometrial ablation, or by hysterecto-my. Repeat resectoscopic ablationresection should be attempted only byexperienced hysteroscopists since thecomplications may be severe.” Themanufacturer also recommends that adiagnostic hysteroscopy should be per-formed just pr ior to treatment toensure that cervical dilation has notcaused a uterine perforation. Alterna-tively, one can “use ultrasonic surveil-lance during the treatment to check forcorrect balloon position inside theuter ine cavity.”22 The system wasapproved for use in Canada in 2003and is presently used throughoutEurope, Southeast Asia, Australia, andmany other countr ies around theworld.

II. Radiofrequency EndometrialAblation (RFA)There are currently two endometri-

al ablation devices that utilize radiofre-quency (RF)—the NovaSure® (HologicInc., Bedford, Massachusetts) and theMinerva® Endometrial Ablation System(Minerva Surgical Inc., Redwood City,California). The Minerva® device, inaddition to RF current, also utilizes twoadditional methods of energy applica-tion to achieve endometrial ablation.The NovaSure System®

In September 2001, the NovaSure®Impedance Controlled EndometrialAblation System was approved andintroduced by Novacept Inc. (PaloAlto, California). The system, consist-ing of a controller (Fig. 5) and an 8 mmdiameter disposable probe (Fig. 6),

delivers radiofrequency bipolar energydispersed through a triangular-shapedgold-plated porous mesh which con-forms to the uterine cavity (Fig. 7) andis designed to deliver deeper coagula-tion at the mid-body of the uterus—where endometrium is thickest—andshallower desiccation at the thinnercornua. The device is also equippedwith an adjustment sheath to protectthe endocervical canal.Prior to the initiation of treatment,

the disposable probe allows measure-ment of both uterine cavity length andwidth (intracornual distance) as shownin Figure 8 and automatically deliverspower based on these variables. TheNovaSure® device also incorporates aCavity Integrity Assessment System

(CIAS)—a feature designed to detect auterine wall defect—which averts ener-gy discharge in the event of a uterineperforation. The CIAS utilizes a hys-teroflator-type of technology24 whichinsufflates carbon dioxide into the uter-ine cavity. Once the intrauterine pres-sure of 50 mm Hg is reached andmaintained for four seconds, the deviceis activated and maintains an energyoutput which is controlled by concomi-tantly monitoring tissue impedance.The procedure, which averages 90 sec-onds, is automatically terminated whenoverall tissue impedance reaches 50U—a value consistent with superficiallyablated myometrium. Another featureof the NovaSure® is its use of continu-ous suction during the treatment cycle

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Figure 7. NovaSure® conforming to the uterine cavity. Figure 8. NovaSure® handpiece with measuring devices.

Figure 9. Market share of GEA devices by manufacturer.

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which provides a two-fold benefit; first,it draws the endometrium into contactwith the bipolar mesh and, second, itremoves debris and steam which arebyproducts of vaporized endometrium.In 2017, Hologic Inc. released a

redesigned version of the orig inalNovaSure® device—the NovaSure®ADVANCED—which offers a slimmer6 mm diameter catheter designed tominimize cervical dilation and improve

patient comfort in an office-based set-ting. The updated device is alsoequipped with an acorn-shaped cervicalseal designed to increase the sealing sur-face within the endocervical canal andimprove its working length. The Nova-Sure® ADVANCED device has beenavailable in Europe, Canada, and Aus-tralia since 2016.The NovaSure® system is the most

commercially successful GEA deviceworldwide.25 The US market share in2016 was 57.1%26 (Fig. 9). By February2017, the company reported the sale of2.5 million devices since its introduc-tion.27 Compared to other NREA sys-tems, the advantages of the NovaSure®device include the need for only mini-mal cervical dilation, a relatively shorttreatment cycle, low complication rate,a uterine integrity test, and automatedself-termination of the treatmentsequence. Additionally, NovaSure® isable to achieve a reproducible depth ofablation, independent of endometrialthickness, thereby obviating the needfor expensive endometrial prepara-tion.28 In fact, the ability to performendometrial ablation without endome-trial preparation distinguishes the Nova-Sure® System from all previous devices.The NovaSure® system has been the

subject of numerous investigationalstudies including four prospective ran-domized clinical trials comparing itwith the THERMACHOICE® EAS,29-32a double-blind randomized trial com-paring it to Cavaterm™,33 a trial com-paring it to a microwave endometrialablation (MEA) system (previously pro-duced by Microsulis Medical Limited,Denmead, United Kingdom),34 as wellas a pivotal trial comparing it to “roller-

ball” endometrial ablation.35Sabbah and Desaulniers36 suggested

that the NovaSure® endometrial ablationprocedure may have a significant clinicalrole in the treatment of menorrhagia inwomen with grade I and II submucousleiomyomas up to 3 cm in greatestdimension. In their study of 65 women,they were able to demonstrate a signifi-cant reduction in menstrual blood lossin nearly 95% of subjects. However,their data is confined to a follow-upperiod of only 12 months. Although theNovaSure® instructions for use (IFU) donot specifically mention the presence ofleiomyomas as a contraindication, themanufacturer lists the presence of sub-mucosal fibroids that distort the uterinecavity as a precaution for use.37

Minerva® Endometrial Ablation System The Minerva® Endometrial Ablation

System was approved by the FDA inmid-2015 and—like NovaSure®—employs radiofrequency current butadditionally incorporates two additionalfeatures to accomplish endometrialablation.38 Since Minerva® is relativelynew, at the time of this writing, thereare fewer clinical studies and publica-tions available for analysis.The system has two major mod-

ules—a proprietary controller unit (Fig.10) and a disposable handpiece (Fig.11). The handpiece, in turn, has a plas-ma formation array (PFA), a cervicalsheath, and a cervical sealing balloon(Fig. 12). The PFA is composed of anexpandable metal frame which is cov-ered by an elastic silicone membrane.During activation, the PFA’s metalframe acts as the internal electrodewhile two laterally placed tissue-con-

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Figure 10. Minerva® controller unit. Figure 11. Minerva® disposable handpiece.

