全文

1. Introduction

Uterine leiomyomas occur in 30–50% of reproductive-aged women [1] and [2], increasing to a 70–80% cumulative incidence by age 50 years [3]. They are commonly associated with menstrual abnormalities, pelvic pain or pressure, infertility and recurrent pregnancy loss, thus they can have a negative impact on multiple aspects of a women’s life [4]. Although most leiomyomas are asymptomatic, some women have significant symptoms that need interventions [5].

 

Treatment options for symptomatic uterine leiomyomas have recently expanded beyond surgery. Medical therapies, including combined oral contraception, gonadotrophin releasing hormone analogues, progesterone receptor modulators, progestins and levonorgestrel-releasing intrauterine systems (LNG-IUSs) [6] and [7], have become more and more widely used. Currently, there is increased concern about safer and more effective methods for treatment of leiomyoma in women with uterine leiomyoma.

 

In recent years LNG-IUSs are increasingly being used for gynecological indications other than contraception. Current indications include but are not limited to: menorrhagia, uterine leiomyoma, endometriosis, adenomyosis, endometrial hyperplasia, early stage endometrial cancer [8], [9] and [10]. LNG-IUSs were marketed as Mirena for general public use. Studies have reported high contraceptive efficacy and an improvement in menstrual blood loss with LNG-IUSs [11] and [12], including in women with uterine leiomyoma [13]. However, the effects of LNG-IUSs on uterine and leiomyoma volumes are still unclear and controversial. Some studies reported a reduction in uterine volume [13] and [14] and leiomyoma volume [13] and [15]; however, other studies concluded that no decreases in uterine volume [16] and leiomyoma volume [17] occurred. To date, there has been no review of the effect of LNG-IUSs on the endometrial thickness and ovarian function for treating symptomatic uterine leiomyoma.

 

In the assessments of the effects of LNG-IUSs for contraception in women with leiomyoma, Zapata et al. [18] has showed that LNG-IUSs could reduce menstrual blood loss, and increase blood haemoglobin, ferritin and hematocrit levels, and also studied IUD expulsion rate and spotting rate. However, they did not study other new outcomes of LNG-IUSs and leiomyoma size to expulsion rate. Hence, a new systematic review was also needed to evaluate the evidence concerning the effectiveness and safety of LNG-IUSs for treating symptomatic uterine leiomyomas in the comparison with other treatments, especially with regard to uterine and leiomyoma volumes, endometrial thickness, hysterectomy rate and adverse effects on ovarian function. The generated results will be fundamental to informing the integration of policies and interventions for the treatment of uterine leiomyoma.

 

2. Materials and methods

2.1. Search strategy

Electronic searches of databases and hand searches of other resources were conducted to search published and unpublished articles for review. We searched Medline (PubMed; up to July 2013), the Cochrane Central Register of Controlled Trials (CENTRAL; up to July 2013) and the WHO International Clinical Trials Registry Platform (ICTRP) for ongoing trials (July 2013) (Appendix). Only studies published in English were included and no limits were placed upon date of publications. We also examined the reference lists of all known primary and review articles to identify cited articles not captured by electronic searches. Finally, we made enquires about unpublished studies from researchers working in this field. The search strategy was performed independently by two authors and is shown in Fig. 1.

 

 

2.2. Criteria for considering studies

We included randomised controlled trials (RCTs), non-randomised trials, and observational studies that compared the efficacy and safety of LNG-IUSs with any other treatments or compared the efficacy and safety of LNG-IUSs before and after insertion of LNG-IUSs in premenopausal women with symptomatic uterine leiomyoma. The comparisons of interest included the comparison between LNG-IUSs and combined oral contraceptive, LNG-IUSs used in leiomyoma-related menorrheagia and in idiopathic menorrheagia and before and after insertion of LNG-IUSs. The primary outcomes were uterine volume, leiomyoma volume and endometrial thickness. The secondary endpoints were menstrual blood loss, blood haemoglobin, ferritin and hematocrit levels, failure rate, device expulsion rate and hysterectomy rate. Adverse effects included abnormalities of ovarian function and irregular bleeding/spotting.

 

2.3. Study selection

Two review authors (Jiang WX, Shen Q) independently evaluated studies to assess eligibility. Disagreements were resolved by discussion. By scanning the titles, abstracts and keywords of every record retrieved, we determined which studies required further assessment and retrieved the full articles if necessary. Authenticity of the original studies was confirmed by contacting the original authors.

