Dysfunctional Uterine Bleeding Advances in Diagnosis and

Dysfunctional uterine bleeding: advances in diagnosis and treatment
Malcolm G. Munro
Dysfunctional uterine bleeding occurs during the reproductive years unrelated to structural uterine abnormalities. Ovulatory dysfunctional uterine bleeding occurs secondary to defects in local endometrial hemostasis; while anovulatory dysfunctional uterine bleeding is a systemic disorder, occurring secondary to endocrinologic, neurochemical, or pharmacologic mechanisms. Evaluation of patients with abnormal uterine bleeding and identifying those with dysfunctional uterine bleeding is achieved with a combination of the following: history; physical examination; and judicious use of laboratory evaluation, endometrial sampling and uterine imaging, with sonographic techniques and/or hysteroscopy. Coagulopathies should be considered as should the notion that intramural and subserosal myomas are unlikely to contribute to AUB. High-quality evidence suggests that medical therapy is frequently successful, and newer approaches, such as local delivery of progestins via intrauterine devices, appear to be particularly promising and devoid of systemic side effects. For those intolerant of medical therapy, and/or for whom fertility is no longer desired, a number of minimally invasive surgical options for hysterectomy now exist and are collectively termed endometrial ablation. Endometrial ablation may be performed with or without hysteroscopic guidance. There is an increasing body of evidence that suggests that nonhysteroscopic endometrial ablation may be at least as effective as hysteroscopic endometrial ablation, even when the hysteroscopic procedure is performed by experts. Curr
Opin Obstet Gynecol 13:475489.
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Introduction
During the reproductive years abnormal uterine bleeding (AUB) may occur secondary to pregnancy, to systemic defects in hemostasis, to structural pathology of the genital tract, or to dysfunctional uterine bleeding (DUB). The latter is diagnosed when AUB occurs and is unrelated to congenital or acquired causes. DUB, especially that associated with heavy bleeding, is frequently associated with symptoms such as fatigue, discomfort and depression, as well as a general decrease in quality of life, including activity limitation and changes in sexual functioning. DUB may be either ovulatory or anovulatory, each of which is unrelated to structural abnormalities of the genital tract, but each may exist in the presence of asymptomatic structural anomalies such as polyps and subserosal or intramural leiomyomas. Ovulatory DUB appears to occur when there is loss of local endometrial hemostasis. Physiologically, progesterone withdrawal is believed to trigger menstrual bleeding, in part by the induction of spiral artery vasoconstriction modulated by agents such as prostaglandin F2a [1,2] and endothelin-1, which are known to exist in abundance in the premenstrual endometrium and supercial myometrium [3,4]. However, it is apparent that prostaglandins with vasodilating activity are also measurable in the endometrial stroma (prostaglandin E2) [5] and supercial myometrium (prostaglandin I2). The ratio of prostaglandin F2a to prostaglandin E2 is decreased in menorrhagic women [6], and levels of prostaglandin I2 are increased [7]. Nitric oxide is another potent vasodilator and inhibitor of platelet aggregation that has recently been localized to the endometrial glands and decidualized stromal cells, and has potential inuence on menstrual hemostasis in a manner similar to that of prostaglandin I2 [8]. To date, however, there are no published data relating nitric oxide levels to the volume or duration of menstrual bleeding. It is apparent that there are other contributors to the induction and control of menstrual bleeding. The extracellular matrix of the endometrium is broken down by matrix metalloproteinases (MMPs) and other proteolytic enzymes that are released as levels of progesterone decline in the late luteal phase of the cycle [913]. MMP production and release may be mediated by cytokines, including interlukin-1 and tumor necrosis factor-a, that
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Evolving concepts of pathogenesis
2001 Lippincott Williams & Wilkins.
Department of Obstetrics and Gynecology, UCLA School of Medicine, Sylmar, California, USA Correspondence to Malcolm G. Munro, MD, Professor, Department of Obstetrics and Gynecology, UCLA School of Medicine, 14445 Olive View Drive, Suite 2B-163, Sylmar, CA 91342 1495, USA Tel: +1 818 364 3222; fax: +1 818 364 3255; e-mail: mgmunro@aol.com Current Opinion in Obstetrics and Gynecology 2001, 13:475489 Abbreviations AUB DUB EA GnRH HEA IUD MMP Nd:YAG NHEA NSAID RCT STH abnormal uterine bleeding dysfunctional uterine bleeding endometrial ablation gonadotropin-releasing hormone hysteroscopic endometrial ablation intrauterine device matrix metalloproteinase neodymium:yttrium aluminum garnet nonhysteroscopic endometrial ablation nonsteroidal anti-inflammatory drug randomized controlled trial subtotal hysterectomy
# 2001 Lippincott Williams & Wilkins 1040-872X
476 Adult and pediatric gynecology
are secreted by mast cells and other endometrial migratory cells that increase late in the luteal phase [14]. However, the levels of MMPs in DUB have not yet been reported. The mechanisms that are involved in anovulatory DUB are systemic in nature, although local hemostatic mechanisms may be rendered decient secondary to the absence of cyclic production of progesterone and the related biosynthesis of endothelin-1, prostaglandins, and other substances that they contribute to endometrial hemostasis. In addition, the absence of ovulation makes the bleeding unpredictable, a circumstance that can negatively impact on the woman's lifestyle because of the constant concern regarding unexpected bleeding. Finally, anovulatory DUB creates an endocrinologic endometrial milieu of unopposed estrogen, which is known to facilitate the development of endometrial hyperplasia and endometrial adenocarcinoma. The etiology of anovulation in any given woman may range from immaturity of the hypothalamicpituitaryovarian axis that is frequently seen in perimenarcheal girls to a number of entities that are known or suspected to impact on the normal function of the hypothalamicpituitary ovarian axis; these are beyond the scope of the present review. Bleeding disorders appear to be far more common than is generally recognized. Von Willebrand's disease was found in 10.7% of women with `menorrhagia' in a casecontrol study recently reported by the US Centers for Disease Control and Prevention [15 . .]. This is much lower than the 17 and 34% recently reported from the UK [16] and Sweden [17], respectively, but is nonetheless higher than previously perceived. In each instance the vast majority of cases were of von Willebrand's disease, a diagnosis that may be increasing at least in part because of a greater understanding of the requirements for diagnosis. An important part of the natural history of a vascular clot is the process of brinolysis mediated by the generation of plasmin from plasminogen after its activation by plasminogen activator. Enhanced brinolysis may impede the attainment of local hemostasis, and has been demonstrated in women with ovulatory DUB who usually respond favourably when antibrinolytic agents are employed [1820]. Although the cause of bleeding associated with leiomyomas remains an enigma, it is clear that the majority of myomas are asymptomatic. It is generally accepted, but not proven, that those myomas that cause bleeding are those that are situated near or adjacent to the endometrium, or those that otherwise expand the endometrial surface area. As a result, asymptomatic
leiomyomas may exist in association with dysfunctional uterine bleeding, a notion that should accompany management planning for any woman with AUB and leiomyomas.
Clinical investigation
The value of the history is often unappreciated and imaging of the endometrial cavity is often underutilized. In addition, the clinician must learn to distinguish asymptomatic lesions from those that may contribute to the bleeding problem. Leiomyomas are a particular problem as those that cause bleeding are frequently not appreciated on the physical examination while those that can be palpated may, in fact, be asymptomatic.