Figure 12. Minerva®—plasma formation array(PFA) with cervical balloon and sheath.

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tacting electrodes of the same polarityreside on the outer surface of the mem-brane. The expanded triangular-shapedPFA is filled with argon gas and isintended to conform to the patient’suterine cavity.The disposable handpiece requires

cervical dilation to 7 mm. Once insert-ed and positioned, the device armsexpand to deploy a silicone balloon.After the cervical balloon is inflated andthe controller unit verifies the adequacyof the cervical seal, the uterine integritytest is initiated. During the integritytest, carbon dioxide is instilled into theuterine cavity from the device’s mainsheath to 28 strategically positioneddelivery ports that allow the detectionof a uterine perforation as small as a 21-gauge needle. Upon successful comple-tion of the uterine integrity test, andafter the anatomic requirements of theuterus have been confirmed, the sili-cone balloon is filled with argon gas andthe controller is activated. During thetwo-minute treatment cycle, bipolarradiofrequency energy is utilized fortwo purposes. First, it is delivereddirectly to the target tissue and, second,it is utilized to ionize argon gas trans-forming it into plasma which is subse-quently used to heat endometriumthrough the membrane. Unlike theNovaSure® system, which evacuatesheated liquids, the Minerva® system uti-lizes them to fill the uterine intersticesthat may have been otherwise leftuntreated, thereby augmenting the EAprocess. The three methods by whichMinerva® accomplishes endometrialablation are summarized in Table II.These three methods operate in a

simultaneous and complimentary fashion.During the procedure, the power level islimited to a maximum of 40 Watts and isautomatically adjusted downwards as a

function of changing tissue impedance.One of the possible, but unproven, bene-fits of the Minerva® system is that it mayprovide some advantage in treating theuterus with an irregular surface or onethat contains deeply recessed uterine cor-nua such as those demonstrated in Fig-ures 13 and 14. The Minerva® system is the first

endometrial ablation system to be evalu-ated and approved by the FDA’s newObjective Performance Criterion (OPC)control,39 which represents a compositeof success rates for all previous FDA-approved non-resectoscopic endometrialablation systems (THERMACHOICE®,NovaSure®, Genesys Hydro ThermAbla-tor® [HTA] System, [Boston ScientificCorp., Natick, Massachusetts], HerOption®, and MEA). In 2015, Laberge etal.40 published a multicenter single-armstudy, which included a total of 105 sub-jects using the OPC methodology. Thestudy revealed a one-year post-proceduresuccess rate (PBLAC <75) of 96.2%,with 69.5% of the patients reportingamenorrhea (PBLAC score 0). Thepatient satisfaction at one year was97.6%, statistically superior to that of theOPC control group. None of the subjectsrequired hysterectomy by the end of thefirst year. Subsequently, Laberge et al.41 pub-

lished the results of a double-arm ran-domized controlled trial (RCT) whichincluded 153 subjects enrolled at 13 clini-cal sites including eight academic and fiveprivate medical centers in the UnitedStates, Canada, and Mexico. The primaryobjective of the study was to evaluate thesafety and efficacy of the Minerva® EAScompared with hysteroscopic rollerballablation in reducing menstrual blood lossas measured by the alkaline hematin (AH)method at 12 months post-treatment, aswell as the occurrence of any adverseevents. In this study, success was definedas a reduction in menstrual bleeding from>160 mL pretreatment to <80 mL at 12months post-treatment. Laberge et al.randomized 153 subjects to two groups:102 subjects in the Minerva® EAS testgroup and 51 subjects in the rollerballendometrial ablation control group.Investigators utilized a variety of anes-thetic and analgesic techniques includinggeneral anesthesia, intravenous sedation(with or without paracervical block), andspinal block. The mean procedure timefor the Minerva® subjects was 3.1 min-utes while the mean procedure time forthe rollerball EA group was 17.2 min-utes. The success rate—defined by thereduction of menstrual bleeding to lessthan or equal to 80 mL/month—was93.1% at one year compared to 80.4%

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Table IIMinerva® Endometrial Ablation System: summary of ablation methodologies

Radiofrequency ablation between electrodes within the plasma formationarray acts directly on endometrium and superficial myometrium.

Radiofrequency is also used to ionize argon, creating a plasma which heatsthe silicone membrane and transmits heat directly to endometrium andmyometrium.

The liquefied products are not evacuated but are instead used to heat areasnot in contact with the silicone balloon.

Figure 13. Deeply recessed left uterine cornua. Figure 14. Deeply recessed right uterine cornua.

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for the rollerball group (p=0.02). Theamenorrhea rate for the Minerva®group was 71.6% and 49% for therollerball group (p=0.01). Patient satis-faction was 91.9% for the Minerva®group and 79.5% for the rollerballgroup (p <0.05). The authors conclud-ed that the Minerva® efficacy was statis-tically significantly superior to therollerball EA group as measured by suc-cess rate, amenorrhea rate, and patientsatisfaction at one year.A comparisonbetween the features of the two FDA-approved radiofrequency devices isshown in Table III.

