The effect of the levonorgestrel-releasing intrauterine system and the copper intrauterine device on subendometrial microvascularization and uterine artery blood flow

The effect of the levonorgestrel-releasing intrauterinesystem and the copper intrauterine device onsubendometrial microvascularization and uterineartery blood flow enez, M.D.,Elisangela Arbo, M.D.,Daniela Vetori, M.D., Fernando Monteiro de Freitas, Ph.D.,and Jo~ ao Sabino Lahorgue Cunha-Filho, Ph.D.
a Programa de Pos-graduacx~ao em Medicina: Ci^encias Medicas, and b Obstetrics and Gynecology Department, Faculdade deMedicina, Hospital de Clınicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), Brazil Objective: To evaluate the effect of the levonorgestrel intrauterine system (LNG-IUS) and TCU 380A on the sub-endometrial vascularization and the uterine artery blood flow during the midluteal phase.
Design: Prospective clinical trial.
Setting: Teaching hospital.
Patient(s): The trial included 27 patients who received the LNG-IUS compared with 25 patients who received theTCU 380A.
Intervention(s): The subendometrial blood flow was evaluated using power Doppler analysis, uterine artery pul-satility index (PI), and resistance index (RI) just before inserting the intrauterine device in the midluteal phase and 3months after.
Main Outcome Measurement(s): Power Doppler analysis, PI, RI, and endometrial thickness.
Result(s): There were no significant differences in subendometrial vascularization between the groups. Pulsatilityindex and RI variability (before and after) increased and endometrial thickness reduced in LNG-IUS users. Weused the multiple logistic regression model to examine the potential confounding bias (age and parity). TheLNG-IUS was independently associated with increased PI.
Conclusion(s): No subendometrial microvascularization difference was found between the groups. It is the firstdirect evidence that LNG-IUS reduced uterine artery blood flow, even after controlling for age and parity. (FertilSterilÒ 2008;90:1574–8. Ó2008 by American Society for Reproductive Medicine.) Key Words: Intrauterine devices, LNG-IUS, TCU 380A, ultrasonography, Doppler, color, power Doppler, micro-vascular density The levonorgestrel intrauterine system (LNG-IUS) was orig- seems to be a decrease in the uterine artery pulsatility index inally developed for contraception, but is also used to control (PI) . Using power Doppler analysis we also demon- excessive menstrual bleeding, and has brought about a signif- strated an increase in subendometrial vascularization in icant change in side effects for intrauterine device (IUD) patients presenting major side effects (dysmenorrhea or men- users. Fifteen percent of copper IUD users experienced increased menstrual blood loss. The LNG-IUS, contrarily, In addition, the local endometrial effect was studied in has markedly reduced blood loss and other IUD-related several endometrial biopsies from LNG-IUS users, which showed a significant change in endometrial vascularization, We and other investigators demonstrated that copper intra- as demonstrated by a decrease in the mean vascular density uterine devices do not induce any major changes in the uter- and an increase in the mean vessel area .
ine artery blood flow resistance However, in patients Indeed, there is some controversy regarding PI and resis- with increased menstrual pain after IUD insertion there tance index (RI) in LNG-IUS users. Some studies suggestthat there are no differences in PI before and after LNG- Received March 9, 2007; revised and accepted October 2, 2007.
IUS insertion others demonstrate a PI increase in ao Sabino Lahorgue Cunha-Filho, Ph.D., Obstetrics and Gynecology Department, Faculdade de Medicina, Hospital de Clıni- cas de Porto Alegre, Human Reproduction Center, Rua Ramiro Barcel- The literature is absolutely scarce regarding the compari- los, 2350, sala 1124, 90053-003 Porto Alegre, RGS, Brazil (FAX: +55 5133881212; E-mail: son of hemodynamic effects in LNG-IUS and copper IUD Fertility and Sterilityâ Vol. 90, No. 5, November 2008 Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.
users . Some investigators found no evidence of any PI Three months after IUD insertion, also in the midluteal difference between the groups, but the spiral artery flow phase (6–9 days after ovulation, confirmed by US), the was significantly reduced in LNG-IUS users.
same study protocol was repeated with all subjects.
Moreover, subendometrial and uterine vascularization The sonographic equipment used consisted of a SO- studies in patients with LNG-IUS lack methodologic and sta- NOACE 9900 (Medison SA, Korea). The PDE, PI, and RI tistical consistence. Furthermore, the vast majority had no were performed on a transvaginal route. The settings for proper control of one of the most important confounding power Doppler sonography were standardized for the highest biases: the menstrual cycle phase in which the ultrasound sensitivity in the absence of apparent noise using a highpass filter at 50 Hz, pulsed repetition frequency at 750 Hz, andmoderate long persistence. The lowest possible measurable The aim of this study is to evaluate the effect of LNG-IUS velocity was below 5 cm/sec. The same investigator, using and TCU 380A use on the subendometrial vascularization the same equipment and parameters, performed the sonogra- and the uterine artery blood flow using power Doppler anal- phy assessments so as to eliminate any interobserver varia- ysis and ultrasonography pulsed color Doppler during the tion. All exams were performed between 08:00 and 10:00 A.M. to avoid interference from the circadian rhythm Power Doppler energy was classified into five categories according to the subendometrial signal area percentage: I (<10%), II (10%–25%), III (25%–50%), IV (50%–75%), We performed a prospective clinical trial.
