Menopause Live - IMS Updates

Date of release: 10 February, 2014

Long-term consequences of LNG-IUS vs. hysterectomy for menorrhagia

Heliövaara-Peippo and colleagues have recently reported on a randomized controlled trial in five Finnish university hospitals to compare the effect of treatment with a levonorgestrel-releasing intrauterine system (LNG-IUS) and the effect of hysterectomy in women with menorrhagia (n = 221) [1]. The studied population that fulfilled the inclusion criteria, initially aged 35–49 years, was monitored for 10 years and the endpoints were health-related quality of life (HRQoL), psychosocial well-being, and cost-effectiveness. Instruments to measure quality of life and psychosocial well-being were used periodically, including the five-dimensional EuroQoL, the 36-item RAND Health Survey, the Spielberger 20-Item State-Trait Anxiety Inventory, the Beck Depression Inventory and the McCoy Sex Scale. Direct and indirect costs, sick-leave days and out-of-pockets costs were calculated from the time of randomization up to the 10-year follow-up control. There have been several previous publications concerning this trial, including the 12-month and the 5-year follow-up results.


HRQoL and psychosocial well-being were improved during the initial 5 years but diminished between 5 and 10 years; the improved HRQOL returned close to the baseline level without any significant difference between the LNG-IUS-treated and hysterectomy-treated groups. The overall costs in the LNG-IUS group ($ 3423/patient) were lower than in the surgery group ($ 4937/patient), despite the fact that 55 women (46%) assigned to the LNG-IUS group subsequently underwent surgery: 24 (44%) during the first year, 26 (47%) between 12 months and 5 years and five (9%) between 5 and 10 years. The main reasons for hysterectomy were bleeding problems during the first 5 years and fibroids and bleeding problems in the five hysterectomies performed between 5 and 10 years. 


At the 10-year follow-up, 44 women had a LNG-IUS in situ; of these 40 women (91%) reported amenorrhea or oligomenorrhea, two hypomenorrhea, one normal menstrual bleeding and one irregular bleeding. In 18 women, the LNG-IUS was removed but hysterectomy was not performed; of these 18 women, 12 women reported amenorrhea or oligomenorrhea, three normal menstrual bleeding, two irregular bleeding, and one woman submitted to thermoablation after reported hypomenorrhea.