III. Heated Free Fluid UnderHysteroscopic Control The Hydro ThermAblator® (HTA)—

first produced and distributed by BEIMedical Systems Co. (Teterboro, NewJersey)—gained FDA approval in 2001and remains the sole global endometrialablation device and procedure performedunder direct hysteroscopic control. HTA utilizes normal saline heated to

90°C which is passed into the endometri-al cavity under a gravity-based system tofacilitate endometrial ablation. Thearrangement calls for a three-liter bag ofnormal saline placed at a height of 115

cm above the uterus to create anintrauterine pressure of 50–55 mmHg—well below the 70 mm thresholdat which heated saline might passthrough the tubal ostia. HTA consists ofa control unit, an outflow fluid pump,and an adjustable support pole on amobile base. The system is connected byinsulated inflow and outflow tubing to astandard 2.9 mm hysteroscope which isencased by a disposable 7.8 mm insulat-ed sheath. The controller contains amicroprocessor to regulate both thetemperature of infused saline and treat-ment time while monitoring both pres-

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Table IIIComparison between NovaSure® and Minerva® Endometrial Ablation Systems

NovaSure® ADVANCED Minerva®

Cervical dilation requiredEndometrial preparation requiredUterine cavity integrity testDisposable active elementRadiofrequency usedHeating from silicone membraneManagement of debrisTreatment time Cervical sealing balloonSystem automatically shuts ofFDA approval for submucous myomasRestrictions on uterine dimensionsAbility to perform repeat ablation

6 mmnoyes

Gold meshto desiccate tissuenot applicable

suctioned and removedaverage 90 secs

noyes ѱ

noyesno

7 mmnoyes

Plasma formation array (PFA)to desiccate tissue & to ionize argon gas

yesutilized to heat tissue

120 secyesyesnoyesno

ѰWhen tissue impedance reaches 50 Ω or at 2 minutes

Figure 15. Hydrothermal ablation with hysteroscopic control. Figure 16. Hydrothermal ablation (monitor view).

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sure and flow. HTA also incorporates animportant safety feature to alert theoperator and interrupt therapy if morethan 10 mL of fluid is lost from the sys-tem.The HTA procedure begins with a

diagnostic hysteroscopy utilizing nor-mal saline kept at room temperature.After confirming a tight cervical seal,normal saline, heated to 90°C, is intro-duced at 300 mL/min at an intrauter-ine pressure of 50–55 mm Hg andcirculated for 10 minutes through aclosed-loop system. The procedure isperformed entirely under hysteroscopiccontrol and is observed on a video dis-play (Figs. 15 and 16) allowing thephysician to monitor all phases of theprocess. This is followed by a one-minute cooling cycle before the instru-ments are removed.The current generation of hydrother-

mal ablation systems was approved in2010 with various safety features. Theprimary objective was to reduce the like-lihood of clinically significant vaginal andvulvar burns. The advantages and disad-vantages of the HTA system are reviewedin Table IV. Most of the currently available clini-

cal trials, and all of those designed forFDA approval, were performed onwomen following pretreatment withleuprolide acetate. In a clinical trialrepor ted by Corson et al.,42 276women were randomized to two groupsin a 2:1 distribution. The first groupconsisted of 187 women who weretreated with HTA while the second wascomprised of 89 subjects treated withrollerball EA. The primary endpoint, or“success rate,” of the study was a Janssenscore—a standardized pictorial men-strual diary—of <75 one year follow-ing treatment. At the end of 12 months,success rates were 77% for HTA and82% for rollerball while amenorrhea

rates were reported to be 40% and 51%respectively.One of the troubling issues of the

first-generation HTA system was a sub-stantial number of reports of deep sec-ond and third degree burns estimated at0.32% as determined by a passive (user)reporting system.43 The incidence ofthese burns was reduced to 0.14% withthe release of the ProCerva™ Sheath(Boston Scientific Corp., Natick, Massa-chusetts). The most recent iteration ofthe HTA (Hydro ThermAblator®) wasapproved for clinical use in 2010 “withan improved design to deliver the sametherapeutic benefits as the earlier HTAsystem, improved operator performance,and impart new safety features for thebenefit of the patient and the deviceoperator.”43 Specifically, the new systemincorporated features to reduce the like-lihood of fluid leaks and subsequent vul-var, vaginal, and cervical burns. TheGenesys system’s ProCerva™ sheathincludes a “cervical seal assist”—a finnedsilicone tube at the distal end used tomaintain a tight seal between the distalportion of the device and the endocervi-

cal canal.Since the Hydro ThermAblator® is

not a fixed geometry system, somehave advocated its applicability inwomen with menorrhagia and submu-cous leiomyomas. Glasser et al.,44 in anoff-label use study, reported on 22 sub-jects with menorrhagia who wereknown to have submucous leiomyomas<4 cm in diameter. He described anoverall success rate—defined as requir-ing no additional medical or surgicalintervention—of 91%. Twelve subjects(54%) reported complete amenorrhea,five (23%) described oligomenorrhea,and three (14%) became eumenorrhe-ic. There were two (9%) failures. A 60-month follow up of the original groupof 22, along with an additional 11patients, had a hysterectomy rate of12%. A larger retrospective study byHachmann-Nielsen et al.,45 on 160consecutive women who underwentHTA between 2004 and 2008, indicat-ed that HTA was associated with a highrate of amenorrhea with or withoutsubmucous leiomyomas. Of the sub-jects studied, submucous myomas were

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Table IVHydro ThermAblator® system advantages

and disadvantagesAdvantages Disadvantages

Possible use in the presence of anom-alies£

Possible use with selected submucousleiomyomas£

Hysteroscopic control during and aftertreatment

8 mm of dilation

Association with vaginal and cervicalburns

Physician must maintain a prolongedfixed position

Endometrial preparation required

£ Note that none of the non-resectoscopic endometrial ablation devices areapproved for use with uterine anomalies or leiomyomas

Figure 17. AEGEA™ Vapor System controller unit. Figure 18. AEGEA™ system treatment of irregular uterine cavity.