History and physical findings
Bleeding that women consider excessive or unacceptable and for which they seek care covers a broad range of volume and predictability. Cyclic, predictable menses every 2135 days are usually associated with ovulation, whereas anovulatory bleeding is typically irregular in timing and ow, and is often interspersed with episodes of amenorrhea. The clinician should also consider a congenital or acquired coagulopathy by reviewing the medical and family history. Although the manual examination may be misleading and is therefore of limited value, a careful bimanual examination of the corpus should be performed, seeking evidence of pregnancy, adenomyosis and leiomyomas, as well as ndings that are suggestive of an adnexal mass or an ectopic gestation.
Laboratory investigation
In addition to measuring hemoglobin, hematocrit and urinary (or serum) b-human chorionic gonadotropin levels, there are a number of other laboratory investigations that may be considered. For those women with associated mucous membrane bleeding (gums, epistaxis), bruising without petechiae, or a family history of abnormal bleeding, particularly with surgery or menses, von Willebrand's disease should be considered, and factor VIII and ristocetin cofactor assays should be obtained [21]. If the diagnosis of ovulation is uncertain, then a serum assay for progesterone conducted during the presumed luteal phase of the cycle is appropriate. For women who are deemed anovulatory, a thyroidstimulating hormone assay will allow evaluation of thyroid function, and serum prolactin or serum free testosterone may be ordered as indicated by the clinical picture.
Evaluation of the endometrial cavity
The historical focus of endometrial cavity evaluation has been the histologic evaluation of the endometrium, generally in order to identify the presence of malignant or premalignant change. However, the techniques that
Dysfunctional uterine bleeding Munro 477
are designed for detecting such endometrial histopathologies are inadequate for identication of structural abnormalities, especially those that may be candidates for minimally invasive surgical intervention.
Histologic assessment
tolerated. Effectiveness may be enhanced by appropriate patient selection; strategies that are appropriate for anovulatory DUB may not be associated with satisfactory results when applied to ovulating women.
Iron
Histologic evaluation of the endometrium with endometrial biopsy is generally recommended as an initial part of the investigation in those women with AUB who are older than 40 years, or in those women of any age with chronic anovulation. Efforts to triage patients for endometrial biopsy using clinical parameters such as cycle regularity have met with inconsistent results [22,23]. Ofce endometrial sampling with narrow disposable catheters has generally been demonstrated to be equivalent to the so-called `formal' dilatation and curettage, utilizing dilators and sharp curettes.
Imaging
For women who have DUB associated with excessive blood loss, iron therapy is considered to be a standard approach or adjuvant. In addition, however, there exist a number of medical therapeutic options for women with DUB that have been demonstrated to be effective; in some instances this is dependent on the ovulatory status of the woman.
Antifibrinolytics
Blind instrumentation has been demonstrated to be inadequate for accurate depiction of the structure of the endometrial cavity [2426]. Consequently, the denitive structural evaluation of the endometrial cavity requires imaging by radiologic or ultrasonographic techniques, or direct inspection with hysteroscopy. In the nonpregnant woman with abnormal bleeding, a thin endometrial stripe in combination with an absence of leiomyomas near to the endometrial `stripe' is strongly associated with a negative hysteroscopic examination [27]. These render transvaginal sonography a suitable screening test for evaluation of the endometrial cavity. In the presence of a thickened endometrium or when myomas exist suspiciously close to the endometrial stripe, however, additional evaluation with sonohysterography or hysteroscopy should be considered. Sonohysterography (also termed saline infusion sonography) is the sonographic (usually transvaginal) evaluation of the endometrial cavity following the transcervical instillation of saline [28], an approach that has comparable sensitivity and specicity for structural anomalies of the endometrial cavity to those of hysteroscopy [29,30]. The major deciency of this technique, as compared with hysteroscopy, is the inability to remove selected lesions concurrently. Most studies [3133] suggest that contrast-based radiographic hysterography is less accurate than hysteroscopy for cavity evaluation. The ability of diagnostic hysteroscopy to provide information that is not predictably obtainable by blind endometrial sampling has been adequately documented [3439].
There is an abundance of high-quality evidence supporting the use of the antibrinolytic tranexamic acid, 1 g every 6 h for the rst 4 days of the cycle, for the treatment of ovulatory DUB. In virtually all cases, bleeding volume reduces by 4060% [4043]. Neither placebo-controlled trials, nor those that compared tranexamic acid with other medical therapies have demonstrated an increase in gastrointestinal side effects [44 . .]. There is no evidence that tranexamic acid increases the incidence of thromboembolic disease, even when used in women who are at high risk [45]. In most of the world antibrinolytic therapy is a mainstay for the treatment of ovulatory menorrhagia, but the approach is rarely used in the USA. The only plausible explanation for the current lack of access to tranexamic acid in the USA is the fact that corporate prot margins are eroded because patents expired long ago.
Cyclo-oxygenase inhibitors
Cyclo-oxygenase inhibitors [nonsteroidal anti-inammatory drugs (NSAIDS)] generally reduce endomyometrial prostaglandin levels via the inhibition of the enzyme (cyclo-oxygenase) that is largely responsible for conversion of arachadonic acid to prostaglandins [46]. Although the exact mechanism is unclear, it is likely that the therapeutic effect is manifested by reductions in the local levels of vasodilating prostaglandins such as prostaglandin E2 and prostaglandin I2. In a recent Cochrane Review [47 . .], ve out of seven randomized trials demonstrated that mean menstrual blood loss was less with NSAIDs than with placebo, whereas two showed no signicant difference. Although most of the published reports evaluated mefenamic acid, there is no available evidence that one product is superior to another. Optimal dose and dose scheduling is more difcult to discern, although most studies have analyzed regimens that start with the rst day of menses and continue for 5 days or until the cessation of menstruation. Mefenamic acid and naproxen are typically prescribed at doses of 250500 mg two to four
Medical options for the management of dysfunctional uterine bleeding
Medical options for the management of DUB can be extremely effective, and are often, but not always, well
times a day, whereas ibuprofen has been studied in dose regimens that range from 600 to 1200 mg/day. Randomized trials that compared NSAIDS with other regimens for ovulatory DUB suggest that both danazol [48] and tranexamic acid [49] are superior at reducing menstrual volume.
Progestins
