Many studies have demonstrated the benefit of DNG in relieving the dysmenorrhea symptoms of adenomyosis [9, 12–15]. To the long-term efficacy of DNG on adenomyosis, Osuga Y et al reported that the mean VAS values decreased 56.7 ± 24.2 mm at 52 weeks of DNG treatment [14]. Neriishi K et al even noted that DNG has a remarkable pain relief effect continued up to menopause or for a long period of > 80 months [15]. Matsushima T et al reported that after 6 months of GnRH-a or DNG, all patients’ subjective symptoms disappeared. But symptoms recurred rapidly in the first six months after discontinuation of GnRH-a treatment [16]. In our study, patients exhibited a higher complete relief of dysmenorrhea after 3–6 injections of GnRH-a than 3–6 months of DNG alone. From 9–12 months, the complete pain relief rate was comparable in both groups. This suggests that long-term (≥ 12 months) treatment with DNG alone or sequential treatment with DNG after GnRH-a is comparable in controlling adenomyosis-related dysmenorrhea.
The effect of DNG alone and GnRH-a + DNG on serum CA125 and CA19-9
Itagaki H et al found that the serum CA125 level correlated positively with the weight of adenomyosis and it is an important indicator for evaluating recurrence [17]. Kil K et al. even proposed that the cut-off value of 19 U/mL for serum CA125 provides a better differentiation between adenomyosis and myomas [18]. In studies assessing the efficacy of DNG on symptomatic adenomyosis, serum CA125 was also an important evaluator. Hirata T et al found that the serum CA125 significantly decreased from 150.6 ± 136.4 U/mL (baseline) to 69.5 ± 88.4 U/mL at 24 weeks of DNG treatment [13]. Neriishi K et al. observed a significant decrease in serum CA125 from 124.1 ± 84.0 to 19.6 ± 6.7 IU/ml with long-term DNG administration (> 80 months) [15]. Matsushima T et al noted that after 16 weeks of treatment, the effect of DNG in lowering serum CA125 can be comparable to that of GnRH-a and lowdose estrogenprogestin combination [19]. In our study, CA125 levels decreased by 22.72%, 50.50% and 58.23% after 3–6, 9–12 and 15–24 months of treatment with DNG alone, respectively. In group 2, CA125 levels dropped by 77.62% after 3–6 injections of GnRH-a. After 3–6, 9–12, and 15–24 months of subsequent maintenance treatment with DNG, CA125 levels declined by 85.07%, 85.29%, and 86.02%, respectively. This suggests that GnRH-a + DNG sequencing therapy is superior to DNG monotherapy in lowering CA125 levels.
The effect of DNG alone and GnRH-a + DNG on uterine volume
Regarding the effect of DNG on uterine volume of adenomyosis, the current studies were inconsistent. Fawzy et al. observed that uterine volume decreased by 12.27% (P > 0.05) after 16 weeks of treatment with DNG [20]. Hirata et al. showed that uterine volume decreased by 8.97% (P > 0.05) in patients treated with DNG for 6 months [13]. Osuga Y et al. found that the mean reduction in uterine size was 20.6 ± 30.3% at 24 weeks and 26.0 ± 27.9% at 52 weeks of DNG treatment [14]. Neriishi K et al. discovered that long-term DNG administration (> 80 months) resulted in a significant 30.49% reduction (P < 0.01) in uterine size [15]. Hassanin AI et al observed that uterine volume decreased 31.57% (P < 0.05) and 8.02% (P > 0.05) respectively when treated with DNG and COCs for 6 months [4]. Similar decreases were observed in the diffuse and focal subtypes of adenomyosis treated with DNG at 12 to 24 months [8]. Nevertheless, Ji et al. found that uterine volume increased by 15.33% (P > 0.05) after 12 weeks of treatment with DNG [9]. Matsushima T et al reported that after treated with DNG for 16 weeks, the uterine volume increased 12.68% [19]. Their team also noticed that the uterine volume decreased by 54.25% after 6 injections with GnRH-a and rebounded to 82.79% of the pre-treatment volume after 6 months of discontinuation. When DNG was supplemented for 6 months after discontinuing GnRH-a, the uterine volume was 72.24% of the pre-treatment level [16]. In our study, when treated with DNG alone, the uterine volume decreased 6.73%, 13.48% and 7.56% at 3–6, 9–12 and 15–24 months respectively (P > 0.05). In group 2, uterine volume shrunk 44.57% (P < 0.05) after 3–6 injections GnRH-a and then rebound to 97.84%, 98.81%, and 86.63% of pre-treatment level at 3–6, 9–12 and 15–24 months of sequential DNG treatment. At the endpoint of this study (15–24 months), GnRH-a combined with DNG sequential therapy was superior to DNG monotherapy in reducing uterine volume.
The effect of DNG alone and GnRH-a + DNG on hemoglobin and uterine bleeding pattern.