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noted in 33 women (24.3%). However,there was a significantly reduced suc-cess rate for women with submucousmyomas >3 cm. As is the case with allother GEA devices, the HTA is notspecifically approved for the treatmentof submucous leiomyomas.IV. Heated Water VaporThe AEGEA™ Adaptive Vapor Abla-

tion System (Aegea Medical Inc., Red-wood City, California) achieved FDAapproval in late-2017 and is a fullyautomated vapor delivery and safetymonitor ing system reminiscent of“atmocausis”—the application of super-heated steam—first described over 120years ago by Professor Sneguireff ofMoscow46 and later refined by LudwigPincus of Danzig.46-49 The AEGEA™system creates and circulates steam atlow pressure within the endometrialcavity for approximately 140 sec-onds—a 20 second “saline flush” and a120 second treatment time.The AEGEA™ Vapor System

includes a vapor generator (Fig. 17) anda disposable procedure kit (Fig. 18).The single-use kit includes a 5.8 mmprobe with a soft flexible tip as well assupply and drain accessories that deliverwater to, and collect it from, the gener-ator. The catheter contains three inflat-able balloons which provide a secureseal at the endocervical canal whileproperly anchoring the Vapor Probe tipwithin the uterine cavity. The devicealso incorporates both a Uterine CavityIntegrity Test (UCIT) and a DeviceLumen Patency Test (DLPT). TheUCIT prevents the discharge of caustic

steam through an accidental uterineperforation or into the endocervicalcanal while the DLPT is designed toinsure proper probe tip placementwithin the uterine cavity.The procedure begins with measure-

ment of the uterus from fundus to theexternal cervical os using a soundingdevice after which the vapor probe’s“cervical slide collar” is adjusted placingthe internal balloon just beyond theinternal cervical os. Once the catheterand cervical collar are properly posi-tioned, both the internal and externalballoons are inflated, thereby preventingthe escape of water vapor into the vagi-na. During the procedure, intrauterinepressure is maintained between 20 and52 mm Hg and the cervical canal tem-perature is monitored with a thermo-couple. The procedure, which takes fourminutes to accomplish, includes a two-minute vapor treatment. The AEGEA™System is intended to treat women withnormal, as well as non-uniform, uterinecavities including women with uterineanomalies50 and leiomyomas—however,as with other NREA systems, theAEGEA™ is not specifically approved foreither.The pivotal trial was a prospective,

single-arm, non-randomized, multicen-ter study conducted at 14 investigation-al sites. Between May 2014 and May2015, 155 patients were treated. Theprimary effectiveness endpoint was areduction in menstrual blood loss asmeasured by a validated Pictorial BloodLoss Assessment Chart (PBLAC) of<75 at one year following treatment.

The AEGEA Vapor System was judgedto be effective in 122 subjects (78.7%)at one year with 30 (19.4%) reportingamenorrhea. At 12 months, 90.8% ofsubjects available for follow up reportedbeing very satisfied (70.2%) or satisfied(20.6%).51

V. Microwave EndometrialAblation (MEA)The technique of microwave

endometrial ablation owes it origins tothe work of Phipps et al.,52 who, in1990, reported the treatment of 42 sub-jects with a radiofrequency probe placedin the endometrial cavity in energydoses varying from 330 kJ to 660 kJ.Phipps’ probe utilized electromagneticenergy at 27.12 MHz to heat theendometrium and destroy the basalis.The technique’s clear advantage was ineliminating the use of distention fluidwhich was both cumbersome and car-ried potential risks. Phipps’ report stim-ulated interest in the use of microwavesas a potentially safer energy source.Microwaves are non-ionizing waveformsthat are absorbed in tissues where theyenergize water molecules and cause tis-sue heating. A domestic microwaveoven, for instance, uses a frequency of2.3 GHz to penetrate deeply into food.However, if the frequency is increased,the result is a shorter wavelength withreduced penetration.The potential for a microwave

endometrial ablation probe promptedthe formation of a research team in1992 at the University of Bath,Microwave Physics Department in con-junction with the Royal United Hospitaldepartments of Gynaecology and Med-ical Physics.53 The team sought to devel-op an intrauterine probe—operating inthe microwave energy spectrum—thatwould provide safe EA with a reducedpower output and treatment times. Thefirst clinical trials began in 1994 andwere reported by Sharp et al. in 1995.54The probe was designed to be 8 mm

in diameter—sufficiently small to facili-tate passage into the uterine cavity andlarge enough to minimize the risk ofuter ine perforation. The depth ofmicrowave tissue heating was to berestricted to 6 mm with a low totalenergy dosage to minimize the risks ofperipheral tissue heating. The teamdeveloped a 9.2 GHz probe that woulddeliver microwave energy through an 8mm dielectrically-loaded waveguide.The probe was fitted with a thermocou-

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Figure 19. Cryoendometrial ablation with Her Option®.

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ple positioned at the tip to constantlymeasure and record endometrial surfacetemperatures.In the or ig inal clinical tr ials,

microwave endometrial ablation wasperformed following endometrialpreparation with either danazol orGoserelin and was carried out utilizingboth general and paracervical blockanesthesia. During the procedure, themicrowave applicator was inserted untilthe tip reached the fundus and was thenactivated after which the cavity wastreated from the fundus toward thelower uterine segment with a side-to-side motion to treat the entire endome-trial surface. The temperature at theapplicator-tissue interface was 100°Cwhich produced micro-pockets ofsuperheated steam. The mean treatmenttime was 3.5 minutes but varied withthe endometrial surface area—the pres-ence of leiomyomas tended to increasetreatment times while pretreatmentwith GnRH agonists typically shortenedthem.A report by Cooper et al.55 compared

123 patients treated with MEA to 132women undergoing transcervical resec-tion of the endometrium. At 12 months,the amenorrhea and patient satisfactionrates were 40% and 78%, respectively,for MEA-treated women while TCRE-treated women reported 40% and76%—nearly identical outcomes. At thetwo-year follow up, the amenorrhearates were 47% for the MEA group and41% for TCRE with patient satisfactionrates of 76% and 67%, respectively.56MEA provided many advantages

compared to the technique describedby Phipps et al.57 The short treatmenttime and low power (30 watts) meanta very low energy dosage (average 4.2kJ)—approximately 1% of what hadbeen utilized by Phipps et al. MEAalso incorporated continuous ther-mometry.The MEA system was approved in

the UK in 1996 and was produced anddistributed by Microsulis Medical Lim-ited. The device earned FDA approvalin the United States in 2003. However,in 2011, Microsulis Medical Limitedsold its MEA system to Hologic Inc.,and the system has since been removedfrom the market.