There exist a variety of routes of administration and dose schedules, ranging from intermittent luteal phase oral administration, through intramuscular injection, to continuous local administration via an intrauterine device (IUD), each of which may have different efcacy depending on the clinical situation. Most of the world literature on the subject pertains to the use of norethindrone, a feature that may limit the generalization of conclusions regarding efcacy and patient tolerance to therapy with other progestins such as medroxyprogesterone acetate. At least 50% of women with anovulatory DUB experience successful regulation of their menses with norethindrone administered cyclically for approximately 10 days per month [50,51]. Women with ovulatory DUB are unlikely to benet from the administration of progestins during the luteal phase of the cycle [52,53], and in some instances menstrual volume may actually increase [41]. The most recent Cochrane meta-analysis of cyclic progestin therapy [54 . .] concluded that lutealphase progestins were less effective than tranexamic acid, danazol, and the progestin-releasing IUD in reducing the volume of ovulatory DUB. In general, there was either a trend or statistical signicance favoring tranexamic acid over luteal progestins with respect to quality of life outcomes such as general health, intermenstrual bleeding, and social and sexual functioning. `Long cycle' administration of progestins may be used effectively. In a randomized controlled trial (RCT) [55] norethindrone 5 mg, administered three times daily from days 526 of the cycle, reduced menstrual volume by 87%. This dose and schedule has more in common with continuous regimens because of the dose and duration of therapy that usually suppress ovulation. In that study, however, women generally preferred the IUD to the oral therapy, because only 22% of those assigned to the progestin were willing to continue with their treatment after 3 months.
Continuous systemic administration Cyclic administration
Progestin-impregnated IUDs have been subjected to the critical scrutiny of RCTs, and appear to have the greatest impact on bleeding volume of any medical therapy reported to date, at least in women whose bleeding is deemed to be ovulatory [56 . .]. A 94% reduction in blood loss at 3 months was reported in one RCT [55], in which 76% of the women assigned the progestin IUD wanted to continue after the 3-month trial period. Another RCT compared the same IUD with hysteroscopic endometrial resection by experts [57], and at 12 months bleeding volume was reduced by 79% in the IUD and by 89% in the resection group. Although these differences were found to be statistically signicant, they were not perceived by the women themselves, and satisfaction with the therapies was equivalent. A similarly designed trial from Scandanavia [58] demonstrated equivalent outcomes. In another open randomized trial that involved 56 women with ovulatory DUB scheduled for hysterectomy [59], 64.3% of those randomized to the IUD chose to cancel surgery compared with only 14.3% of the group allocated to their current medical management.
Estrogens
Local administration
The most widely used medical treatment for acute heavy uterine bleeding in nonpregnant women, regardless of cause, is parenteral administration of high-dose conjugated equine estrogens, 25 mg intravenously every 4 h. The mechanism of action of conjugated equine estrogens is unclear, and may not be specic to the endometrium itself, because similar approaches have been successfully reported in the gastrointestinal and otolaryngology literature [60,61]. Despite the widespread use of this approach, there remains only one RCT [62] that has demonstrated it to be more effective than placebo (71% versus 38%). Oral contraceptives are generally considered to be effective in the management of both ovulatory and anovulatory DUB, but there are few available data to support this contention. An RCT that included a monophasic combined oral contraceptive [63] demonstrated that ow was reduced by approximately 50% in those women with either ovulatory or anovulatory DUB. However, the sample size of that study was small and precludes any further conclusions. A recently reported randomized trial [64 . .] compared the use of a triphasic oral contraceptive with placebo in a cohort of 201 women who apparently suffered from anovulatory DUB. Approximately 50% of the treatment group were `much improved', compared with about 20% of the placebo group, and standardized health-related quality of life scores (SF-36) also improved in the former group.
Estrogens plus progestins
Continuous administration of progestins may be more effective at treating ovulatory menorrhagia than cyclic dosing. However, there are no published data evaluating such an approach in women with DUB.
Androgens
Danazol is a synthetic isoxazol derivative of 17a-ethinyl testosterone with impeded androgenic activity that functions by suppression of ovulation, reduced ovarian production of 17b-estradiol, or direct effects on estrogen receptors in the endometrium and elsewhere. Higher doses of danazol (200 mg/day or greater) appear to be more successful at treating DUB, possibly because of their inhibitory affect on ovulation [65]. In RCTs, approximately 50% of individuals experience a decrease in menstrual volume with either 200 mg/day or a declining daily dose regimen (200 mg/day during month 1,100 mg/day during month 2, and 50 mg/day during month 3) [53,66]. Danazol has also been demonstrated to reduce menstrual blood loss more effectively than mefenamic acid [67]. However, the relatively frequent occurrence of adverse side effects such as weight gain, oily skin, acne, and deepening of the voice make the medication undesirable for many.
Gonadotropin-releasing hormone agonists and antagonists
hysterectomy have been introduced or rediscovered, and a variety is under development. Some of these procedures provide alternatives for women with DUB that reduce morbidity or decrease the direct and indirect costs of care. For others, the impact is less certain, because at least some clinical and cost outcomes may not be as advantageous as anticipated. Nevertheless, women now have access to a wider variety of choices for the surgical management of their DUB. Such a circumstance creates a number of challenges for gynecologists and gynecologic surgeons, who now must critically analyze these options and, at least for those that are viable, acquire the necessary skills and equipment to perform them. Approximately 550 000 hysterectomies are performed each year in the USA, making it the second most common surgery performed. The proportion of hysterectomies estimated to be for DUB has been reported at 4.540% [70,71 .,72,73], a range that reects differences in such diverse factors as procedure coding and patterns of practice. The value of laparoscopic hysterectomy varies in large part on the training and ability of the surgeon, but is designed to reduce the need for abdominal hysterectomy. Clearly, if vaginal hysterectomy can be performed, then laparoscopic hysterectomy is unnecessary and is more expensive [74]. Those with signicant skill at vaginal hysterectomy nd laparoscopic hysterectomy to be of value in a limited number of patients [75]; those with less training and skill in vaginal hysterectomy appropriately utilize laparoscopic hysterectomy more often to reduce the need for abdominal hysterectomy. Many suspect that complications associated with laparoscopic hysterectomy are more prevalent than is generally known, although it is difcult to substantiate such concerns. Supracervical or subtotal hysterectomy (STH) is a procedure that has enjoyed a modest, although controversial renaissance, and is applicable to women with chronic DUB [7679]. Much of the controversy revolves around the perceived value of removing or retaining the cervix. Those who are opposed to the procedure express concern regarding the risk of cervical cancer. On the other hand, advocates of STH argue that, at least in selected populations, the additional dissection associated with total hysterectomy adds unnecessary surgical time and an increased risk of short-term complications such as infection, hemorrhage, and injury to the bladder and uterus. In addition, it is proposed that removal of the cervix may increase the incidence of longer term complications involving bladder and sexual function, as well as increasing the rate of delayed postoperative
Hysterectomy