The prevalence of menorrhagia is very high among women in their late pre- and perimenopausal years. These women may have fatigue, iron depletion and anemia, social and job limitations, work loss, anxiety and low quality of life [2, 3]. The assessment of heavy menstrual bleeding is mandatory to select an appropriate treatment [4]. In women in their post-reproductive years, several studies have suggested that the LNG-IUS is among the most cost-effective treatments [5, 6]. Women treated with the LNG-IUS had more effective control of their menorrhagia as compared to other medical treatments, although LNG-IUS users reported side-effects such as unexpected bleeding and breast tenderness which are very disturbing for patients. Hysterectomy is not devoid of some inconvenience and some women do not wish to lose their uterus. On the other hand, some women may prefer hysterectomy as a definitive menorrhagia treatment without any further follow-up after surgery. However, there is limited information concerning long-term costs, well-being and quality of life; some women treated with the LNG-IUS may need further treatment if this first treatment fails, including surgery. Any current clinical or therapeutic intervention should consider several aspects, including clinical solutions, side-effects of intervention, initial treatment failures, economic costs, quality of life and long-term sequelae. 
The Heliövaara-Peippo trial [1] has several merits, including the randomization of a large enough population to compare the surgical procedure with a non-surgical treatment, its long-term (10 years) follow-up and its detailed clinical information. The initial population was exhaustively studied to discard organic causes of heavy menstrual bleeding, genital cancer, endocrine disorders and severe depression, as recently recommended by FIGO. Ten years after randomization, the mean cost of LNG-IUS treatment/patient was less in economic terms than the cost of hysterectomy. However, the Finnish study also showed that a significant fraction (46%) of women randomized to the LNG-IUS had a clinical evolution which was not sufficiently satisfactory for them or for medical reasons, thus necessitating a subsequent hysterectomy. These 'rescue' hysterectomies may be considered as failures (mainly due to bleeding) of the initial non-surgical treatment and occurred in the early years after the device insertion. 
The measurements of well-being and quality of life have a high subjective component, reaching higher individual values than objective measures; these aspects were also studied by the authors. Although HRQOL and psychosocial well-being improved during the first 5 years, they diminished in later years and returned close to the baseline values in both arms of the study; these may be analogous to age- and menopause-related changes. Thus, in otherwise healthy mid-aged women, quality of life worsens in relation to age, menopausal status and social factors [7]. It is likely that both treatments (initial hysterectomy + rescue hysterectomy vs. LNG-IUS for 10 years) produced similar or comparable levels of well-being and quality of life. However, 46% of the patients randomized to the LNG-IUS group were retreated with hysterectomy due to undesired clinical aspects or for unexpected unsatisfactory results. It is likely that well-being and quality of life would not be sufficiently good in these women who changed to the surgery option.
Circulating levonorgestrel has been detected in women using oral levonorgestrel administration and has been linked with cardiovascular risk. Women using the LNG-IUS for contraceptive purposes have plasma levonorgestrel levels of about 200 pg/ml and these decrease during the recommended period of use, although levonorgestrel may still be detectable in the 8th year after device insertion [8-10]. In young women using the LNG-IUS device for contraceptive purposes, plasma levonorgestrel levels are about 200 pg/ml and are associated with a decrease in endothelium-dependent, flow-mediated dilatation in the brachial artery as compared with the control group (wearing a TCu 380A intrauterine device) during the first year after insertion [10]. There is a need for information about plasma levonorgestrel levels in women using the LNG-IUS to treat menorrhagia and about functional vascular changes or their circulatory consequences, if any, after 10 years of LNG-IUS use. 
During the last decade, different new treatments have been proposed for the management of menorrhagia including new steroid hormones, non-hysteroscopic endometrial ablation, and 'second-generation' devices such as balloon, radiofrequency or microwave ablation, which are safe and technically easy to perform under local anesthesia and which involve only a short hospital stay [6,11,12]. This scenario opens new management possibilities to compete with hysterectomy and the LNG-IUS. Pandora’s beautiful jar (pithos) is still open to search for new solutions in terms of clinical endpoints, economic costs, quality of life, long-term risks and patients’ desires for the such as yet unsolved gynecologic problem of menorrhagia.


Faustino R. Pérez-López
Professor of Obstetrics and Gynecology, University of Zaragoza Faculty of Medicine & Lozano Blesa University Hospital, Zaragoza, Spain


  1. Heliövaara-Peippo S, Hurskainen R, Teperi J, et al. Quality of life and costs of levonorgestrel-releasing intrauterine system or hysterectomy in the treatment of menorrhagia: a 10-year randomized controlled trial. Am J Obstet Gynecol 2013;209:535.e1-14

  2. de Souza SS, Camargos AF, Ferreira MC, et al. Hemoglobin levels predict quality of life in women with heavy menstrual bleeding. Arch Gynecol Obstet 2010;281:895-900

  3. Munro MG, Dickersin K, Clark MA, Langenberg P, Scherer RW, Frick KD. The Surgical Treatments Outcomes Project for dysfunctional uterine bleeding: summary of an Agency for Health Research and Quality sponsored randomized trial of endometrial ablation versus hysterectomy for women with heavy menstrual bleeding. Menopause 2011;18:445-52

  4. Munro MG, Critchley HO, Fraser IS. The FIGO systems for nomenclature and classification of causes of abnormal uterine bleeding in the reproductive years: who needs them? Am J Obstet Gynecol 2012;207:259-65

  5. Blumenthal PD, Dawson L, Hurskainen R. Cost-effectiveness and quality of life associated with heavy menstrual bleeding among women using the levonorgestrel-releasing intrauterine system. Int J Gynaecol Obstet 2011;112:171-8

  6. Matteson KA, Abed H, Wheeler TL II, et al. A systematic review comparing hysterectomy with less-invasive treatments for abnormal uterine bleeding. J Minim Invasive Gynecol 2012;19:13-28