VI. Cryoendometrial AblationCryoablation of the endometrium is

unique among other global ablationtechnologies which utilize thermal

energy to heat the endometrium.Cryosurgery causes endometrialdestruction by three separate mecha-nisms. First, coagulation necrosis iscaused by intracellular and extracellularice crystal formation which results inthe rupture of cells walls. Second,cryoablation causes avascular necrosis ofthe endometrium by producing capil-lary obstruction and stasis. Third,cryoablation causes intracellular andextracellular dehydration.57The first use of cryosurgery within

the uterine cavity was described byCahan and Brockunier58 in 1967 atMemorial Sloan Kettering Cancer Cen-ter utilizing a 6 mm curved stainless-steel liquid-nitrogen-cooled probe. Thetreatment cycle called for five separatefreeze-thaw positions within theendometrial cavity. The limitations ofthis early technology included the diffi-culty in controlling liquid nitrogen andin monitoring temperatures during thetreatment cycle. Additional studies onendometrial cryoablation were carriedout by Droegemueller and his col-leagues working first with Freon andthen nitrous oxide.59,60 Nitrous oxidebrought the probe temperature to -50°C,60 but the probe designs wereinsufficient to cause predictable andtotal endometrial destruction.In 1992, Pitroff et al.61 reported 15

cases in which saline was used toimprove contact between the nitrous-oxide-cooled cryoprobe and theendometrium. This allowed tempera-tures of approximately -40°C at theendometrial surface. Pitroff’s improve-ments are still utilized in today’s HerOption® (American Medical SystemsInc., Minnetonka, Minnesota) endome-trial ablation system.In 2001, the US Food and Drug

Administration approved the HerOption® In-Office Cryoablation Ther-apy. Her Option® (Fig. 19) utilizes aproprietary compressed gas mixturethat generates temperatures between -90 and -120°C at the probe tip. In2010, Cooper Surgical Inc. (Danbury,Connecticut) acquired the HerOption® Office Cryoablation TherapySystem. The system consists of a smallportable console along with a dispos-able 5.5 mm cryoprobe. The probe isechogenic, allowing for constant ultra-sound guidance, and is equipped witha surface temperature monitoring sys-tem that allows for continuous directtemperature measurements during

freezing and rewarming phases. Final-ly, the probe has an auxiliary portwhich allows small amounts of salineto be injected to improve contactbetween the cryoprobe andendometrium. Ultrasound monitoringis recommended during cryoablationas it assures the operator of properprobe placement and allows one tomeasure the developing “iceball”. Avar iety of techniques have beendescribed with respect to probe place-ment and freeze patterns.

In 2003, Duleba et al.62 reported aprospective randomized study of 279women comparing endometrial cryoab-lation (N=193) to rollerball EA(N=86). In this study, all subjects werepretreated with a gonadotropin-releas-ing hormone and the procedures werecarried out under sonographic guid-ance. One of the study’s observationswas that minimal analgesia was requiredfor women undergoing cryoendometrialablation. At 12 months, the successrates—defined as a PBAC score <75—were 67.4% and 73.3%, respectively,for cryoendometrial and electrosurgicalablation.

Endometrial Ablation: Where arewe now?When Goldrath et al.63 and DeCher-

ney64 re-introduced second-generationendometrial ablation in the 1980s, theyeach envisioned EA under visual—hys-teroscopic—control. The growth ofthese late 20th century techniquesrequired solving three separate prob-lems:

Addressing the technical challenges ofhysteroscopic endometrial ablation,

Minimizing the incidence of seriousintraoperative complications—dis-tention fluid mismanagement, uterineperforation, and visceral injury, and

The demonstration of long-term effi-cacy.

Minimizing technical challenges and intraop-erative complications of endometrial ablation Paradoxically, the 21st century success

of endometrial ablation was the result ofreplacing second-generation, hystero-scopically-controlled EA with non-hys-teroscopic modalities—the so-calledglobal endometrial ablation (GEA), orthird-generation devices. Until thesedevices and techniques were introducedand refined, EA was practiced by only afew devoted and early proponents

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o f minimally invasive gynecologicendoscopy. However, the lack of ade-quate training, fluid management sys-tems, and protocols soon gave way tounfortunate and well-publicized compli-cations.3-7 It was the implementation ofGEA—in many ways a return to theprinciples of first-generation tech-niques65—that enabled endometrial abla-tion to gain widespread acceptance in thegynecologic community. GEA device manufacturers have sim-

plified the technique and reduced therisks associated with EA and accom-plished it by eliminating operative hys-teroscopy and its associated risks.66 Riskreduction has also been fur therenhanced with the adoption of uterinecavity integrity tests (UCITs) prior tothe application of thermal energy. Theseintraoperative assessments have beenincorporated into the NovaSure®, Min-erva®, and AEGEA systems. Based onutilization estimates from the mostwidely distributed GEA device—Nova-Sure® ADVANCED—the approximaterate of reported thermal bowel injury isless than one per 25,000 procedures.67,68These improvements have propelled

the use of endometrial ablation as aminimally invasive surgical techniquefor abnormal uterine bleeding (AUB).In 2008, GEA, or third-generation EA,constituted the most common surgicaltreatment for heavy menstrual bleedingin the United States69 and, by 2016, theUS. GEA market improved to over halfa million units sold annually.70 Althoughall of the NREA devices have beenshown to reduce menorrhagia andimprove short-term quality of lifescores,22,29,41-44 there is still a relativelack of reliable information regardingthe long-term impact of these tech-niques 10–30 years postoperatively.

