Long-term administration of dienogest reduces recurrence after excision of endometrioma
J Endometr Pelvic Pain Disord 2015; 7(2): 63 - 67
Article Type: ORIGINAL ARTICLE
AuthorsYoshiaki Ota, Masaaki Andou, Shiori Yanai, Saori Nakajima, Mika Fukuda, Mizuki Takano, Shozo Kurotsuchi, Keiko Ebisawa, Tomonori Hada, Ikuko Ota
Pain-relieving effects of dienogest against endometriosis are comparable to leuprolide acetate for 24 weeks. We assessed whether long-term dienogest administration reduces recurrence after endometrioma excision.
In this retrospective cohort study, 568 women with MRI-based diagnosis of ovarian endometrioma, who underwent laparoscopic stripping between 2008 and 2013, were studied. Recurrence rates and side effects over 5 years were investigated in 417 without postoperative medication and 151 who received dienogest postoperatively at 2 mg. Transvaginal sonography was performed every 3 months, and when cystic lesions ≥2 cm were observed, diagnostic MRI was conducted. Recurrence was defined as a lesion previously diagnosed as endometrioma by MRI, equal in size or larger 3 months later on ultrasonography. Cumulative recurrence rates were calculated with the Kaplan-Meier method, and group comparison involved log-rank tests. Blood examinations were completed every 3 months, and bone mineral density was measured with DEXA every 6 months.
Cumulative recurrence rates at the 5th postoperative year in the no-postoperative-medication and 2-mg dienogest groups were 69 and 4%, respectively, showing significant decreases (odd ratio [OR] = 0.09, 95% confidence interval, 0.03-0.26). Anemia occurred in 4% due to metrorrhagia directly after administration, metrorrhagia including spotting was observed in 20% at 1 year and decreases in bone mineral density and depression were observed in 4 and 2.6%, respectively, in the dienogest group.
Dienogest significantly prevented postoperative endometrioma recurrence. However, side effects such as metrorrhagia and a decreased bone mineral density were observed. Therefore, careful long-term follow-up is necessary.
- • Accepted on 09/06/2015
- • Available online on 24/06/2015
- • Published in print on 22/07/2015
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The current rate of endometriosis among women of reproductive age is 6 to 10% (1). Fifty-five percent of women with ovarian endometriosis concurrently show endometrioma (2). It has been reported that the mere existence of an endometrioma reduces the quality of oocytes (3), and European Society of Human Reproduction and Embryology (ESHRE) guidelines state that surgery is indicated for endometriomas ≥4 cm. Therefore, surgery is often required in clinical fertility treatment.
Laparoscopic stripping and ablation of the ovaries have been employed as surgical treatment; however, damage to the ovaries is a concern when patients wish to preserve fertility. Moreover, the recurrence of endometrioma at 2 to 5 years after conservative surgery was reported to be 12-30% (4-5-6-7-8-9).
Therefore, it is considered necessary to prevent recurrence by medication until the patient desires to become pregnant, avoid surgery if possible and continue long-term management until menopause.
The long-term use of gonadotropin-releasing hormone (GnRH) agonists and danazol, which have been conventionally employed to treat endometriosis in Japan, have raised concerns as this may decrease the bone density and cause impaired liver functioning. On the other hand, dienogest, a 4th generation progestin, has a moderate central depressant action and does not cause a marked decrease in estrogen after prolonged use, and so it is considered to be appropriate for the long-term treatment of endometriosis. However, although the safety of dienogest use for 52 weeks has been reported, there has been no report on its side effects on long-term (5 years) use, such as a decrease in the bone mineral density and metrorrhagia (10). Therefore, we considered it necessary to investigate the details of the effects and side effects of long-term dienogest use to prevent the recurrence of endometrioma. Prevention of the postoperative recurrence of endometrioma to avoid reoperation is essential for women of childbearing age. However, medication to prevent it should not decrease their quality of life (QOL). The effect of oral contraceptives (OCs) to reduce the postoperative recurrence of endometrioma (11) and their safety on use for more than 2 years (12) have been reported. However, it is still unclear if dienogest can also be one of the options for women in whom the prevention of endometrioma recurrence is necessary, from the perspective of its effect and safety. We report our experience of using dienogest with careful observation of recurrence and its side effects.
Materials and methods
We conducted a retrospective cohort study of 568 women (mean age 32.8 ± 5.7 years old) who had ovarian endometrioma, wished to preserve fertility and underwent laparoscopic stripping between January 2008 and December 2013. Ovarian endometrioma was diagnosed based on magnetic resonance imaging (MRI). Stripping was performed in all cases by laparoscopic surgery. When deep infiltrating endometriosis (DIE) was observed during the operation, its excision was performed at the same time.
Institutional ethics committee approval was obtained, as well as consent from the patients for the future use of their anonymized data. The study was conducted according to the Declaration of Helsinki for Medical Research involving Human Subjects.
Four hundred and seventeen patients (mean age 33.2 ± 6.0 years) who desired to become pregnant or did not wish to receive medication after the operation were assigned to a no-postoperative-medication group.