Gonadotropin-releasing hormone (GnRH) agonists, administered continuously, create a reversible hypogonadotropic state by downregulation of GnRH receptors, which in turn results in dramatically decreased gonadotropin production from the anterior pituitary. The use of GnRH agonists has been described for women with ovulatory DUB, in conjunction with `add-back' treatment of vasomotor symptoms and prevention of osteopenia using a cyclic estrogenprogestin regimen [68]. Not surprisingly, the women experienced a signicant reduction in bleeding volume and tolerated the regimen well, with 90% willing to continue for longer than 12 months. In women with anovulatory DUB, 3 months of GnRH agonist resulted in improved bleeding in 21 out of 38 women evaluated during the fourth posttreatment cycle. The long-awaited introduction of GnRH antagonists will provide an additional method for central suppression and one that is devoid of the gonadotropin `are' that accompanies the use of agonist therapy. The are can be an inconvenience because of its potential for induction of bleeding in the second week after initiation of therapy. If prolonged GnRH agonists are to be considered, then gonadal steroid add-back regimens may be appropriate, both for reduction of vasomotor symptoma and for the prevention or reduction of treatmentrelated osteopenia [69].
Surgery for dysfunctional uterine bleeding
Surgery for DUB is generally utilized when medical therapy fails, when it is not tolerated by the woman, or because of patient or surgeon choice. Over the past 20 years a number of surgical alternatives to
vaginal vault prolapse. The advent of electromechanical laparoscopic morcellators has facilitated the performance of laparoscopic STH by reducing the time required for performance of the procedure.
Endometrial ablation for dysfunctional uterine bleeding
Surgery that attempts selective destruction of the endometrium is commonly known as endometrial ablation (EA). Hysteroscopically directed endometrial ablation (HEA) has been introduced as a surgical option for women with chronic DUB, with the advantages of short duration of hospital stay, absence of surgical incisions, and subsequent rapid return to normal activity. However, it has been recognized that optimal outcomes with HEA require a level of skill and experience that may not be achieved by the average surgeon. Consequently, nonhysteroscopic endometrial ablation (NHEA), a procedure that was initially conceived and introduced in Germany during the 1930s [80], was rened and reintroduced during the 1990s.
Hysteroscopic endometrial ablation
Hysteroscopic endometrial electrocoagulation was originally described using a urologic resectoscope and a 2mm ball electrode [91], although any electrode with a large surface area (ball, barrel, ovoid, bar) may be utilized. Any of modulated, dampened current (`coagulation'), continuous current (`cutting'), or modulated (`blend') low-voltage output may effectively result in ablation of the endometrium [9297]. During the late 1980s and early 1990s a number of series of electrosurgical endometrial coagulation were reported, each of which had similarities and differences based on physician experience, patient selection, electrode type, and duration of follow-up [98104]. Most employed `coagulation waveforms', and the endometrium was almost always prepared preoperatively by hormonal therapy (usually GnRH agonists). The reported outcomes are very similar to those described above for laser HEA. Approximately 90% of patients attained satisfactory reduction in their menstrual ow and were approximately equally divided between amenorrhea and either hypomenorrhea or normal ow. Treatment failures occurred in approximately 8% of cases, and half of those retreated attained satisfactory results after undergoing a second ablative procedure. Signicant complications were encountered with a frequency similar to that observed for laser EA. A loop electrode may be utilized to excise the endometrium and supercial myometrium [105,106]. In an attempt to ablate endometrial tissue that may have escaped excision, some surgeons routinely coagulate the entire resected surface area. Potential advantages of endometrial resection include histologic sampling of the endometrium, better treatment of supercial adenomyosis, a lower risk of subsequently concealed endometrial hyperplasia or carcinoma, and a reduced need for preoperative hormonal preparation of the endometrium. If there are unanticipated submucous myomata or polyps, then they can be simultaneously resected or removed without the need to change instrumentation or to abort the procedure. However, there is lack of proof of most of these hypothesis, and there are some disadvantages to a technique that requires greater hysteroscopic skill and a more extensive understanding of uterine anatomy. For example, uterine perforation causing intraoperative hemorrhage is more likely to occur with resection as compared with other techniques, and direct thermal injury to adjacent structures (great pelvic vessels, the ureter) has been reported more often with resection than it has for coagulation/desiccation [107,108]. This danger is greatest at the isthmus and cornual regions where the thickness of the myometrium leaves little margin for error [109], thereby justifying the use of coagulation rather than resection. The likelihood of intravascular absorption of distention media and
The hysteroscope may be used to direct destruction of the endometrium using laser, radiofrequency, electrical, or thermal energy to coagulate or vaporize tissue. Endomyometrial resection is achieved with a loop electrode deployed via a modied urologic resectoscope. Energy from the neodymium:yttrium aluminum garnet (Nd:YAG) laser can be transmitted to the endometrial cavity hysteroscopically and directed to the endometrium via either a touch or no-touch technique, resulting in a zone of self-limited necrosis that is 45 mm deep. Critics of this technique point out that the small size of the quartz ber makes the procedure unduly laborious and time consuming, restricting its use to uteri with small endometrial cavities. Class II-2 (US Preventive Services Task Force classication) evidence suggests that the majority of treated patients (490%) experience a signicant reduction in uterine blood ow; approximately half of these patients have amenorrhea and half have either hypomenorrhea or normal menstrual ow [8189]. The use of Nd:YAG laser has in general declined, in part because of the training and costs associated with its deployment, and in part because of the proliferation of other hysteroscopic and nonhysteroscopic approaches. Electrosurgical techniques have largely superceded laser vaporization in clinical practice. For purposes of both safety and effectiveness, it is important that the surgeon who aspires to perform electrosurgical EA have a clear and complete understanding of the bioeffects and control of radiofrequency electrical energy on tissue [90 .].
intraoperative hemorrhage are potentially increased by the transection of supercial vessels as the endometrium is systematically shaved. Amenorrhea after EA does not necessarily reect total resection of endometrial tissue, a feature that raises issues regarding future hormone replacement therapy [110]. Clinical success rates in the published (class II studies) follow-up intervals are similar to those for laser HEA and electrosurgical coagulation, with approximately 90% experiencing satisfactory reduction of their abnormal uterine bleeding [111115]. These studies appear to suggest that only approximately one-third of these women ended up with amenorrhea, whereas approximately two-thirds experienced hypomenorrhea or eumenorrhea. Menstrual blood ow was unchanged or worse in 10% of the patients, and about 75% of those retreated after failing the initial procedure attained satisfactory results. Endometrial electrosurgical vaporization utilizes a relatively large electrode with multiple edges or elevations, each of which is capable of generating enough current density to vaporize tissue, provided that there is sufcient power from the electrosurgical generator or unit. The potential advantages of such an approach over resection include attainment of a visual end-point (depth of endometrial destruction) without the need for often frequent removal of endomyometrial fragments that prolongs surgical time. Endometrial vaporization has been demonstrated to be superior to resection in an RCT [116] when systematic absorption of distension media was used as an outcome. Mean systemic absorption of distension media with vaporization was 109+126 cm3 versus 367+257 cm3. In that trial, only one out of 47 patients undergoing vaporization had a uid decit over 500 cm3, whereas such a decit occurred in 14 out of 44 patients who underwent resection. Clinical outcomes, including patient satisfaction with therapy, as well as bleeding patterns and duration of ow, were similar between the groups. The presumed reason for this reduction in systemic absorption is the increased amount of adjacent tissue electrocoagulation imparted by the vaporizing electrode when compared with the resection loop [117].