Demonstration of long-term efficacy Longinotti et al.,71 in a now-famous

study of 3681 women who underwentboth resectoscopic and third-generationprocedures, repor ted that 26% ofwomen eventually required hysterecto-my by their eighth postoperative year.Though some of these hysterectomieswere performed for issues such as vagi-nal prolapse or adnexal pathology, themost common reason for subsequentuterine extirpation was intractable vagi-nal bleeding (51.6%) followed by cyclicpelvic pain (20.3%). Remarkably, thestudy revealed no relationship betweenthe type of EA and the ensuing require-

ment for hysterectomy. However, thisconclusion is limited by the study’sdesign.Late-onset endometrial ablation fail-

ures72 typically presents in one of threeways—recurrent abnormal uterinebleeding, cyclic pelvic pain, or theinability to adequately evaluate andsample the endometrium in the pres-ence of abnormal uterine bleeding.71-74While the majority of women whoundergo EA are able to successfullyavoid hysterectomy, the precise numberof women who require medical treat-ment for persistent vaginal bleeding orcyclic pelvic pain is unknown.The most important determinant of

long-term efficacy and hysterectomyavoidance appears to be proper patientselection. Risk factors of LOEAFinclude relative youth (women underthe age of 35 years), severe dysmenor-rhea, unexplained pelvic pain, and thepresence of submucous leiomyomas or auterus with an enlarged surfacearea.26,71-75 There is also evidence thatEA procedures performed in outpatientcenters under intravenous sedation andanalgesia may provide women with bet-ter outcomes than those performed inan office-based setting. Wishall et al.,76in a retrospective cohort study of 300patients who underwent EA between2007 and 2013, found that operatingroom-based procedures decreased thesubsequent risk of hysterectomy by76% (adjusted OR 0.24, 95%; CI0.07–0.77). However, randomizedprospective studies on whether or notthe incidence of LOEAFs are affectedby the type of analgesia and sedationutilized have not been published.Another incompletely unresolved

issue with respect to “long-term effica-cy” is whether or not EA may mask ordelay the diagnosis of endometrial can-cer. In 1987, DeCherney et al.77 fore-warned that the consequence of failingto destroy a “nest of endometrial tissue”during EA could result in a sequesteredisland of endometrial carcinoma (EC)inaccessible to standard biopsy tech-niques, possibly delaying or obscuringthe diagnosis. In 1993, Copperman etal.78 described the first case of post-ablation endometrial carcinoma (PAEC)in a 56-year-old who presented withpostmenopausal bleeding five yearsfollowing a resectoscopic EA. Severalauthors have since reported cases ofPAEC.79,80 Dood et al.81 conducted aretrospective cohort study in nearly 500

outpatient general practices in the UKwho were treated for abnormal uterinebleeding between 1994 and 2010. Ofthe 234,721 women who met the studycriteria, 4776 underwent endometrialablation while the remainder receivedmedical management. The authorsobserved no difference in endometrialcancer rates in the two groups. Howev-er, the study is limited by its retrospec-tive nature and its failure to investigatethe effect of prior EA exposure on his-tology and stage. Although there is nodata to suggest that PAECs present atadvanced stages of disease, it is clearthat the assessment of the uterine cavityin women with abnormal uterine bleed-ing following an EA is unreliable by tra-ditional methods—hysteroscopy,endometrial biopsy, and sonography.72,79

Endometrial Ablation: The FutureAs endometrial ablation technology

matures, several issues will requireattention by physicians, manufacturers,and professional organizations.

Clarifying the role of EA in women withabnormal uterine bleedingThe gynecologic landscape has

undergone many significant changessince the early 1980s when EA first re-emerged from blind, first-generationtechniques. Hysteroscopic and resecto-scopic EA were introduced at a timewhen fewer medical and surgicaloptions existed for women requestingtreatment for AUB. In the early 1980s,neither the levonorgestrel-releasingintrauterine system (LNG-IUS) nor thelaparoscopic hysterectomy, were avail-able. With the introduction of thosetechnologies, physicians were requiredto develop algorithms that offered safe,economical, and minimally invasivetreatment strategies in a patient-cen-tered approach.The LNG-IUS was first developed by

Luukkainen82 in 1977 and approved bythe FDA in 2000 as a contraceptivedevice—the Mirena® IUD (BayerHealthcare Pharmaceuticals, Wayne,New Jersey). In 2009, the Mirena® IUDwas also sanctioned for the managementof heavy menstrual bleeding (HMB)83and remains the only LNG-IUS devicecurrently available in the US84 with thisapproval. The LNG-IUS has sincebecome an important addition to thegynecologic armamentarium for man-aging women with AUB. In a review of15 randomized controlled trials com-

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paring conservative surgery or hysterec-tomy to medical therapy, Marjoribankset al.85 concluded that there was nodemonstrable difference in satisfactionrates between surgery and LNG-IUS,though the latter is more often associat-ed with vaginal bleeding and spotting.The authors reported that while “oralmedication suits a minority of womenin the long term [that] the LNG-IUSdevice provides a better alternative tosurgery in most cases.” This finding sup-ports the notion that the treatment forAUB should begin with minimally inva-sive and reversible medical approachesas a first-line management strategy.In addition to changes in the medical

management of menstrual disorders,the surgical approaches have changed aswell. With the invention of the laparo-scopic hysterectomy,2 some have advo-cated for uter ine extirpation as afirst-line surgical approach to managingwomen with abnormal uterine bleeding.In 2015, Zuppi et al.86 observed thatafter a mean follow up of 14.4 years,29% of women treated with endometri-al ablation underwent additionalsurgery, whereas no patients afterlaparoscopic subtotal hysterectomy(LSH) suffered symptom recurrence.The authors concluded that “because ofan improved quality of life and lowerreoperative rate, LSH (laparoscopicsupracervical hysterectomy) shouldbecome the treatment of choice inwomen with abnormal uterine bleedingresistant to medical treatment andshould be proposed to all womeninstead of HEA (hysteroscopic endome-trial ablation).” While Zuppi et al. right-fully advocates for hysterectomy’sdefinitive role in treating AUB, theirstatement asks us to accept the premisethat LSH—a far more invasive, morbid,and expensive procedure—should bethe initial surgical approach for womenwho are resistant to medical manage-ment. Unfortunately, this deeply flawedconclusion fails to consider the manyfactors that determine the appropriate-ness of any patient-centered manage-ment strategy. These variables includethe patient’s age, emotional predisposi-tion to hysterectomy, a history of previ-ous abdominal procedures, coexistingmorbidities, medical insurance cover-age, and whether or not she can accepta comparatively long period of recovery.As the risks, benefits, costs, and limi-

tations of each of these medical and sur-gical treatment modalities is clarified,

the role of EA will be more completelyunderstood.