Menorrhagia and anemia are the common clinical manifestations in patients with adenomyosis. It has been observed that the Hb increased from 11.6 ± 1.5 mg/dL to 12.3 ± 2.0 mg/dL at 24 weeks of DNG treatment [13]. Osuga Y et al. reported that DNG treatment caused an improvement of Hb from 12.8 ± 1.2 g/dL to 13.5 ± 0.9 g/dL (24 weeks) and 13.5 ± 0.9 g/dL (52 weeks) [14]. Matsushima T et al found that the elevated levels of Hb were comparable between patients treated with GnRH-a and DNG for 6 months. [16]. Hassanin et al. also observed that the improvement of Hb in patients taking DNG for 6 months was comparable to that of patients taking COC for 6 months [4]. Our study also showed that either DNG alone or GnRH-a followed by DNG significantly increased Hb levels and improved anemia symptoms. (P < 0.05).
Irregular uterine bleeding is a common symptom experienced by women treated with DNG, especially in the first 3 months of treatment. Fortunately, as treatment continues, the length and intensity of uterine bleeding decreases [21]. Uterine bleeding induced by DNG was more likely to occur in subjects with adenomyosis than in those with endometriosis alone [22]. In endometriosis, the number of discontinuations due to heavy or irregular bleeding was low (2/332) [23]. However, in adenomyosis, the number of these patients increased greatly. Nagata C et al. reported that 36 of 51 patients (70.6%) continued DNG treatment for more than 12 months, and 8 (15.7%) patients discontinued treatment due to uterine bleeding. High risk factors for discontinuation of DNG treatment included age < 38 years, Hb < 12 g/L prior to treatment, and estradiol ≥ 60 pg/ml at the third month of treatment [24]. Matsubara S et al. found that 14 of 37 patients (37.8%) with symptomatic adenomyosis experienced severe unpredictable bleeding during DNG treatment that was associated with subtype I (intrinsic) adenomyosis [25]. Neriishi K et al. discovered that 22.2% (4/18) of patients stopped DNG therapy because of severe metrorrhagia and the mean duration of DNG treatment was 7.0 ± 3.5 months. Compared with patients taking DNG continuously, the dysmenorrhea VAS score and serum CA125 level at baseline were significantly increased and the basal Hb level and the frequency of subtype II (extrinsic) were significantly decreased in the cases of discontinuation [15]. Ono N et al observed that 35% (7/20) of women discontinued DNG within 12 months due to unbearable metrorrhagia. The uterus size was significantly larger and anterior wall lesions were more common in the discontinued group than in the continued group. They proposed that patients with uterine major axis of less than 9 cm, minor axis of 6 cm, maximum myometrial thickness of 4cm, and uterine body length of 4.5cm could tolerate DNG treatment [26]. In our study, pretreatment with GnRH-a achieved better amenorrhea rates and lower spotting bleeding rate.
However, both groups had cases of heavy breakthrough bleeding during treatment, that is, four patients (4/61,6.56%) in group 1 and three cases (3/88,3.41%) in group 2. The clinical characteristics of these patients were analyzed retrospectively. 6 patients (6/7, 85.71%) had diffuse adenomyosis lesions, 5 patients (5/7, 71.43%) showed lesions compressing the endometrium, and 5 patients (5/7, 71.43%) had hemoglobin < 105 g/L before treatment. Regarding the CA125 level, three patients (3/4,75.00%) treated with group 1 and two patients (2/3, 66.67%) in group 2 were above the average level within the group.
As to the management of unpredictable bleeding during DNG treatment, a 5 ~ 7-day break of DNG, DNG dose increased from 2 mg to 4 mg daily for 5–7 days or a short-term application of 1 mg estradiol have been described as valid approaches to interrupt the uterine bleeding [27–29]. Another option was to treat with GnRH-a to achieve amenorrhea and then switch to DNG [30]. In this study, two patients in the group 1 increased to 3–4 mg/day for 7 days and then continued at 2 mg/day maintenance without unpredictable breakthrough bleeding during the next follow-up. Another two patients in group 1 were switched to GnRH-a injection followed by DNG because of poor efficacy after double-dose treatment with DNG. Two patients in group 2 were re-injected with GnRH-a followed by DNG.
The safety of DNG
Overall, DNG was a well-tolerated treatment for symptomatic adenomyosis with a good safety for long-term use. It had no adverse effects on hepatorenal and coagulation function during the treatment. As to the effect of DNG on breast, four randomized clinical trials of 2 mg DNG treatment in 332 women with endometriosis, 18 (5.4%) women reported breast discomfort, including 11 cases of breast tenderness, 4 cases of breast swelling, and 3 cases of breast pain [23]. In this study, A few patients showed variations in the size and location of breast nodules. But none of the breast nodules progressed to BI-RADS 4 lesions. More cases and longer time are required to further evaluate the effect of DNG on breast.