We prospectively enrolled 63 consecutive patients who Student’s t test was used for comparing age and body mass wanted to use IUDs (LNG-IUS or TCU 380A). We evaluated index (BMI). The Wilcoxon–Mann–Whitney test was used subendometrial blood flow using power Doppler analysis, to compare skewed data (PI, RI, and ET), whereas the chi- uterine artery blood flow using PI and RI, and endometrial square test was used for categoric data (PDE).
thickness before IUD insertion and 3 months later.
We used a multiple logistic regression model to examine The inclusion criteria were: regularly menstruating women outcome association (PI variability, before and after IUD in- (menstrual cycle varying between 24–35 days); normal se- sertion, categorized in percentile 50) and the independent rum TSH, FSH, and prolactin levels (as measured on day variables: IUD (LNG-IUS or TCU 380A), age (years), and 3); and under 40 years of age. Contraceptive pills or any parity (0, 1, or >1). A value of P<.05 was considered statis- kind of hormonal medication had not been taken for at least tically significant. The power calculation before this study 3 months before the study, and any IUD had necessarily been protocol required the inclusion of 19 patients for a Pb ¼ 80%.
removed at least 3 months earlier. Patients were not allowedto use nonsteroidal anti-inflammatory drugs within 24 hoursbefore any examination.
A total of 63 patients were included in our prospective study.
The exclusion criteria were: pregnancy, acute or chronic A total of 11 patients were excluded: two had large ovarian pelvic inflammatory disease, uterine bleeding, menorrhagia, cyst before IUD insertion, one had uterine miomatosis, one copper allergy, cervicitis, dysplasia in the cervix, or genital had polycystic ovarian syndrome, and seven were anovula- tumor. All patients underwent a gynecologic examination tory in two control cycles before IUD insertion. There were and had a Papanicolaou smear taken in the previous 12 27 patients in group A (LNG-IUS) and 25 patients in group All patients were examined daily with US after the eighth The mean standard error of the mean age (years), BMI day of the cycle, and follicular development was observed to (kg/m2), PI, and RI before IUD insertion was no different confirm ovulation; they were then examined in the midluteal phase, 6–9 days after ovulation, to obtain the power Dopplerenergy (PDE) measurement, PI, RI, and endometrial thick- There were no significant changes in the power Doppler ness (ET) by US scans. The study was approved by the Eth- subendometrial evaluation between groups after IUD inser- ical Committee at the Hospital de Clınicas de Porto Alegre, tion: P¼.45 using the chi-square test ().
institutional review board approval (number: 02-127), and in- To evaluate the effect of the IUDs on uterine vasculariza- formed consent was obtained from all patients.
tion we analyzed the variability (%D) before and after IUD Patients were continually allocated into two groups insertion in both groups. The PI and RI variability (before according to the IUD: LNG-IUS (group A) or TCU 380A and after) were significantly increased in group A (LNG- IUS) (P¼.001 and P¼.046, respectively). Moreover, there The demographic characteristics, pulsatility index (PI), and resistance index (RI) of the 52 insertion) in the pulsatility index (PI), women before IUD insertion: mean (SEM).
resistance index (RI), and endometrialthickness (ET) between LNG-IUS and TCu Note: BMI ¼ body mass index; IUD ¼ intrauterine de- vice; LNG-IUS ¼ Levonorgestrel-releasing intrauter- Note: Wilcoxon-Mann-Whitney (WMW) test.
LNG-IUS ¼ Levonorgestrel-releasing intrauterine sys- enez. LNG-IUS and TCu 380: vascularization. Fertil Steril 2008.
enez. LNG-IUS and TCu 380: vascularization. Fertil Steril 2008.
was a significant reduction in endometrial thickness in groupA (LNG-IUS) (P<.001) ).
We clearly demonstrated that there is a significant decrease in Using the univariate analysis, LNG-IUS IUD was signifi- endometrial thickness after LNG-IUS insertion, probably cantly associated with an increase in PI variability related to the main LNG-IUS effect in endometrial morphol- (P¼.015; odds ratio ¼ 4.25; confidence interval: 1.33– ogy: glandular atrophy associated with pseudodecidualiza- tion Moreover, it was not possible to detect the IUD In addition, we used a multiple logistic regression model to effect on the uterine cavity by power Doppler analysis, as examine any potential confounding bias. The PI variability no changes were found in the power Doppler analysis, (before and after), categorized in percentile 50, was the suggesting that power Doppler energy (in the midluteal phase) dependent variable, and IUD (LNG-IUS or TCU 380A), was not able to identify the local progestational effect on age (years), and parity (0, 1, or >1) the independent variables. Even after controlling for age and parity the asso- Copper IUDs do not induce any major changes in the PI ciation remained significant (P¼.014) ): LNG-IUS and RI of the uterine artery either; however, copper is independently associated with an increased pulsatilityindex.