Improving patient education, selection, andinformed consentMost women, when given the best

available information and guidance inselecting treatment options, often selectan appropriate management strategy.Proper patient counseling for a womanconsidering EA requires an honestassessment of her specific risk factorsfor developing a late-onset endometrialablation failure (LOEAF).72 All issuesthat increase a woman’s chance ofdeveloping a late-onset failure—age,leiomyomas, uterine size, severe dys-menorrhea, or unexplained pelvicpain72—need to be scrupulously pre-sented. For patients who are consider-ing an office-based EA, they should alsobe provided with a realistic expectationof the pain that may be associated withprocedures performed under minimalsedation or local anesthesia. Important-ly, both the patient and the physicianshould have a clear strategy for manag-ing intolerable pain.Issues of informed consent regarding

endometrial ablation are different frommost gynecologic procedures whichtypically focus on immediate complica-tions. In addition to discussing issuesrelated to intraoperative complica-tions—which are uncommon withmodern EA—attention should befocused on the incidence and presenta-tion of LOEAFs. In the author’s experi-ence, accurate information best allowsthe woman to participate in the treat-ment modality best suited for her cir-cumstances and lifestyle.

Protocols for long-term follow up of womenwho undergo endometrial ablationAs of this writing, specialty groups,

such as ACOG and the American Asso-ciation of Gynecologic Laparoscopists(AAGL), have not yet developed proto-cols for following women who haveundergone endometrial ablation. In1991, McLucas87 suggested that subse-quent to EA, women “should beencouraged to undergo a baseline ultra-sound three months after ablation andthen annually as part of their healthmaintenance.” The author (MW) incor-porated this practice in 1994 and hasfound annual sonography to be helpfulfor detecting asymptomatic areas ofendometrial regrowth and hematome-trae—often a precursor to symptomatic

LOEAF. Women should be reminded—at the time of their annual examina-tion—to report any changes in theirmenstrual pattern as well as any unex-plained pelvic pain. Whether or notannual ultrasound examinations arecost-effective is a subject that requiresfurther investigation. However, theauthor has found that an annual ultra-sound examination and review ofLOEAF-associated symptoms isextremely helpful in reducing both anx-iety and unnecessary emergency roomvisits for women who experience unan-ticipated pelvic pain or vaginal bleeding.

The management of abnormal perimenopausalor post-menopausal bleedingIrregular vaginal and postmenopausal

bleeding is often encountered in womenwith a prior history of endometrialablation. Ahonkallio et al.88 demonstrat-ed the limitations of endometrial sam-pling and sonohysterography followingEA. The authors evaluated 57 women(ages 47–52) who had undergone a pre-vious EA for the treatment of heavyuterine bleeding with both endometrialbiopsy and sonohysterography. Anendometrial sampling could not beobtained in 23% of subjects using aPipelle® device (Cooper Surgical Inc.,Trumbull, Connecticut). During sono-hysterography, the uterine cavity dis-tended regularly in only 16% of womenand did not distend at all in 42% of sub-jects. In 18% of attempts, the sonohys-terography catheter did not enter theuterine cavity at all. Ahonkallio et al.concluded that endometrial assessmentis compromised following EA and thatintrauterine adhesions may diminish thereliability of endometrial sampling.AlHilli et al.89 studied 91 patients whohad undergone radiofrequency EA andwho underwent subsequent transvaginalultrasound examinations. Symptomaticpatients (69.2%) were significantlymore likely than asymptomatic patientsto have an endometrial thickness of 3mm or more, a heterogeneous endome-trial echotexture, and leiomyomas.Unfortunately, sonographic criteria thatmight obviate the need for endometrialsampling have not yet been establishedand physicians are often left with fewguidelines for managing women withrecurrent perimenopausal or post-menopausal bleeding who have under-gone an EA.Although the author (MW) has

described ultrasound-guided reopera-

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tive hysteroscopic surgery90 as a tech-nique for evaluating women whorequire endometrial biopsy, this methodis impractical and should be utilizedonly by the most experienced hystero-scopists. Unfortunately, many womenwho require endometrial sampling, fol-lowing an LOEF, presently require ahysterectomy for a proper histologicdiagnosis. There is clearly a need toimprove both non-invasive and mini-mally invasive techniques to evaluatewomen who have undergone EA andwho require endometrial assessment.