 

2.4. Data extraction and management

For eligible studies, two review authors independently extracted the relevant data concerning study populations, interventions and outcomes using a data extraction form designed for this review (Table 1). Any required relevant missing information on the trial was sought from the original author(s) of the article. Discrepancies were resolved through discussion and data were analysed with software provided by the Cochrane Library (RevMan 5.1).

 

 

2.5. Assessment of risk of bias in included studies

We planned to assess the risk of bias of randomised controlled trials using the quality criteria specified in the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 [19]. Assessment of the methodological quality of the observational studies was based on the Methodological Index for Non-Randomized Studies [20], which consisted of 12 criteria, the first eight being specifically for non-comparative studies and all the twelve being for comparative studies.

 

2.6. Data synthesis

When data were reported in different forms, the outcome data were first transformed into a standard measure. Dichotomous data were expressed as a Risk Ratio (RR) with 95% confidence intervals (95% CI), and continuous variables were expressed as differences in means (MD) with 95% confidence intervals (95% CI). A qualitative meta-analysis was conducted by summarising, comparing, and contrasting the abstracted data, as standard measure was used to calculate the effect across different studies.

 

3. Results

3.1. Results of the search

The initial Medline, CENTRAL, and ICTRP searches using the electronic search strategy described above yielded 645 total studies. After scanning the studies identified, eleven studies were included, one randomised controlled trial [21] and ten observational studies [13], [14], [15], [16], [17], [22], [23], [24], [25] and [26].

 

3.2. Details of included 11 studies and reasons of excluded studies

Details of the characteristics of the included randomised controlled study and observational studies were shown in Table 1. The included randomised controlled study was of randomised, non-blinding and parallel design with duration of follow-up ranging from 3 to 12 months and with 58 participants [21]. Of the ten observational studies, two were cohort studies [17] and [22], one was an historical controlled study [25], one was a case series study [16], and six were of prospective before-after comparing designs [13], [14], [15], [23], [24] and [26]. The duration of follow-up of the observational studies ranged from 3 to 48 months, and the number of participants ranged from 10 to 104.

 

All included studies examined premenopausal women with uterine leiomyoma complicated or not complicated menorrhagia and used inserted LNG-IUSs. The LNG-IUSs inserted in all studies were Mirena® with a reservoir of 52 mg of LNG- releasing 20 μg/day.

 

Uterine volume was determined by transvaginal ultrasound in eight studies, three of which compared uterine volume in a leiomyoma-related menorrhagia group to that in an idiopathic menorrhagia group. Changes in uterine leiomyoma volume were examined in six studies [13], [15], [17], [22], [23] and [24]. Uterine and individual leiomyoma volumes were calculated by measuring the three diameters of the uterus and each leiomyoma and using the formula for ellipsoid tumours: (4/3) × (π) × (R1) × (R2) × (R3)/8, where R1, R2, and R3 were the diameters of each of the three uterine or leiomyoma dimensions, respectively [27]. In cases of multiple leiomyomas, the volume of each tumor was calculated and added to estimate the total leiomyoma volume. Two studies analysed the endometrial thickness [14] and [17]. The randomised controlled trial study [21] and seven observational studies [13], [15], [22], [23], [24], [25] and [26] analysed menstrual blood loss measured using the pictorial blood assessment chart (PBAC) and/or alkaline haematin. Seven studies investigated blood haemoglobin levels [13], [14], [16], [23], [24], [25] and [26], three studies referred to ferritin [13], [14] and [24] and two studies investigated hematocrit [15] and [16].

 

Four studies [28], [29], [30] and [31], shown in Table 2, were excluded after a review of the full articles. Three because the studies included women with menorrhagia, only part of which were with uterine leiomyoma [29], [30] and [31] and did not analyse the outcomes separately in women with leiomyoma, and one because it was a review [28].

 

 

3.3. Risk of bias in included studies

An overview of the quality of the randomised controlled study was shown in Table 3.

 

 

To determine the potential risk of bias in the observational studies, we assessed the 12 bias domains on every study including: (1) Clearly stated aim; (2) Inclusion of consecutive patients; (3) Prospective collection of data; (4) Endpoints appropriate to aim of study; (5) Unbiased assessment of study endpoint(s); (6) Follow-up period appropriate to aim of study; (7) Loss to follow-up <5%; (8) Prospective calculation of study size; (9) Adequate control group; (10) Con-temporary groups; (11) Baseline equivalence of groups; (12) Adequate statistical analyses. The results were shown in Table 4.

