Introduction

Adenomyosis is a common disease affecting primarily premenopausal women and regresses rapidly after menopause. It is characterized by the presence of heterotopic endometrial glands and stroma in the myometrium, associated with adjacent myometrial hyperplasia [1]. Although adenomyosis and endometriosis are different diseases, both grow and regress in an estrogen-dependent fashion [2]. The definitive treatment of symptomatic adenomyosis is hysterectomy. However, conservative surgery involving endomyometrial ablation, laparoscopic myometrial electrocoagulation or excision has proven to be effective in more than 50 % of patients [3]. Alternative management, including uterine artery embolization and levonorgestrel intrauterine system also can be considered [4, 5].

To date, there is no uniform agreement on the most appropriate therapeutic methods for managing women with uterine adenomyosis who wish to preserve their uterus. Hormonal treatment that aims to reduce the proliferation of endometrial cells is promising in recent literature. Gonadotropin-releasing hormone analogues (GnRHa) have been used in several studies to produce a constant hypoestrogenic state in a woman with adenomyosis [6, 7]. Dienogest (Dn) is a selective synthetic oral progestin that uniquely combines the pharmacological properties of progesterone and 19-norprogestin derivative, offering pronounced local effect on endometrial tissue [8]. Dienogest at 2 mg once daily is recommended as the optimal dose for improving the underlying pathology and symptoms of endometriosis [9].

To the best of our knowledge, there is no substantial report addressing the comparison of the effectiveness of dienogest versus triptorelin acetate (TA) for symptomatic adenomyosis. To examine this issue, we compared both modalities in a prospective study in premenopausal women.

Materials and methods

This prospective study enrolled premenopausal women complaining of menorrhagia and pelvic pains among those attending the Outpatient Gynecologic Clinic at Mansoura University Hospital and a private practice setting, Mansoura, Egypt, in the period from May 2013 to November 2014. This study was given approval by the ethics committee of Mansoura University Hospital.

A detailed history and examination was carried out in the first visit. Transvaginal sonography (TVS) evaluation was carried out by the same physician. Diagnosis of adenomyosis using TVS included globular uterine enlargement in the absence of leiomyoma, asymmetric enlargement of the anterior or posterior wall, Cystic anechoic lakes or spaces in the myometrium and Subendometrial echogenic linear striations. After identification of the adenomyosis, the uterine volume was assessed using the formula for an ovoid (length × width × depth × 0.52) [10].

The inclusion criteria were, married premenopausal women (35–45 years old) with uterine adenomyosis, complaining of menorrhagia and dysmenorrhea, dyspareunia, and chronic pelvic pain. Patients were excluded if they had any of the following conditions: hormonal therapy in the preceding 3 months, myoma, endometriosis, chronic pelvic inflammatory disease, or abnormal coagulation profile. Each woman provided written informed consent before participating in the study. Women were allocated by alternation to one of two treatment groups. First group (n = 22) received oral dienogest (Visanne, Bayer Pharma AG, Germany) at a dose of 2 mg once daily on days 2–5 of menstruation without a break for 16 weeks. The second group (n = 19) received subcutaneous triptorelin acetate injections (3.75 mg/4 weeks, Decapeptyl CR, Ferring, Germany) on days 2–5 of menstruation for 16 weeks. Women were advised to use barrier methods during the study period if they required reliable contraception.

Outpatient follow-up was undertaken after 8 weeks, but mean values were calculated at baseline and after 16 weeks (end of treatment). Level of adenomyosis-associated pelvic pains (dysmenorrhea, dyspareunia, and chronic pelvic pain) assessed by a 100-mm visual analogue scale (VAS) in which 0 indicated no pain and 100 indicated an intolerable pain at baseline and at the end of treatment. After 16 weeks, menstrual flow was assessed and classified into three groups: Group 1 (unsatisfied): persistent, heavy, prolonged, or irregular menstruation; Group 2 (satisfied): light, infrequent, scanty or normal menstruation; Group 3 (satisfied): complete cessation of menstruation (amenorrhea). Blood cell count and serum ferritin (SF) levels were determined in each patient just before treatment. Hemoglobin (Hb) and SF were re-evaluated after 16 weeks treatment in both groups.