Innovations for reducing the incidence of late-onset endometrial ablation failures (LOEAFs):EA/LNG-IUSAlthough patient selection remains

the most important tool for reducingthe incidence of LOEAFs, five authorshave demonstrated improved successrates of EA with the postoperativeinsertion of an LNG-IUS. In 1997, Römer91 published a series

of 26 subjects with refractory hyperme-norrhea who were treated with roller-ball endometrial ablation (RBEA).Thirteen of the subjects were treatedwith RBEA alone while the remaining13 women underwent RBEA followedby the insertion of an LNG-IUS. Afternine months, 54% of women in theRBEA group reported amenorrheacompared to 92% of women whoreceived combined therapy. In 2000,Hans Bratschi92 reported the results of99 subjects treated with both hystero-scopic endometrial resection and anLNG-IUS and reported amenorrhea orhypomenorrhea in 95.9% of subjectswho were followed for at least 18months—a rate far superior to whatmight be expected with any ablation orresection technique alone.In 2003, Maia et al.93 reported the

results of a retrospective observationalstudy in which 95 women were identi-fied with pelvic pain, menorrhagia, andan ultrasound diagnosis of adenomyosis.All of the subjects underwent endomy-ometrial resection (EMR). In the 42women who underwent EMR alone, theincidence of amenorrhea at 12 monthswas only 9%, whereas 100% of the 53subjects who underwent both EMR fol-lowed by the insertion of a Mirena®intrauterine device reported amenor-rhea (p <0.001). The authors notedthat the rates of amenorrhea in theirstudy were significantly greater than lit-erature reports in which Mirena® was

used alone and not in association withendometrial resection to treat adeno-myosis.An observational study by Vaughan

et al.94 reviewed the outcomes of 105women who were offered both a ther-mal balloon EA and an LNG-IUS andfollowed for a mean duration of 25months. Fifty-three (50.5%) of thecohort described menses “lighter thannormal,” while 49 (46%) subjectsrepor ted amenorrhea. Ninety-five(90.5%) subjects described their treat-ment as a “complete success” and two(1.9%) subjects felt the treatment wasa failure. Only one subject required ahysterectomy during the follow-upperiod.In 2015, Papadakis et al.95 reported

the results of combined EA and LNG-IUS on the incidence of late-onset fail-ure. In this prospective cohort study, 23women with HMB and secondary dys-menorrhea were treated with bothendometrial ablation—thermal balloonor radiofrequency device—and anLNG-IUS and were monitored for fouryears. Their results were compared to acohort of 65 women who underwentEA alone. Treatment failure was definedas persistent pain, bleeding, or therequirement for a hysterectomy. Of the23 women who underwent the com-bined EA/LNG-IUS treatment, noneunderwent hysterectomy for treatmentfailure at four years, while 24% ofwomen who underwent EA alonerequired uterine extirpation. Althoughpersistent HMB was not significantlydifferent between the two groups, thegroup that underwent combined treat-ment reported significantly less postop-erative pain.These studies certainly suggest that

additional research is warranted in clar-ifying the role of combined EA/LNG-IUS treatment in women who have notadequately responded to medical man-agement alone for HMB and who are athigh risk for developing LOEAF. Thepotential benefits of this combinedEA/LNG-IUS approach include (a) pro-viding contraception to women whohave not undergone a sterilization pro-cedure and (b) suppression of any resid-ual endometrium in women whoundergo EA. Importantly, the LNG-IUSmay provide a platform around whichpostoperative fibrosis is allowed tooccur, possibly preventing completeobstruction and sequestration of resid-ual endometrial tissue. It needs to be

emphasized that the use of the LNG-IUS in the setting of EA is an off-labelapplication not approved by the Foodand Drug administration and thatremoval of the device may present somechallenges.

Conclusions

Since Soranus of Ephesus first intro-duced the use of uterine astringents inthe second century, the deliberatedestruction of the endometrium hasbeen offered as a minimally invasiveapproach for managing intractable uter-ine bleeding unresponsive to contempo-rary medical interventions. The late 19thcentury witnessed the introduction offirst-generation endometrial ablation assuperheated steam that was utilized tocause thermal destruction of theendometrium—atmocausis. As otherenergy sources and methods becameavailable—electrosurgery, radium, X-rays—each was given an opportunity toremediate intractable uterine bleedingwhile avoiding major intra-abdominalsurgery. During the early 20th centu-ry—a time when both hysterectomyand anesthesia were far riskier thantoday—the ability to perform EA in anoffice-based setting had clear rewards. Early practitioners of EA were soon

aware of the immediate risks and bene-fits of EA and even described the occur-rence of late-onset complications.In the midst of a hysterectomy epi-

demic, the 1980s saw renewed interestin EA as a variety of minimally invasiveendoscopic techniques were intro-duced. These second-generation modal-ities allowed EA under direct visualcontrol. The earliest of these techniquesutilized Nd:YAG laser energy deliveredthrough a quartz fiber that was co-locat-ed with a hysteroscope. This techniquewas soon supplanted by the moreaffordable resectoscope which requiredonly inexpensive and readily availableelectrosurgery. Unfor tunately, theenthusiasm for these second-generationtechniques was soon dampened byreports of severe complications result-ing from uterine perforation, fluid mis-management, and a scarcity of adequatetraining. In the latter part of the 20th century,

a variety of EA devices were introducedthat obviated the need for hysteroscopiccontrol and fluid distention. With the

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exception of hydrothermal ablation,these techniques—like their first-gener-ation counterparts—were “blind” andreminiscent of late 19th century prac-tices. Despite the lack of visual control,these third-generation techniques wereequipped with a variety of innovativesafeguards that produced excellentresults with unprecedented safety. Thecombination of safety, efficacy, andaffordability has propelled third-genera-tion—or “global”—endometrial abla-tion to remarkable growth in the earlypart of the 21st century. In the decades ahead, use of EA in

the United States is forecast to increaseat an annual rate of 5.5% from 2016 to2024. In this setting, a variety of ques-tions remain in the ever-changing land-scape of menstrual disorder remedies.Can we reduce EA failures with properpatient selection or by combining EAwith LNG-IUS? How do we followwomen who may require periodic eval-uation following EA? How can we safelymanage women who may require evalu-ation for AUB or postmenopausal bleed-ing following EA? As advocates forwomen’s health, our primary responsi-bility continues to be the search foreffective patient-centered and cost-effective strategies. Though medicineand technology will continually evolve,these remain achievable and worthwhilegoals.

Author’s Disclosures

Dr. Wortman is a consultant forOcon Medical Ltd.

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