 

 

3.4. Effects of interventions

The results of outcomes in different comparisons were shown in Table 5.

 

 

3.5. Primary outcomes

3.5.1. Uterine volume

3.5.1.1. LNG-IUS versus thermal balloon ablation

One study [25] reported no significant difference in uterine volume change between the LNG-IUSs group and the thermal balloon ablation group.

 

3.5.1.2. LNG-IUS used in leiomyoma-related menorrhagia versus in idiopathic menorrhagia

One prospective comparative study [17] reported a greater and more significant reduction in uterine volume of 63.60 ± 19.00 cm3 in the leiomyoma-related menorrhagia group compared to a reduction in uterine volume of 36.40 ± 15.30 cm3 in the idiopathic menorrhagia group and to a reduction of 2.90 ± 5.40 cm3 in the control group (used the device as a contraceptive method). Another study [22] reported a significant reduction in uterine volume of 63.60 ± 19.00 cm3 compared to that of 43.40 ± 15.30 cm3 in the idiopathic menorrhagia group. Another study [22] also reported the reduction of uterine volume was greater in the group with leiomyoma-related menorrhagia compared to that with idiopathic menorrhagia.

 

3.5.1.3. Before versus after LNG-IUS insertion

At 3 and 6 months, two studies [16] and [24] reported no significant alteration in uterine volume, and at 12 months one studies [14] found a decrease but no significant alteration in uterine volume. The other five studies all reported a significantly decreased uterine volume after LNG-IUSs insertion after different follow-up durations: After 3 months, a significant decrease was reported in two studies [13] and [17]. After 6 months, it was reported in three studies [13], [15] and [17]. After 12 months, it was reported in three studies [13], [17] and [23]. After 24 months, one study [22] reported that uterine volume decreased from 154.6 ± 70.10 to 91.00 ± 72.30 cm3, and the other study [17] showed a uterine volume reduction from 156.60 ± 52.90 to 120.10 ± 41.90 cm3. After 36 months, a significant reduction was reported from 156.60 ± 52.90 to 93.00 ± 33.90 cm3[17].

 

3.5.2. Uterine leiomyoma volume

3.5.2.1. LNG-IUS versus combined oral contraceptive

The randomised controlled study [21] showed a greater reduction in leiomyoma volume in the LNG-IUSs group than that in the combined oral contraceptive group at 12 months, but did not detect statistically significant differences between the two groups (P = 0.79).

 

3.5.2.2. Before versus after LNG-IUS insertion

One study [15] showed a significant reduction in leiomyoma volume 6 months after LNG-IUSs insertion with the median volume decreasing from 19.82 cm3 (range 1.01–546.65) to 11.63 cm3 (range 0.35–377.43). Another prospective study [13] reported a statistically significant decrease in total leiomyoma volume by 6 months, but no significant change in leiomyoma volume after 3 months and no change after 12 months compared to the change after 6 months. The other three studies [17], [22] and [23] all reported no statistically significant reduction in leiomyoma volume at 3, 6, 9, 12, 24 or 36 months. One [17] showed a reduction of 5.20 ± 3.10 cm3 (P = 0.4099) after 36 months, and another study [22] showed a reduction of 6.10 ± 3.10 cm3 (P = 0.4099) after 24 months.

 

3.5.3. Endometrial thickness

In one study [17], among 87 of the women who were admitted to the study, the women who had an endometrial echo (double layer) >6 mm and/or an increase in ultrasonographic echogenicity (endometrial acoustic reflection enhancement) had an endometrial biopsy prior to insertion. Nine of these women had the endometrial biopsy, and four of the women were shown to have simple endometrial hyperplasia. However, this study did not study the change in endometrial thickness after LNG-IUSs insertion in any of the nine women. The other study [14] showed endometrial thickness decreased from 7.47 ± 4.34 to 3.47 ± 1.22 mm after LNG-IUS insertion (P = 0.204).

 

3.6. Secondary outcomes

3.6.1. Menstrual blood loss

Menorrhagia was measured using a validated pad scoring method known as a pictorial blood loss assessment chart (PBAC) in seven observational studies [13], [15], [22], [23], [24], [25] and [26] and was measured using a PBAC and an alkaline haematin method in the randomised controlled study [21].