Medical preparation of the endometrium before endometrial ablation
not known. A cost-effectiveness analysis of endometrial suppression with danazol compared with GnRH agonists [119] suggested that total health care costs may be greater with GnRH agonists. However, the study also concluded that amenorrhea rates were slightly higher in the GnRH-treated group, and that study withdrawals were greater in the danazol group, a factor that may have skewed the results of the analysis. There are no highquality objective data that indicate similar outcomes associated with preoperative progestins or mechanical preparation of the endometrium. Evidence to be discussed subsequently suggests that systemic media absorption may be less with preoperative GnRH agonists. The reported incidence of complications associated with HEA and resection is relatively low. To some extent, this may reect the expertise and experience of those who have reported results. However, a recently published Dutch survey of 87 hospitals [120 .] appears to suggest that, even with widespread use, complications are infrequent and that half of these are related to entry into the endometrial cavity (uterine perforation, cervical trauma). Other complications include those related to anesthesia, failed access, hemorrhage, and especially the systemic absorption of distension media. The comprehensive `Mistletoe' study from the UK [121] suggests that endometrial resection or combined resection and ablation are the techniques that are most often associated with serious complications secondary to hemorrhage or perforation. Furthermore, these complications were most commonly encountered in the rst 100 cases of a given surgeon. Standard electrosurgical operative hysteroscopy requires that electrolyte-free, low-viscosity solutions be used for distension of the endometrial cavity. The most commonly employed agents are 3% sorbitol, 1.5% glycine, 5% mannitol, and combined solutions of sorbitol and mannitol. Each of these, if sufciently absorbed into the systemic circulation, will result in dilutional hyponatremia and (with the possible exception of mannitol) hypoosmolality [122,123]. Hyponatremia and hyposmolarity may result in brain edema and, in some instances, permanent neurologic damage; this feature may be more common in premenopausal women because of the inhibitory impact of estrogen and progesterone on the brain's sodium pump, making such women more vulnerable to cerebral edema. In rare instances longterm morbidity and death have been reported, making appropriate uid management critical to the safety of hysteroscopic surgery. The recent development of hysterscopic electrosurgical systems that can operate in electrolyte-rich media, such as normal saline, has provided an opportunity to eliminate the risk of
Complications of hysteroscopic endometrial ablation
There is high-quality evidence from a Cochrane review (class I evidence) [118 . .] that danazol or GnRH agonists used before endometrial ablation result in shorter procedures, greater ease of surgery, a lower rate of postoperative dysmenorrhea, and a higher rate of postsurgical amenorrhea. Whether the short-term doubling in amenorrhea rates associated with adjuvant medical suppression is sustained for multiple years is
hyponatremia [124,125], but risks of uid overload remain. Systemic absorption of distension media may be reduced with the preoperative use of GnRH analogs [126,127] or with the administration of dilute intracervical vasopressin [128]. Other measures that may be effective at reducing the incidence of intravasation include operating at the lowest effective intrauterine pressure and avoidance of preoperative overhydration. Early detection of intravasation is enhanced by adherence to a strict protocol or an automated system that captures uid from three sources: the resectoscope, the perineal collection drape, and the oor. The management of intraoperatively recognized signicant intravasation varies according to the patient's medical condition, her intraoperative assessment, the status of the procedure, and the amount of absorbed uid. If the decit reaches 7501000 cm3, then serum electrolytes are measured and 1040 mg furosemide is given intravenously. Should the serum sodium fall below 125 mmol/l, or should the decit reach 15002000 cm3, then the procedure should be expeditiously terminated.
Randomized trials comparing hysterectomy with hysteroscopic endometrial ablation
increased, however, the two were virtually the same at 4 years. Nevertheless, although indirect costs vary widely with the patient's economic situation, the Aberdeen trial suggests that it is likely that those associated with HEA probably remain substantially lower than for hysterectomy. Application of these conclusions to US women should be done with caution. Apart from cultural and socioeconomic differences related to dissimilarities in health care systems, the dominant procedure performed in all but the Italian study [133] was abdominal hysterectomy. In North America, most such women are treated with vaginal hysterectomy, an approach that could have a signicant impact on a number of these outcome variables. Furthermore, it is not clear that North Americans and Europeans are consistently similar in their denitions of DUB, and consequently the women selected for surgical therapy may differ. A federally funded randomized trial has now completed recruitment (the Surgical Treatments Outcomes Project for Dysfunctional Uterine BleedingSTOP-DUB), and initial, 1-year results are expected to be published during 2003 [137].
Randomized trials that compared one method of hysteroscopic endometrial ablation with another
At this time there exist ve randomized studies, four from the UK [129132] and one from Italy [133], that have, in addition, resulted in a number of important additional publications comparing hysterectomy with HEA and which comprise the core of the meta-analysis in the Cochrane Database [134 . .]. Hysterectomy is clearly superior in attaining amenorrhea and, although satisfaction with HEA is high, there are greater patient satisfaction rates when the uterus is removed. It seems clear that woman vary with respect to their desires regarding amenorrhea; some see it as a primary goal, whereas others would prefer to continue to menstruate, albeit with normal ow [135]. Women who received HEA had shorter hospital stays and fewer postoperative complications, and resumed activities earlier than those with hysterectomy. These studies found reoperation rates (either repeat ablation or hysterectomy) in HEA patients to increase steadily over time, up to approximately 40% at 4 years of follow up in the one study that had such a lengthy follow-up interval [136]. Both hysterectomy and HEA were associated with positive outcomes with respect to mental health and depressive symptoms, and, importantly, there were no apparent differences in postprocedural sexual function. In some of these trials there has been an opportunity to compare the direct and indirect resources that were used to accomplish the two types of procedures. In the Aberdeen randomized trial [67] the direct costs of HEA were about half those of hysterectomy within months of the procedure. As the frequency of visits and reoperation
There is a paucity of randomized trials comparing the different techniques of HEA. In the randomized trial conducted by the Aberdeen group [138], patients assigned to EA were subsequently randomized to either laser ablation or endometrial resection. Although both procedures were associated with similar levels of patient satisfaction and clinical outcomes at 12 months, laser ablation was signicantly more expensive, largely because of the longer procedure time.
Factors that affect outcome of hysteroscopic endometrial ablation or resection