  7. Monterrosa-Castro A, Romero-Pérez I, Marrugo-Flórez M, Fernández-Alonso AM, Chedraui P, Pérez-López FR. Quality of life in a large cohort of mid-aged Colombian women assessed using the Cervantes Scale. Menopause 2012;19:924-30

  8. Hidalgo MM, Hidalgo-Regina C, Bahamondes MV, Monteiro I, Petta CA, Bahamondes L. Serum levonorgestrel levels and endometrial thickness during extended use of the levonorgestrel-releasing intrauterine system. Contraception 2009;80:84-9

  9. Seeber B, Ziehr SC, Gschlieβer A, et al. Quantitative levonorgestrel plasma level measurements in patients with regular and prolonged use of the levonorgestrel-releasing intrauterine system. Contraception 2012;86:345-9

  10. Selim MF, Hussein AF. Endothelial function in women using levonorgestrel-releasing intrauterine system (LNG-IUS). Contraception 2013;87:396-403

  11. Madhu CK, Nattey J, Naeem T. Second generation endometrial ablation techniques: an audit of clinical practice. Arch Gynecol Obstet 2009;280:599-602

  12. Bhattacharya S, Middleton LJ, Tsourapas A, et al. Hysterectomy, endometrial ablation and Mirena® for heavy menstrual bleeding: a systematic review of clinical effectiveness and cost-effectiveness analysis. Health Technol Assess 2011;15:iii-xvi, 1-252

El siguiente comentario es una traduccin de una contribucin original en Ingls enviada a los miembros el Abril 22, 2013. La traduccin ha sido gentilmente efectuada por el

Dr Konstantinos Tserotas

Depresión, ansiedad y síntomas somáticos en mujeres peri y postmenopáusicas

Terauchi y colegas [1] informaron recientemente que, en mujeres Japonesas peri y posmenopáusicas referidas a una clínica especializada de la menopausia para el tratamiento de los síntomas climatéricos, los dolores de cabeza se asociaron significativamente con la depresión (odds ratio (OR) 1.49, intervalo de confianza (IC) del 95% 1.06 a 2.10), mientras que las náuseas y el entumecimiento se asociaron significativamente con la ansiedad (OR 1.65, IC 95%: 1.15 a 2.39; OR 1.39, IC 95%: 1.05 a 1.84 y OR 1.36, IC 95%: 1.23 a 1.50, respectivamente). El análisis mediante la prueba exacta de Fisher reveló que la prevalencia de los seis síntomas somáticos investigados (náuseas, mareos, entumecimiento, dolores musculares y articulares, cansancio y dolores de cabeza), así como sudores nocturnos fue significativamente mayor en las mujeres que sufren de depresión y ansiedad. Aunque las náuseas, mareos, entumecimiento, fatiga, sudores nocturnos y la depresión diagnosticados mediante la Escala Hospitalaria de Ansiedad y Depresión (Hospital Anxiety and Depression Scale [HADS]) mostraron una correlación significativa con la ansiedad severa en el análisis de regresión simple, las únicos puntajes que fueron significativos después del ajuste en el análisis de regresión logística multivariada fueron náuseas (OR 1.65, IC 95%: 1.15 a 2.39; p = 0.007), entumecimiento (OR 1.39, IC 95%: 1.05 a 1.84; p = 0.020) y depresión (OR 1.36, IC 95%: 1.23 a 1.50; p < 0.001). Sin embargo, a diferencia de todos los informes que analizan poblaciones europeas y norteamericanas, no hubo correlación entre la depresión y la prevalencia de los sofocos.