 

3.6.1.1. LNG-IUS versus combined oral contraceptive

The randomised controlled study reported a reduction in menstrual blood loss when comparing LNG-IUSs and combined oral contraceptive [21]. There was a significantly greater reduction of menstrual blood loss in the LNG-IUS group than in the combined oral contraceptive group at a follow-up time of 12 months as measured using a PBAC (88.0 ± 16.5% vs 53.5 ± 51.2%, P = 0.02) and by an alkaline haematin (90.9 ± 12.8% vs 13.4 ± 11.1%, P < 0.001).

 

3.6.1.2. LNG-IUS versus thermal balloon ablation

No significant difference in menstrual blood loss reduction measured by the PBAC was seen in one historical controlled study [25] comparing LNG-IUSs and thermal balloon ablation after 12 months (MD 7.00, 95% CI 14.84–28.84).

 

3.6.1.3. LNG-IUS used in leiomyoma-related menorrhagia versus in idiopathic menorrhagia

In addition, one prospective comparative study [22] reported that the reduction of menstrual blood loss in leiomyoma-related menorrhagia was similar to that in idiopathic menorrhagia 1, 3, 12, 24, 36 months or 48 months after LNG-IUSs insertion.

 

3.6.1.4. Before versus after LNG-IUS insertion

Six observational studies [13], [22], [23], [24], [25] and [26] compared menstrual blood loss among women with uterine leiomyoma before and after insertion of LNG-IUSs. An analysis of menstrual blood loss results after different follow-up durations in every observational study showed a significant reduction after insertion of LNG-IUSs compared to before, and some studies reported that menstrual blood loss was reduced by 50.0–91.0% at 6 months [23], [24], [25] and [26] and by 69.0–97.40% at 12 months [13], [22], [23], [25] and [26]. The results of menstrual blood loss changes in the randomised controlled study [21] were similar (P < 0.001).

 

3.6.2. Blood haemoglobin, ferritin and hematocrit levels

3.6.2.1. LNG-IUS versus combined oral contraceptive

The randomised controlled study [21] reported that haemoglobin levels were significantly higher in the LNG-IUS group than in the combined oral contraception group at the 12-months follow-up (P < 0.001). Ferritin levels were also higher (P < 0.001).

 

3.6.2.2. LNG-IUS versus thermal balloon ablation

One study [25] showed no significant difference in the reduction of haemoglobin when comparing LNG-IUSs use to a historical control (thermal balloon ablation).

 

3.6.2.3. Before versus after LNG-IUS insertion

There was a significant increase in blood haemoglobin with insertion of LNG-IUSs. The only exception was the study by Mercorio et al. [26], in which haemoglobin was significantly decreased at 9 and 12 months despite exogenous administration of iron, which had a baseline mean level was of 109 g/dL. After excluding the exception, the 7 included studies [13], [14], [16], [21], [23], [24] and [25] all showed a statistically significant increase in blood haemoglobin.

 

Serum ferritin levels changed little in 3 months (25.00 ± 22.00 ng/mL vs. 24.00 ± 23.00 ng/mL) [13], but showed a significant increase after 6 months [13] and [24] and 12 months [13]. At the same time, hematocrit levels were shown to significantly increase in two studies [16] and [24], one of which [24] also showed a significant increase in iron levels over 6 months.

 

3.6.3. Treatment failure

3.6.3.1. Treatment failure rate

The randomised controlled study [21] showed a significantly lower treatment failure rate (6 of 29, 23.1%) in the LNG-IUSs group than in the combined oral contraceptive group (11 of 29, 37.9%), (OR 0.46, 95% CI 0.17–1.17, P = 0.1).

 

3.6.3.2. Device expulsion rate

The most common cause of treatment failure in using LNG-IUSs was spontaneous device expulsion. Six studies [13], [16], [17], [21], [23] and [26] examined the occurrence of device expulsion. Reported device expulsion rates ranged from 6.3 to 12%, with one study [26] reporting that 12% (4/32) of cases experienced device expulsion during the first 3 months, and another two studies [21] and [23] reporting 10.3% (3/29) and 6.3% (6/96) of cases expelled the device during the one-year study period.