There are a number of factors that have been demonstrated to affect clinical outcome of HEA, including those relating to patients and some that are related to the surgeon. Women older than 45 years are less likely to have subsequent hysterectomy and are more likely to be amenorrheic and satised with their outcome (class II-2 evidence) [139,140 .]. Surgeon experience or ability may also be important, because in one study [70] the hysterectomy rate was reported to be 12.6% when endometrial resection was performed exclusively by the consultant surgeon, as compared with 38% if all or part of the ablation was done by a trainee. Adenomyosis has been associated with an increased risk of HEA failure [141] and has been found in up to 75% of hysterectomy specimens [142]. It is less clear that adenomyosis affects the same outcomes in women undergoing endometrial resection or vaporization. With increasing depth of resection and ablation, however,
there is some evidence that the failure rate with hysteroscopic resection drops (from 22 to 5%), including that for women with adenomyosis [143]. There has been concern that failures may be higher in women with larger uteri and correspondingly larger endometrial cavities. At least in experienced and able hands, however, success rates in large uteri (412 weeks size) may be equivalent to those in women with smaller uteri [144 .]. One of the concerns regarding EA is the potential for later development of endometrial carcinoma, possibly with a diagnosis delayed for reasons that relate to the ablative procedure. It seems clear that those women who have been reported to develop endometrial malignancy after EA are those who have the usual risk factors for endometrial hyperplasia [145]. Consequently, women who are at enhanced risk for endometrial hyperplasia because of chronic anovulation may be counseled that they are at greater risk than ovulatory women for developing such a disorder after endometrial ablation.
Nonhysteroscopic endometrial ablation
NHEA is blind destruction of the endometrium using computer-assisted energy delivery systems, and appears to require less training, skill, and experience than HEA. These techniques are attractive because they are rapidly performed, there is a low risk of uterine perforation, a reduced or eliminated risk of systemic uid absorption, and a potential for ofce or clinic use, thereby reducing resource utilization. Radiofrequency (RF) electrosurgery using alternating current and either monopolar or bipolar electrodes is utilized widely in operating rooms for virtually any surgical procedure. Endometrial ablation using RF energy was rst described by Badenhauer in 1937 [11], and was resurrected during the latter part of the past century with a number of innovative approaches. A unipolar system (VestablateTM, Valleylab Division of Tyco Healthcare Group LP, a division of Tyco International Ltd, Pembroke HM, Bermuda) using 12 electrodes deployed over a balloon attached to an 8mm-diameter cannula and designed to t the normal endometrial cavity works in conjunction with standard electrosurgical units. When the balloon is inated, the electrodes are held in close proximity to the endometrial surface, allowing the process of electrodesiccation to occur relatively rapidly (approximately 4 min) and in an evenly distributed manner, provided the shape of the endometrial cavity is symmetric. There is evidence that this approach may be equivalent to HEA performed by expert surgeons using the technique of electrosurgical resection and ablation [146]. At this time, however, the device is not marketed in the USA.
Radiofrequency electrosurgical ablation
Another novel radiofrequency electrosurgical design utilizes a unique bipolar mesh electrode that expands after insertion into the endometrial cavity, and which, in combination with suction, allows for electrosurgical vaporization and underlying desiccation in a relatively rapid manner (6075 s). The design of the system (NovaSureTM; Novacept, Palo Alto, California, USA) allows for variable depth of vaporization and desiccation less in the cornual areas and more in the fundus and body that is controlled by the increasing tissue impedance of desiccated tissue (shut-off 450 O). Suction evacuation maintains contact of the electrode surface with the endometrium and evacuation of the vapor that could impede such contact. As is the case with the Vestablate system, the endometrial cavity must be symmetric and of relatively normal size to allow proper function. Observational studies [147] have been reported with short-term results that are similar to those with other nonhysteroscopic systems, and a randomized trial that compared the Novasure device with HEA has been completed with results expected shortly. Release of this device in the USA is anticipated in late 2001 or early 2002. In 1994, preliminary experience with a thermal balloon ablation system (CavatermTM, Walleston Medical SA, Morges, Switzerland) was reported [148,149], and this device was subsequently shown to reduce the volume of DUB signicantly in a majority of treated patients [150]. A similar device, the ThermachoiceTM balloon ablation system (Gynecare Division of Ethicon Inc., Somerville, N.J., USA) has been available to US markets for more than 2 years and was the rst NHEA system that met with US Food and Drug Administration approval. The device is approximately 5 mm in diameter (uninated), and requires the endometrial cavity to be of normal size (510 cm fundus to external cervical os) and symmetric, without congenital anomalies or submucous myomas. Performance of the procedure requires the purchase of a disposable balloon system and a reusable controller box. The patient is generally given some sort of general or regional anesthesia, but local or neureleptic analgesia may be all that is necessary. The original ThermachoiceTM system was subjected to a rigorous multicenter RCT [151,152 . .] that demonstrated that it is at least equivalent to HEA at both 1 and 2 years with a rollerball electrode for a number of outcomes, including patient satisfaction (6465% satised or very satised in each group) and reduction in bleeding volume (by approximately 80% in each group). There were only a few minor complications in the NHEA group, whereas the HEA patients experienced both minor and major complications. In addition, the procedure was generally completed in less time than was HEA, and was performed more often under local or neureleptic anesthesia.
Local hyperthermia
Free uid, instilled into the endometrial cavity and then heated to an appropriate temperature, may be used to ablate the endometrium effectively. Although it appears intuitive that free intrauterine uid can migrate to the peritoneal cavity via the fallopian tubes, or to the vagina via the cervical canal at low insufation pressures (540 cmH2O) such an event is quite uncommon. Furthermore, by creating a closed system, migration of uid via either the cervix or fallopian tubes reduces pressure, allowing automatic alarms and shutoff systems to act as safeguards. An additional potential advantage afforded by free uid is the ability to perform endometrial ablation in the presence of congenital malformations (e.g. Mullerian fusion or absorption anomalies), or acquired defects such as leiomyomas. One of these systems has recently been approved by the US Food and Drug Administration for use under hysteroscopic guidance (HydroThermalAblation#, BEI Medical Systems Co Inc, Teterborough NJ, USA), and has been demonstrated to yield short-term (1 year) success rates similar to those for other NHEA and HEA techniques. Freezing of the endometrium for treatment of DUB was rst reported more than 30 years ago [153]. Pittrof et al. [154] from the UK reported a cohort of 67 women, 63% of whom experienced improvement in symptoms at follow-up intervals that ranged from 3 to 18 months. Rutherford et al. [155] reported a 75.5% amenorrhea rate at 6 months, which dropped to 50.3% at 22 months in a group of 15 patients. The US Food and Drug Administration has recently approved a device that utilizes a 5.5-mm-diameter probe that creates an elliptic freeze zone approximately 1.5 mm deep by reducing the local endomyometrial temperature to below 7908C. Concerns regarding the potential for such a freeze depth to involve adjacent structures, particularly bowel in the cornual region, are offset by the ability to monitor the depth of the freeze, generally using transabdominal ultrasound. The required number of freeze cycles depends in part on the size and shape of the endometrial cavity, but is usually two or three, contributing to a treatment time of 1020 min. Short-term (1 year) clinical outcomes are comparable to those of the other NHEA and HEA approaches.