Esta aparente contradicción sobre la asociación de los sofocos con la depresión entre mujeres caucásicas y japonesas se puede resolver, no considerando el síntoma en sí, sino por su importancia dentro de la calificación local de los síntomas climatéricos. Siguiendo el trabajo básico de Margaret Lock et al [2], es bien sabido que la expresión clínica del síndrome climatérico varía fuertemente entre Europeas/Norteamericanas y las mujeres japonesas, muy probablemente en función de los respectivos antecedentes culturales y étnicos. Mientras que casi dos tercios de las mujeres europeas y norteamericanas posmenopáusicas experimentan sofocos [3,4], la prevalencia de sofocos y sudoración nocturna es significativamente menor en Japón [2,5]. En Japón, los síntomas típicos del climaterio son parte de la construcción cultural "kônenki 'y' kônenki shogai" [2]. Kônenki incluye, entre otros síntomas, dolores de cabeza, rigidez en el hombro, mareos, náuseas, entumecimiento, insomnio, irritabilidad y depresión. Por otro lado, en las mujeres japonesas, los síntomas vasomotores no se cuentan entre los síntomas climatéricos principales: su prevalencia es sólo entre 5–10% [2] y 12% [5]. Por lo tanto, en las culturas occidentales y en algunos países asiáticos industrializados, las molestias de la menopausia más importantes son los síntomas vasomotores, mientras que, en Japón, dolor de cabeza, náuseas y entumecimiento pertenecen a los síntomas principales del 'kônenki shogai'. Como consecuencia de ello, en pacientes Caucásicas de los EE.UU. [6] y pacientes chinas de Taiwán [7], los sofocos y los sudores nocturnos se asocian significativamente con la depresión y la ansiedad en mujeres peri y posmenopáusicas, mientras que, en Japón, la depresión y la ansiedad se asocian con dolores de cabeza, náuseas y entumecimiento [1]. Por tanto, se concluye que la depresión y la ansiedad se asocian significativamente con los síntomas climatéricos líderes respectivos dentro de cada entidad cultural. Para ambas, mujeres caucásicas y japonesas, se requiere la evaluación de trastornos del estado de ánimo subyacentes para el manejo óptima de mujeres de mediana edad que presentan síntomas somáticos y pertenecen a los respectivos patrones locales típicos del síndrome climatérico. Las mujeres caucásicas que reportan mayor ansiedad (evaluada con herramientas estandarizadas de ansiedad) también se ven muy afectadas por los síntomas vasomotores, pero muestran una mayor respuesta terapéutica al tratamiento que se usa para la depresión y la ansiedad (antidepresivos, hipnóticos o estrógenos) [8]. Se esperaría la misma ventaja terapéutica en mujeres japonesas muy deprimidas o ansiosas que sufren de severos dolores de cabeza climatéricos, náuseas y entumecimiento, pero aún esto tiene que ser demostrado.

Martin Birkhäuser

Professor Emeritus for Gynecological Endocrinology and Reproductive Medicine, Department of Obstetrics and Gynecology, University of Berne, Switzerland


  1. Terauchi M, Hiramitsu S, Akiyoshi M, et al. Associations among depression, anxiety and somatic symptoms in peri- and postmenopausal women. J Obstet Gynaecol Res 2013 Feb 4. Epub ahead of print

  2. Lock M, Kauder P, Gilbert P. Cultural construction of the menopausal syndrome: the Japanese case. Maturitas 1988;10:317-32.

  3. Stearns V, Ullmer L, Lopez JF, et al. Hot flushes. Lancet 2002;360:1851-61.

  4. Avis NE, Stellato R, Crawford S, et al. Is there a menopausal syndrome? Menopausal status and symptoms across racial/ethnic groups. Soc Sci Med 2001;52:34556.

  5. Obermeyer CM. Menopause across cultures. A review of the evidence. Menopause 2000;7:184-92.

  6. Joffe H, Hall JE, Soares CN, et al. Vasomotor symptoms are associated with depression in perimenopausal women seeking primary care. Menopause 2002;9:3928.

  7. Juang KD, Wang SJ, Lu SR, Lee SJ, Fuh JL. Hot flashes are associated with psychological symptoms of anxiety and depression in peri- and post- but not premenopausal women. Maturitas 2005;52:11926.

  8. Cohen LS, Pasciullo E, Joffe H. Anxiety predicts reduction in menopausal vasomotor symptoms with hormonal and non-hormonal treatments. Poster presented at the 2008 North American Menopause Society Annual Meeting; September 24-27, 2008; Orlando, FL, USA.

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