Analysis was done on the recruited women who continued the study. Means were compared using the two-tailed grouped unpaired Student’s t test while proportions were compared using Fisher’s exact test. A p value of <0.05 was considered to be statistically significant. Data obtained were statistically analyzed using SPSS ver. 15.0 (SPSS Inc., Chicago, IL, USA).

Results

Forty-one patients who met the above-mentioned criteria were included in this study. In Dn group, one woman was lost to follow-up, and two discontinued treatment for prolonged irregular genital bleeding, so the number of women analyzed was 19. In TA group, one woman was lost to follow-up, so the number of women analyzed was 18. Four patients in both groups of the study were not included in the final analysis. Patient characteristics and symptoms are presented in Table 1. No significant difference was found between basal values of both groups.

Table 1 Basal characteristics in Dn and TA groups
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Table 2 shows significant reduction of dysmenorrhea, dyspareunia and chronic pelvic pain in both Dn and TA groups at the end of treatment. The efficacy of both Dn and TA was similar in management of dyspareunia (20.7 ± 16.5 vs. 25.8 ± 19.1, p = 0.3899) and chronic pelvic pain (21.7 ± 11.6 vs. 24.5 ± 13.8, p value = 0. 5076). There was a significant difference in the post-treatment dysmenorrhea between Dn and TA at 16 weeks (30.6 ± 18.4 vs. 0.0; p < 0.0001). Triptorelin acetate was associated with a significant reduction of post-treatment uterine volumes in comparison with dienogest (p = 0.0108 and p = 0.4822, respectively).

Table 2 Outcomes in Dn and TA groups
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Table 3 shows improvement of menorrhagia in 14/19 patients (73.7 %) of Dn group versus 18/18 patients (100 %) of the TA group at the end of treatment. Triptorelin acetate was superior to dienogest in achieving amenorrhea (94.4 versus 21.1 %), respectively, after 16 weeks treatment. There was a significant improvement of mean Hb levels in Dn group (9.9 ± 1.2 vs. 11.6 ± 1.4, p = 0.0003) and TA (9.6 ± 1. 3 vs. 12.5 ± 1.6, p < 0.0001). Also mean SF levels were markedly improved in Dn group (12.7 ± 6.9 vs. 24.4 ± 8.3, p < 0.0001) and TA (10.1 ± 5.8 vs. 29.7 ± 11.9, p < 0.0001) group after the end of treatment. There was no significant difference in Hb and SF values between Dn and TA groups after treatment (p = 0.0768, p = 0.1235 respectively) as shown in Table 2.

Table 3 Effects of Dn and TA treatment on menorrhagia
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Discussion

Hysterectomy is considered as the only procedure, which is able to cure the adenomyosis definitively. Recently, surgical conservative interventions have been reported [11, 12]. Because of the considerable hazards of surgical intervention and anesthetic complications, a nonsurgical treatment may be a better option for women who are suffering from symptomatic adenomyosis.

Many studies have reported the potential usefulness of the hypoestrogenic state induced by GnRHa for the treatment of adenomyosis [6, 7]. The efficacy of dienogest for endometriosis-associated pelvic pain has been established [13]. Harada et al. reported the beneficial effects of dienogest on extragenital endometriosis [14]. Recently in a pilot study, dienogest was effective in alleviating the pain symptoms associated with adenomyosis and uterine fibroids [15]. The present trial is a prospective clinical study comparing the efficacy of Dn in comparison to TA on adenomyosis pelvic pains and hypermenorrhea.

In this study, both Dn and TA were highly effective in improving the dysmenorrhea, dyspareunia, and chronic pelvic pain associated with adenomyosis (Table 2). This was consistent with Tetsuya et al. who reported that Dn was effective in alleviating the pain symptoms associated with adenomyosis [15]. Dienogest has been reported to exhibit high selectivity for binding to progesterone receptors [16] and inhibitory effects on the secretion of cytokines in endometriotic stromal cells [17]. Dienogest directly inhibits cellular proliferation and also induces apoptosis in human adenomyotic stromal cells [18]. These pharmacological features add pathophysiological arguments for the therapeutic strategy of using dienogest in the treatment of adenomyosis. Triptorelin acetate was more effective than Dn in relieving dysmenorrhea, but had similar efficacy in treatment of dyspareunia and chronic pelvic pain. Kang et al. reported relief of dysmenorrhea in all patients with endometriosis and adenomyosis treated with triptorelin depot regimen after 6 months [19]. In a comparison between endometriosis and adenomyosis, GnRHa administration in women with clinical suspect of adenomyosis induces a greater reduction in chronic pelvic pain when compared to women with endometriosis [20].