Microwave Cryotherapy
cavity by the surgeon for a treatment time that ranges from 1 to 4 min, depending on the conguration of the endometrial cavity. The results in the 263 women studied are similar to those from other trials with other NHEA techniques. About three-quarters of each group were satised with their therapy at 12 months after treatment. Surgical time was shorter for those treated with microwave ablation, and most of the SF-36 scores were improved in each group. This technique is presently being evaluated by an RCT in the USA. The application of low-power Nd:YAG laser light has been shown to have potential as a NHEA technique. In a study from Belgium, Donnez and coworkers [158,159] reported initial and 1-year follow-up results using this technique (GyneLaseTM ESC Medical Systems Ltd, Yokneam, Israel), with results similar to those with other NHEA technologies. The energy (wavelength 830 nm) is delivered to the endometrial cavity using a 6-mmdiameter probe with an expanded tripolar structure that resembles that of an IUD. Each pole delivers 57 W for approximately 7 min. The laser generator is very small in size, and is considered to be less costly than previous laser devices. At this time the device is not available in the USA. The potential application of photodynamic therapy for the treatment of menorrhagia is being evaluated by a number of investigators. Successful destruction of endometrium with photosensitive agents has been reported in both rat and rabbit models [160,161]. The systemic or local pretreatment of target tissues such as endometrium with agents that are activated by monochromatic light can produce a local cytotoxic effect. For each photosynthesizer molecule, a specic wavelength (usually laser light) accurately matched to the absorption peak must be used in order to produce local tissue necrosis. The activated photosensitizer molecule is believed to react with tissue oxygen producing singlet oxygen, which is cytotoxic. Further studies are needed in animals to determine the safety of this technique for nontarget tissues that bind the photosensitizer molecules, and whether endometrial regeneration will be prevented.
Other nonhysteroscopic endometrial ablation techniques
Conclusion
NHEA using microwaves was initially reported in 1995 [156]. The technique was compared with hysteroscopic endometrial resection in the context of a RCT performed by the Aberdeen group in Scotland [157], who used a 9.2-GHz, 30-W system on an 8-mm probe that, when activated, results in heating of the local tissue to about 958C to a depth of approximately 6 mm. The nondisposable probe is moved over the endometrial
In order to provide women with appropriate options for therapy, the clinician must be prepared to distinguish ovulatory DUB from that which is anovulatory, and to utilize appropriate ancillary tests to identify systemic, structural and endocrinologic anomalies, or lifestyle factors that may explain the bleeding. In undertaking such an investigation, it is important for the clinician to be able to distinguish lesions that may be asymptomatic, and unrelated to the bleeding, from those that truly are
the source of the problem. With this information, a rationally determined set of medical and, if appropriate, surgical therapeutic options may be presented to the woman. Medical therapy has the potential to improve symptoms in the short term or long term for a number of women, but it is clear that it is not for everyone. For many women the treatments simply do not work, or do not work sufciently well to justify continuing their use. Nevertheless, most women deserve the opportunity to at least attempt medical therapy before they commit themselves to a surgical approach that removes the opportunity for future pregnancy. For those women who wish to retain fertility, such an attempt is a necessity. HEA was originally developed for patients suffering from disabling DUB who are poor surgical candidates for `major' surgery such as hysterectomy, and who had no desire for future childbearing. Clearly, it is now an option for otherwise healthy women who have failed or refused medical intervention. Available evidence suggests that these ablative procedures signicantly reduce menstrual blood ow and, in some instances, decrease secondary dysmenorrhea. However, it is clear that, although most women are probably satised with their choice of EA, many subsequently choose or require either additional EA or hysterectomy. Although it is possible that those with anovulatory DUB might be less likely to nd satisfaction with EA than those women with ovulatory DUB, such a hypothesis remains to be proven. The Aberdeen experience suggests that direct costs of EA may be greater than hysterectomy if patients are followed long enough after their index procedure. Despite this, however, for many women the indirect costs of EA may still be much less than for hysterectomy, and therefore may be a signicant factor to be considered as they make their choice. For example, the lawyer with DUB will be back earning money sooner if she has an EA instead of a hysterectomy, and that even if an additional EA is required in a few years the net economic impact to her will be less than that of hysterectomy. Such indirect economic advantages may not be so signicant for women of lower socioeconomic status. The discussion of hysteroscopic techniques in the present review generally addressed studies that reect the results obtained by experts under controlled conditions (efcacy), and they should not be interpreted to reect clinical and cost outcomes when the procedures are deployed outside the constraints of a clinical trial (effectiveness). Available evidence suggests that optimal training, ability, and experience generally culminate in the best surgical results. NHEA techniques, because
they are automated and usually computer controlled, largely remove the requirements of skill and ability, and require only a modicum of training. In addition, largely because of the removal of the specter of uid overload, they may be performed in a less resource-intense surgical environment, thereby reducing the direct costs of the procedure. Ultimate judgment of the value of EA awaits the results of longer term followup of the Aberdeen trial as well as those of other carefully crafted long-term longitudinal studies, such as STOP-DUB, which compare the economic, social, and medical benets of hysterectomy with those of EA for the treatment of chronic DUB.
Papers of particular interest, published within the annual period of review, have been highlighted as: . of special interest .. of outstanding interest 1 Abel MH, Baird DT. The effect of 17 beta-estradiol and progesterone on prostaglandin production by human endometrium maintained in organ culture. Endocrinology 1980; 106:15991606. Lumsden MA, Brown A, Baird DT. Prostaglandin production from homogenates of separated glandular epithelium and stroma from human endometrium. Prostaglandins 1984; 28:485496. Rees MCP, Parry DM, Anderson ABH, Turnbull AC. Immunohistochemical localisation of cyclooxygenase in the human uterus. Prostaglandins 1982; 23:207214. Word RA, Kamm KE, Casey ML. Contractile effects of prostaglandins, oxytocin, and endothelin-1 in human myometrium in vitro: refractoriness of myometrial tissue of pregnant women to prostaglandins E2 and F2 alpha. J Clin Endocrinol Metab 1992; 75:10271032. Hoffman GE, Rao CV, DeLeon FD, et al. Human endometrial prostaglandin E2 binding sites and their profiles during the menstrual cycle and in pathological states. Am J Obstet Gynecol 1985; 151:369375. Smith SK, Abel MH, Kelly RW, Baird DT. Prostaglandin synthesis in the endometrium of women with ovular dysfunctional uterine bleeding. Br J Obstet Gynaecol 1981; 88:434442. Makarainen L, Ylikorala O. Primary and myoma associated menorrhagia: role of prostaglandins and effects of ibuprofen. Br J Obstet Gynaecol 1986; 93:974978. Cameron IT, Campbell S. Nitric oxide in the endometrium. Hum Reprod Update 1998; 4:565569. Woessner Jr JF. The family of matrix metalloproteinases. Ann NY Acad Sci 1994; 732:1121.