Subendometrial power Doppler analysis comparisonbetween groups: LNG-IUS users and TCu 380A users. Chi-square test P¼ .45.
Note: Dependent variable: PI variablility (before and after IUD insertion). Independent variables: IUDtype (LNG-IUS or TCu 380A), age (years), and parity(0, 1, or >2).
PI ¼ pulsatility index; CI ¼ confidence interval; IUD ¼ in- trauterine device; LNG-IUS ¼ Levonorgestrel-releas-ing intrauterine system.
enez. LNG-IUS and TCu 380: vascularization. Fertil Steril 2008.
enez. LNG-IUS and TCu 380: vascularization. Fertil Steril 2008.
IUD-related menorrhagia and pain might be caused by de- Our study brings some important evidence to clarify the creased vascular resistance in the uterine artery with in- physiopathology of LNG-IUS and TCU 380A changes in menstrual patterns and side effects in IUD users. As alreadyassessed by J€ a I et al. , the levonorgestrel circulating Others evaluated the RI and PI before and 30 days levels may antagonize normal uterine response to the midlu- after IUD insertion with no differences in the uterine artery teal rising estradiol levels leading to a decrease in uterine blood flow. We have shown an increase in subendometrial blood flow. Postmenopausal estrogen therapy has been shown vascularization in power Doppler analysis in patients to increase endometrial thickness and reduce uterine artery with major IUD-related side effects (dysmenorrhea or menor- PI. This effect was gradually abolished within 6 months of LNG-IUS insertion, which is in accordance with our results: Several Doppler flow studies evaluated hemodynamic changes in LNG-IUS users. The uterine artery PI was not The PI and RI were also studied in premenopausal women different before or 3 months after LNG-IUS insertion in with menorrhagia after LNG-IUS insertion with RI in- 10 women of fertile ages Contrarily, another study creasing, but not PI and endometrial thickness. It has been found that the LNG-IUS appears to be associated with an shown earlier that levonorgestrel circulating levels tend to de- increase in blood flow resistance in the uterine arteries dur- cline during when LNG-IUS is being used. Accordingly, ing the midluteal phase, and also appears to be dependent it is possible that the increase in PI and RI observed in our on the concentration of circulating levonorgestrel after The increased impedance in uterine artery blood flow, The RI was increased in premenopausal women with men- demonstrated in our study, is one hypothesis to explain the orrhagia after LNG-IUS insertion but not the PI and endome- action mechanism in pelvic pain relief in endometriosis trial thickness In addition, Doppler flow did not reveal medicated with LNG-IUS: a reduction in pelvic any significant change in the uterine artery between the groups (LNG-IUS and copper IUD users), whereas therewas a marked reduction in subendometrial blood flow (spiral In conclusion, LNG-IUS reduced uterine artery blood flow as evidenced by the RI and PI variability (%D) before and af-ter IUD insertion using pulsed color Doppler ultrasonogra- However, most studies on subendometrial and uterine vas- phy. It is important to emphasize, however, that the cularization in patients with LNG-IUS lack methodologic multiple logistic regression model demonstrated that, even and statistical consistence. Indeed, the vast majority did not controlling for age and parity, a significant increase in the properly control one of the most important confounding PI difference was associated with LNG-IUS. The use of PI biases: the phase of the menstrual cycle in which the US and RI variability (%D) and the precise midluteal phase makes those differences evident. Moreover, there are no Some studies used a different duration of IUD use or differences between LNG-IUS and copper IUD users in the a short period of use (30 days) . In fact, the local proges- subendometrial microvascularization, as evidenced by power tative effect of LNG-IUS on the endometrium was already manifested within a period of 3 months or more after inser-tion and there were differences in endometrium when Acknowledgments: All authors have nothing to disclose. Financial support comparing the first 3 months with long-time users .
for this article from Conselho Nacional de Desenvolvimento Cientıfico e Tec-nol We performed this study in view of the different results x~ao de Aperfeicxoamento de Pessoal de Nıvel regarding uterine and subendometrial blood flow in IUD x~ao de Amparo a Pesquisa do Rio Grande do users. It is the first study using precise midluteal phase: ovu- edicas, Faculdade de Medicina, Universidade Federal do Rio Grande do lation was confirmed by daily US. We observed a significant Sul (UFRGS), Porto Alegre (city), Rio Grande do Sul (state), Brazil (country) increase in the PI and RI difference after IUD insertion in LNG-IUS users meaning that levonorgestrel circulatinglevels affect uterine vascularization. Moreover, only onestudy evaluated the uterine blood flow in copper IUD and LNG-IUS users and appeared to be contradictory: it did 1. Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper- not reveal any significant change in the uterine artery releasing (Nova T) IUDs during five years of use: a randomized compar- between groups, but lacks precision in midluteal phase ative trial. Contraception 1994;49:56–72.
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