 

In the randomised controlled study [21], the device expulsion rate in women whose leiomyoma were greater than 3 cm (2/13, 15.4%) was higher than in women whose leiomyoma were equal to or less than 3 cm (1/16, 6.3%). Furthermore, the mean leiomyoma size in women experiencing device expulsion was 4.30 ± 2.80 cm compared to 2.80 ± 1.20 cm in women who did not experience device expulsion (P = 0.04). Although the three women who experienced device expulsion had interstitial leiomyomas, the likelihood of expulsion based on leiomyoma type showed no significant difference (P = 1.00) [21].

 

3.6.3.3. Hysterectomy rate

Hysterectomies were performed in 4/16 (25.0%) women within 6 months in one study [15] for device expulsion in one woman and for heavy menstrual blood in the other three, and in 7/32 (22%) women within 3 and 6 months in another study [26] for persistent menorrhagia. Another study [17] reported that 3/27 (11.1%) women underwent hysterectomies after spontaneous device expulsion or because of bleeding/pain after approximately 12 months of use. The other study [23] reported 3/96 (3.1%) women for device displacement underwent hysterectomies.

 

3.6.4. Adverse effect

Two studies reported the occurrences of ovarian cysts. One study reported a rate of 3.7% [22]. Socolov et al. [23] reported that 15 new ovarian cysts and two persistent cysts presented at 3 months, seven new cysts and five persistent cysts presented at 6 months and two new cysts and four persistent cysts presented at 12 months with a diameter of 35–55 mm, which did not elicit any symptoms or require treatment.

 

The most common adverse effects of the LNG-IUSs were irregular bleeding/spotting followed by amenorrhea. Three prospective observational studies [17], [22] and [23] were identified that described irregular bleeding/spotting. It was worthwhile to note that an effective reduction in the incidence of irregular bleeding/spotting was reported in 9% [23], 52.3% [17], and 67.3% [22] of the cases after 3 months; in 3.0% [23] and 48% [17] after 6 months; in 3.1% [23], 23.8% [17], and 51.2% [22] after 12 months; in 15.0% [17] after 24 months; and in 11.1% [17] after 36 months of LNG-IUS use.

 

The prevalence of irregular bleeding/spotting was higher in leiomyoma-related menorrhagia (11.0%) compared to that in idiopathic menorrhagia (7.7%) and in the control contraception group (4.0%) (P = 0.024) [17]. Moreover, a similar observation of a higher irregular bleeding/spotting rate in leiomyoma-related menorrhagia (decreasing from 67.3% at 3 months to 51.2% at 12 months) was observed in a comparative study [22] when compared to that in idiopathic menorrhagia (decreasing from 58.9% to 42.4%). Two studies reported 3/16 (18.8%) [15] and 1/61 (1.6%) [13] women discontinued using the device because of LNG-IUS-induced heavy menstrual bleeding or menstrual irregularity. No data were available concerning the treatment of irregular bleeding/spotting.

 

Although no authors reported on the occurrence of amenorrhea experienced by these women prior to LNG-IUS insertion, five studies described the occurrence of amenorrhea after insertion of LNG-IUSs. In 1.0% women [23], amenorrhea occurred by 3 months, in 10.0% women [23] and 40.0% women [16] by 6 months, and in 30.0% women [23], 19.0% women [14], and 21.9% women [22] by 12 months. Another two studies reported that the occurrence rate of amenorrhea increased from 9.5% at 3 months to 44.5% at 6 months [17] and from 10.0% at 3 months to 20.0% at 6 months and to 40.0% at 12 months [13].

 

Other adverse effects included breast tenderness in 31.3% [15] and 5.6% [22] of women, weight gain in 10.0% [23] and 18.5% [22], pelvic pain in 12.0% [23] and 18.8% [15], and headache in 12.0% [23], 6.3% [15] and 9.3% [22]. However, none of the women were reported to have discontinued LNG-IUSs use because of these adverse effects.

 

4. Discussion

In our review, there was a significant reduction in menstrual blood loss and a significant increase in serum levels of haemoglobin, ferritin and hematocrit after LNG-IUSs insertion and a greater reduction of menstrual blood loss with LNG-IUSs compared to combined oral contraceptive, which was similar to the systematic review by Zapata et al. [18]. However, Zapata et al. did not refer to the effect of LNG-IUSs in uterine and leiomyoma volumes and endometrial thickness.

 

Our review suggested that LNG-IUSs be of benefit to decreasing uterine volume after insertion of LNG-IUSs at different follow-up times. The reduction in uterine volume in the leiomyoma-related menorrhagia group was significantly greater than that in the idiopathic menorrhagia and contraception groups. However, there was no evidence that LNG-IUSs caused decreases in uterine leiomyoma volume. Furthermore, LNG-IUSs had a beneficial effect on decreasing endometrial thickness and had no adverse effects on the ovarian function except for ovarian cysts after using LNG-IUSs.