In this study, uterine volume was assessed by TVS. Magnetic resonance imaging has been demonstrated to be a valuable tool for non-invasive diagnosis of adenomyosis, but its use is limited by costs and varying availability [21]. In low socioeconomic level, TVS instead of MRI as a simple, low cost and non-invasive method is able to confirm a clinical suspect of the adenomyosis. Fedele et al. showed that TVS presents a high sensitivity (87 %) and specificity (98 %) in the diagnosis of uterine adenomyosis [22]. There was a significant reduction in uterine volume in the TA group in comparison to Dn, which had a minimal effect on after 16 weeks treatment. This difference in uterine size in the TA group may be explained by a hypo-estrogenic and a direct anti-proliferative effect of GnRHa on peripheral endometriosis tissues [23]. On the other hand, dienogest had a mild inhibition of ovarian function and maintained mean estradiol level of more than 450 pg/ml during 24 weeks treatment [15]. Grow and Filler reported 65 % reduction in uterine volume after 4 months of GnRHa therapy for uterine adenomyosis and the uterus remained small several months after discontinuation of therapy [24]. Kang et al. reported a 39.2 % reduction in uterine volume after 6 months of GnRHa therapy for uterine adenomyosis [19].

In this study, majority of the women in the Dn group (73.7 %) were relieved of menorrhagia and satisfied with treatment. It has been reported that Dn decreased proliferative appearances in endometrium in a dose-dependent manner at daily doses of 0.5 mg or more [25]. There were no patients with severe genital bleeding that required blood transfusions, but there were two patients of dienogest group, who discontinued treatment for persistent metrorrhagia. Dienogest-induced breakthrough bleeding originated mainly from pseudodecidua that occurs commonly with progestational agents [26]. Triptorelin acetate has shown a greater effect (94.7 %) than dienogest (21.1 %) in achieving amenorrhea (Table 3).

Patients in both dienogest and TA groups were anemic before treatment (Table 2). These findings are consistent with Negata et al. [27] who reported that patients with adenomyosis are considered to be at a high risk of anemia. Most women with menorrhagia had totally depleted iron stores [28]. Iron deficiency is often insidious as women have great difficulty in assessing the amount of their menstrual losses, and they may lose abnormally high amounts of blood during each menstruation period without being aware that the loss is excessive [29]. No iron medications were given to patients to allow indirect assessment of menstrual blood loss in this comparative study. Dietary advice was given to patients in both groups. There was a significant improvement in Hb and SF in both groups (Table 2). Triptorelin acetate was superior to Dn in the improvement of Hb and SF which may be attributed to amenorrhea induced by TA.

Both oral Dn and TA treatments were tolerated for 16 weeks. Dienogest was associated with fewer hot flashes 1/19 (5.3 %) compared with 17/18 (94.4 %) women in the TA group, who suffered from hot flashes. Gonadotropin agonist use is associated with temporary induction of menopausal symptoms [30]. Dienogest has been reported to have low hypoestrogenic symptoms and minimal effect on bone mineral density, which can be explained by mild suppression of estradiol [13]. Dienogest was less costly in developing country (Egypt) in comparison to TA in repeated courses’ treatment. Though this study is a prospective comparative study, there are several limitations that should be considered: subjective assessment rather than objective evaluation was used for hypermenorrhea diagnosis; adenomyosis diagnosis was based on TVS, which has a sensitivity varying between 68 and 89 % and a specificity between 65 and 99 % [22, 31]; the follow-up period was short term for 16 weeks treatment, without further follow-up for recurrence of symptoms; the number of adenomyosis patients in both groups was small. Therefore, further multicenter, randomized trials are necessary to compare this issue.

In conclusion, oral dienogest may be a valuable treatment alternative to triptorelin acetate in management of dysmenorrhea, dyspareunia and chronic pelvic pain in premenopausal women with uterine adenomyosis, who wish to preserve their uterus, though triptorelin acetate is superior to dienogest in control of menorrhagia.