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110 Magos AL, Baumann R, Lockwood GM, Turnbull AC. Experience with the first 250 endometrial resections for menorrhagia. Lancet 1991; 337:1074 1078. 111 Maher PJ, Dill DJ. Transcervical endometrial resection for abnormal uterine bleeding: report of 100 cases and review of the literature. Aust N Z J Obstet Gynaecol 1990; 30:357360. 112 Pyper RJD, Haeri AD. A review of 80 endometrial resections for menorrhagia. Br J Obstet Gynaecol 1991; 98:10491054. 113 Serden SP, Brooks PG. Treatment of abnormal uterine bleeding with the gynecologic resectoscope. J Repro Med 1991; 36:697699. 114 Dwyer N, Hutton J, Stirrat GM. Randomised controlled trial comparing endometrial resection with abdominal hysterectomy for the surgical treatment of menorrhagia. Br J Obstet Gynecol 1993; 100:237242. 115 Wortman M, Daggett A. Hysteroscopic endomyometrial resection: a new technique for the treatment of menorrhagia. Obstet Gynecol 1994; 83:295 298. 116 Vercellini P, Oldani S, Yaylayan L, et al. 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A cost effectiveness analysis of goserelin compared with danazol as endometrial thinning agents. BJOG 2000; 107:340346. 120 Jansen FW, Vrredeviigd CB, Van Ulzen K, et al. Complications of hysteroscopy: . a prospective multicenter study. Obstet Gynecol 2000; 96:266270. This is a good and comprehensive report of hysteroscopic complications in The Netherlands, showing that complications may be more common than is generally appreciated. 121 Overton C, Hargreaves J, Maresh M. A national survey of the complications of endometrial destruction for menstrual disorders: the MISTLETOE study. Minimally invasive surgical techniques: laser, endothermal, or endoresection. Br J Obstet Gynaecol 1997; 102:13511359. 122 Istre O, Shahaa K, Schjoensky AP, et al. Changes in serum electrolytes after transcervical resection of endometrium and submucous fibroids with the use of 1.5% glycine for irrigation. Obstet Gynecol 1992; 80:218222. 123 Kim AH, Keltz MD, Arici A, et al. Dilutional hyponatremia during hysteroscopic myomectomy with sorbitol-mannitol distention medium. J Am Assoc Gynecol Laparosc 1995; 2:237242. 124 Isaacson K, Nardella P. Development and use of a bipolar resectoscope in endometrial electrosurgery. J Am Assoc Gynecol Laparosc 1997; 4:385 391. 125 Vilos GA. Intrauterine surgery using a new coaxial bipolar electrode in normal saline solution (Versapoint): a pilot study. Fertil Steril 1999; 7:740743. 126 Donnez J, Vilos G, Gannon MJ, et al. Goserelin acetate (Zoladex) plus endometrial ablation for dysfunctional uterine bleeding: a large randomized, double-blind study. Fertil Steril 1997; 68:2936. 127 Taskin O, Buhur A, Birincioglu M, et al. Endometrial Na+, K-ATPase pump function and vasopressin levels during hysteroscopic surgery in patients pretreated with GnRh agonist. J Am Assoc Gynecol Laparosc 1998; 5:119 124. 128 Golderberg M, Zolti M, Bider D, et al. The effect of intracervical vasopressin on the systemic absorption of glycine during hysteroscopic endometrial ablation. Obstet Gynecol 1996; 87:10251029. 129 Gannon MJ, Holt EM, Fairbank J, et al. A randomised trial comparing endometrial resection and abdominal hysterectomy for the treatment of menorrhagia. Br Med J 1991; 303:13621364. 130 Dwyer N, Hutton J, Stirrat GM. Randomised controlled trial comparing endometrial resection with abdominal hysterectomy for the surgical treatment of menorrhagia. Br J Obstet Gynecol 1993; 100:237243. 131 Pinion SB, Parkin DE, Abramovich DR, et al. Randomised trial of hysterectomy, endometrial laser ablation, and transcervical endometrial resection for dysfunctional uterine bleeding. Br Med J 1994; 309:979983. 132 O'Connor H, Broadbent JAM, Magos AL, McPherson K. Medical research council randomised trial of endometrial resection versus hysterectomy in management of menorrhagia. Lancet 1997; 349:897901. 133 Crosignani PG, Vercellini P, Apolone G, et al. Endometrial resection versus vaginal hysterectomy for menorrhagia: long-term clinical and quality-of-life outcomes. Am J Obstet Gynecol 1997; 177:95101. 134 Lethaby A, Sheooard S, Cooke I, Farquhar C. Endometrial resection and .. ablation versus hysterectomy for heavy menstrual bleeding [Cochrane Review]. In: The Cochrane Library, issue 2. Oxford: Update Software; 2001. This is a meta-analysis of the principle and secondary outcomes from the five randomized trials published to date. Efficacy seems to be similar for patient satisfaction, complications rates are higher for hysterectomy, and one trial indicates that the direct costs advantage experienced by women undergoing EA may be lost by 4 years. 135 Sculphur M. The cost-effectiveness of preference-based treatment allocation: the case of hysterectomy versus endometrial resection in the treatment of menorrhagia. 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152 Grainger DA, Tjaden BL, Rowland C, Meyer WR. Thermal balloon and rollerball . . ablation to treat menorrhagia: two-year results of a multicenter, prospective, randomized, clinical trial. J Am Assoc Gynecol Laparosc 2000; 7:175179. The clinical and patient satisfaction outcomes found in this randomized trial, which compared NHEA with HEA by electrosurgical coagulation, are relatively unchanged at 2 years when compared with those at 1 year, and remain essentially equivalent. 153 Droegmueller W, Geer BE, Makowski EL. Preliminary observations of cryocoagulation of the endometrium. Am J Obstet Gynecol 1970; 107:958 961. 154 Pittrof R, Majid S, Murray A. Transcervical endometrial cryoablation (ECA) for menorrhagia. Int J Gynaecol Obstet 1994; 47:135140. 155 Rutherford TJ, Zreik TG, Troiano RN, et al. Endometrial cryoablation, a minimally invasive procedure for abnormal uterine bleeding. J Am Assoc Gynecol Laparosc 1998; 5:2328. 156 Sharp NC, Cronin N, Feldberg I, et al. Microwaves for menorrhagia: a new fast technique for endometrial ablation. Lancet 1995; 346:10031004. 157 Cooper KG, Bain C, Parkin DE. Comparison of microwave endometrial ablation and transcervical resertion of the endometrium for treatment of heavy menstrual loss: a randomized trial. Lancet 1999; 354:18591863. 158 Donnez J, Polet R, Mathieu PE, et al. Endometrial laser interstitial hyperthermy: a potential modality for endometrial ablation. Obstet Gynecol 1996; 87:459464. 159 Donnez J, Polet R, Rabinowitz R, et al. Endometrial laser intrauterine thermotherapy: the first series of 100 patients observed for 1 year. Fertil Steril 2000; 74:792796. 160 Yang JZ, Van Vugt DA, Kennedy JC, Reid RL. Evidence of lasting functional destruction of the rat endometrium after 5-aminolevulinic acid-induced photodynamic ablation: prevention of implantation. Am J Obstet Gynecol 1993; 168:9951001. 161 Bhatta N, Anderson RR, Flotte T, et al. Endometrial ablation by means of photodynamic therapy with photofrin II. Am J Obstet Gynecol 1992; 167:18561863.

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Dysfunctional uterine bleeding: advances in diagnosis and treatment

Evolving concepts of pathogenesis

2001 Lippincott Williams & Wilkins.

# 2001 Lippincott Williams & Wilkins 1040-872X

476 Adult and pediatric gynecology

Dysfunctional uterine bleeding Munro 477

Medical options for the management of dysfunctional uterine bleeding

478 Adult and pediatric gynecology

Dysfunctional uterine bleeding Munro 479

Surgery for dysfunctional uterine bleeding

480 Adult and pediatric gynecology

Dysfunctional uterine bleeding Munro 481

482 Adult and pediatric gynecology

Dysfunctional uterine bleeding Munro 483

484 Adult and pediatric gynecology

Dysfunctional uterine bleeding Munro 485

References and recommended reading

486 Adult and pediatric gynecology

Dysfunctional uterine bleeding Munro 487

488 Adult and pediatric gynecology

Dysfunctional uterine bleeding Munro 489

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