 

The mechanisms by which the LNG-IUSs promote a reduction in menorrhagia and in uterine volume are not yet clear. It may be suggested that LNG-IUSs release high doses of levonorgestrel into the uterine cavity, promoting rapid decidualization of the endometrial stroma and acting on the uterine vasculature and the receptors in myometrium, at last decreasing menorrhagia and uterine volume. The action of LNG-IUSs in leiomyoma volume cannot be concluded in this review, and the mechanism was also controversial. Some research suggested that progestin might stimulate mitosis within the leiomyoma and promote its multiplication [32]. Other research indicated that progestin may play a dual role in regulating the growth of leiomyoma, and that high local concentrations of levonorgestrel may suppress the proliferation of uterine leiomyoma cells and promote cell apoptosis [33].

 

The identified studies in our review focused mainly on premenopausal women and analysed the effect of LNG-IUSs on premenopausal women with systematic uterine leiomyomas. Although premenopausal women were the most common population with uterine leiomyomas, studies showed that LNG-IUSs may have a beneficial effect on decreasing endometrial thickness, and LNG-IUSs have been FDA-approved for use in endometrial hyperplasia. Hence, LNG-IUSs could be used for women with uterine leiomyoma and endometrial hyperplasia, and future studies should include other population groups such as perimenopausal and postmenopausal women who have had leiomyoma-complicated endometrial hyperplasia.

 

LNG-IUSs expulsion has been identified as the major cause of treatment failure. Device expulsion rates appeared to be higher among women with leiomyoma-related menorrhagia than with idiopathic menorrhagia and be higher among women with uterine leiomyoma than those without leiomyomas [18], indicating that leiomyomas may have an effect on the expulsion of LNG-IUSs. In addition, expulsion rate seemed to associate with leiomyoma size but did not associate with leiomyoma type such as submucosal, intramural or subserosal leiomyoma, suggesting that LNG-IUSs expulsion was more common among women with larger leiomyomas (more than 3 cm in diameter).

 

The most frequently encountered side effects for LNG-IUSs were irregular bleeding/spotting followed by amenorrhea. Irregular bleeding/spotting occurred more in leiomyoma-related menorrhagia than in idiopathic menorrhagia, perhaps indicating that leiomyoma can have a large impact on irregular bleeding/spotting. An increased incidence and prevalence of irregular bleeding/spotting was observed at the beginning of the follow-up period, especially during the first 3 months, and then decreased. Few users of the LNG-IUS reportedly requested removal of the device because of irregular bleeding/spotting, and no data were available concerning the treatment of irregular bleeding/spotting.

 

One potential limitation of this study should be considered. The inclusion criteria for uterine volume sizes were different among the included studies. For instance, some included studies only included women with uterine volume ⩽12 weeks pregnancy, while other studies include women with uterine volume in any size, which may affect our conclusion. Therefore, the result of uterine volume change after insertion of LNG-IUSs should be interpreted with caution, and further studies including women with any uterine sizes are required to investigate this result.

 

In conclusion, the results suggest that LNG-IUSs are beneficial for reducing uterine volume and endometrial thickness in premenopausal women with symptomatic uterine leiomyoma. However, there is no evidence to support the effectiveness of LNG-IUSs on uterine leiomyoma volume. LNG-IUSs are also an effective means of reducing menstrual blood loss and increasing blood haemoglobin, ferritin and hematocrit levels. LNG-IUSs expulsion was related to leiomyoma size (larger than 3 cm). In addition, LNG-IUSs had no adverse effects on the ovarian function except for ovarian cysts after using. The most common side effect, irregular bleeding/spotting, occurred at the beginning of the follow-up period and may decrease progressively.

 

More high quality studies, including controlled trials (following the CONSORT criteria), and high quality cohort studies are required for assessing the effects of LNG-IUSs for using in uterine leiomyomas. Studies should be large and long-term, and include participants in premenopause, perimenopause and postmenopause, and also include women with any uterine volume sizes. Additionally, more attention should be paid to the treatment of irregular bleeding/spotting and the effect of LNG-IUSs on endocrine function.

 

Conflict of interest statement

The authors declare that there are no conflicts of interest in regard to this