One hundred and fifty-one patients who did not wish to become pregnant were administered dienogest at 2 mg, and were classified as the dienogest group. Outcomes were compared between the 2 groups. The chi-squared test was performed to investigate group differences. There were no significant differences in the age or laterality of endometriotic cysts (unilateral or bilateral) among the 2 groups. The ratio of the presence to absence of DIE was significantly lower in the no-postoperative-medication group. The presence of DIE was defined as adhesions in the Douglas pouch and uterosacral ligament that required removal (
Demographic and clinical data for study participants
|No postoperative medication (n = 417)||Dienogest 2 mg treatment (n = 151)||p Value||χ2|
|*The presence of DIE was defined as adhesions in the Douglas pouch and uterosacral ligament observed during surgery, requiring surgical removal.|
|†The revised American Society for Reproductive Medicine (rASRM) classification.|
|Age (years)||33.23 ± 6.01||32.56 ± 5.23|
|Presence of deep infiltrating endometriosis*|
|Laterality of endometriotic cysts|
Transvaginal ultrasonography was conducted every 6 months to assess postoperative recurrence of endometrioma, and retrospective evaluation was conducted. MRI was performed when a cyst ≥2 cm was observed with transvaginal ultrasonography to diagnose endometrioma. Recurrence of endometrioma was defined as a lesion which had been previously diagnosed as endometrioma by MRI, which was equal in size or larger 3 months later on ultrasonography. We used 3-Tesla MRI to diagnose endometrioma with MRI, and cystic lesions presenting typical findings such as a high intensity on fat-suppressed T1-weighted images and T2-weighted images, and the accumulation of various sizes of cyst with various stages of hemorrhage, lesions with shading and ones presenting as irregular forms with adhesions were diagnosed as endometrioma. Ultrasonography was conducted to follow up the size of the lesions previously diagnosed as endometrioma by MRI.
The recurrence rates of endometrioma during the observation period were 22.4% (93/416) and 2.6% (4/151) (odds ratio [OR] = 0.09, 95% confidence interval [95% CI], 0.03-0.26) and the mean observation periods were 56.4 ± 1.9 and 61.2 ± 1.1 months in the no-postoperative-medication and dienogest groups, respectively.
The cumulative recurrence rates 5 years after the surgery were 0.69 ± 0.022 and 0.043 ± 0.063 in the no-postoperative-medication and dienogest groups, respectively, being significantly lower in the latter (log-rank test, p<0.0001, OR = 8.44) (
Recurrence ratios after surgery in the no-postoperative-medication and dienogest groups.
Concerning side effects of dienogest, there was no abnormality in serum lipid concentrations or liver enzymes during the 5 years. Metrorrhagia in the first 1 year of administration was observed in 96.0% (145/151). The rate of abnormal vaginal bleeding including spotting after 1 year was 20.5% (31/151). When bleeding continued 6 months after the start of administration, cytology of the endometrium was performed to exclude malignancy. The administration of dienogest was planned to be discontinued if anemia developed. However, anemia was not observed in any of the 31 cases in which metrorrhagia was present after the first year of administration, and bleeding was mostly best described as spotting. Breast tenderness was observed in 16.6% (25/151) of the patients, with its peak in the 2nd month, but it resolved spontaneously within a few months. A decrease in the bone mineral density of more than 4% within 1 year was observed in 4.6% (7/151) of the patients, and bazedoxifene acetate, which is a selective estrogen receptor modulator (SERM), was administered at 20 mg/day unless symptoms suggesting a low level of estrogen, such as hot flash, were present. A decrease in the bone mineral density and increased level of TRACP-5b improved with SERM administration in all patients. Depression was observed in 2.6% (4/151) of the patients, and symptoms appeared within 6 months after the start of administration. Symptoms were mild and medication to improve them or the discontinuation of dienogest was not necessary (
Side effects of dienogest
|Side effects||Occurrence rate (%)|
|*Metrorrhagia in the early stage was defined as bleeding starting within a month from the initiation of administration that lasted more than 2 weeks.|
|†Abnormal vaginal bleeding was defined as bleeding starting more than 1 year after the initiation of administration, from spotting to a moderate amount. When bleeding continued for more than 2 weeks, cytology of the endometrium was performed to exclude malignancy.|
|‡Decrease in bone mineral density was defined as a decrease of more than 4% a year in the lumbar or femoral neck bone mineral density (L2-L4) measured with DEXA, with an increase in the TRACP-5b level (≥420 mU/dL; standard value, 120-420 mU/dL) and decrease in the serum level of estradiol.|
|Metrorrhagia in the early stage*||96.0% (145/151)|
|Abnormal vaginal bleeding†||20.5% (31/151)|
|Breast tenderness||16.6% (25/151)|
|Decrease in bone mineral density‡||4.6% (7/151)|
|Increase of weight||3.3% (5/151)|
|Hot flash||3.3% (5/151)|
Dienogest has been reported to be effective in relieving patient-reported symptoms, including the intensity of dyspareunia, dysmenorrhea and diffuse pelvic pain in some clinical trials (10, 14).
To reduce the recurrence of endometrioma and therefore the necessity of reoperation for a prolonged period, a 2-mg per day administration of dienogest is suggested to be the most effective. However, side effects due to low estrogen levels, such as a decrease in the bone mineral density, should be carefully observed.
- Ota, Yoshiaki [PubMed] [Google Scholar] 1, * Corresponding Author (email@example.com)
- Andou, Masaaki [PubMed] [Google Scholar] 1
- Yanai, Shiori [PubMed] [Google Scholar] 1
- Nakajima, Saori [PubMed] [Google Scholar] 1
- Fukuda, Mika [PubMed] [Google Scholar] 1
- Takano, Mizuki [PubMed] [Google Scholar] 1
- Kurotsuchi, Shozo [PubMed] [Google Scholar] 1
- Ebisawa, Keiko [PubMed] [Google Scholar] 1
- Hada, Tomonori [PubMed] [Google Scholar] 1
- Ota, Ikuko [PubMed] [Google Scholar] 2
Department of Obstetrics and Gynecology, Kurashiki Medical Center, Kurashiki City - Japan
Department of Gynecology, Kurashiki Heisei Hospital, Kurashiki City - Japan