Long-Term Administration of Dienogest Reduces Recurrence after Excision of Endometrioma

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

Dienogest Laparoscopy Endometrioma Endometriosis Recurrence

Introduction

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 –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 4^th 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

Subjects

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.

Ethical approval

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.

Group classification

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 (Tab. I). In the dienogest group, complete blood count, level of serum estradiol and tartrate-resistant acid phosphatase 5b (TRACP-5b) as a bone turnover marker were measured every 3 months (13), and the lumbar bone mineral density (L2-L4) was measured with dual-energy X-ray absorptiometry (DEXA) every 6 months. If the hemoglobin level was below 10 g/dL, iron was administered. The administration of dienogest was discontinued in cases with increased TRACP-5b and a decrease in the bone mineral density of over 4% a year. An increase in weight was defined as weight gain of more than 10 kg within 6 months after the initiation of administration.

Table I

Demographic and clinical data for study participants

	No postoperative medication (n = 417)	Dienogest 2 mg treatment (n = 151)	p Value	χ²
Age (years)	33.23 ± 6.01	32.56 ± 5.23
Presence of deep infiltrating endometriosis^*
Absent	208	20	<0.001	61.92
Present	209	131
rASRM classification^†
III	115	42
IV	302	109	0.955	0.0031
Laterality of endometriotic cysts
Unilateral	231	79
Bilateral	186	72	0.515	0.42

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.

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.

Results

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) (Fig. 1). Reoperation was performed in patients with endometrioma ≥6 cm who desired it after informed consent was obtained. A total of 3.6% (15/417) of patients underwent reoperation in the no-postoperative-medication group, while none did in the dienogest group.

Fig. 1

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 (Tab. II).

Table II

Side effects of dienogest

Side effects	Occurrence rate (%)
Metrorrhagia in the early stage^*	96.0% (145/151)
Abnormal vaginal bleeding^†	20.5% (31/151)
Breast tenderness	16.6% (25/151)
Headache	8.6% (13/151)
Constipation	4.6% (7/151)
Decrease in bone mineral density^‡	4.6% (7/151)
Increase of weight	3.3% (5/151)
Hot flash	3.3% (5/151)
Depression	2.6% (4/151)

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.

Discussion

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). In vitro, dienogest has been reported to directly reduce endometriotic lesions through a number of biological mechanisms. It induces a hypoestrogenic, hypergestagenic local endocrine environment, causing a decidua lization of endometrial tissue followed by atrophy of the endometriotic lesions (15). Laparoscopic stripping is performed to treat ovarian endometrioma, but a high rate of postoperative recurrence is a problem. It was reported that initial stripping for bilateral endometrioma caused premature ovarian failure (POF) in 16.3% of patients (16). Therefore, dienogest is considered to be effective for not only symptoms but also endometriosis itself. This study suggests the possibility of dienogest significantly reducing the long-term recurrence of endometrioma. Dienogest was considered to be effective as postoperative medication similar to OCs and GnRH agonists, also from the perspective of the ovarian reserve, if it prevents resurgery (17). On the other hand, dienogest may also reduce plasma estradiol levels directly through inducing the apoptosis of granulosa cells in the ovary (18). Ovarian activity was effectively suppressed at the dose of 2 mg (19). Dienogest establishes an estrogen level within the therapeutic window for endometriosis, which is 30-50 pg/mL (20), and the level is considered to be low enough to cause hypoestrogenic side effects such as bone mineral loss. Therefore, side effects such as a decrease in the bone mineral density should be borne in mind with the long-term administration of dienogest. Furthermore, consistent with other comparative trials, dienogest was associated more frequently with irregular bleeding than the GnRH agonist (21). It was associated with higher rates of treatment discontinuation. In this study, we only treated anemia in patients with metrorrhagia occurring within 6 months after the start of administration, but the use of GnRH agonists has been reported as a treatment to reduce the occurrence of metrorrhagia (22). Furthermore, the combined use of dienogest and estradiol valerate has been reported to be as effective as the combined use of a GnRH analogue and estradiol valerate (23). Therefore, when side effects such as metrorrhagia and a decreased bone mineral density are of concern, the combined use of dienogest and another agent may be worth considering. Clinically, bone turnover markers such as TRACP-5b should be measured in addition to serum estradiol levels when dienogest is used long-term, and the use of add-back estradiol should be considered when an increase in TRACP-5b and marked decrease in estradiol are observed. In this study, 4% of the patients presented with a significant decrease in the bone density during the 5 years, and this suggests that the use of add-back estradiol does not need to be considered in all patients administered dienogest, but it can be applied to patients considered to require it through the clinical course. The postoperative prevention of recurrence is necessary to preserve the ovarian function and avoid reoperation. On the other hand, the QOL of patients should also be taken into consideration. Dienogest is as effective at preventing the recurrence of endometrioma as OCs, and its use improves the QOL as it is safe and stops menstruation. However, its administration should be reviewed carefully from the perspective of the QOL when side effects such as prolonging metrorrhagia, depression and a decrease in the bone density are observed.

Conclusion

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.

Footnotes

Financial support: None.

Conflict of interest: The authors report no declarations of interest.

References

Giudice

L.C.

, Kao

L.C.

. Endometriosis. Lancet. 2004; 364(9447): 1789–1799.

Liu

, Yuan

, Shen

, Zhu

, Jiang

, Guo

S.W.

. Patterns of and risk factors for recurrence in women with ovarian endometriomas. Obstet Gynecol. 2007; 109(6): 1411–1420.

Kitajima

, Dolmans

M.M.

, Donnez

, Masuzaki

, Soares

, Donnez

. Enhanced follicular recruitment and atresia in cortex derived from ovaries with endometriomas. Fertil Steril. 2014; 101(4): 1031–1037.

Busacca

, Marana

, Caruana

. Recurrence of ovarian endometrioma after laparoscopic excision. Am J Obstet Gynecol. 1999; 180(3 Pt 1): 519–523.

Saleh

, Tulandi

. Reoperation after laparoscopic treatment of ovarian endometriomas by excision and by fenestration. Fertil Steril. 1999; 72(2): 322–324.

Ghezzi

, Beretta

, Franchi

, Parissis

, Bolis

. Recurrence of ovarian endometriosis and anatomical location of the primary lesion. Fertil Steril. 2001; 75(1): 136–140.

Jones

K.D.

, Sutton

C.J.

. Recurrence of chocolate cysts after laparoscopic ablation. J Am Assoc Gynecol Laparosc. 2002; 9(3): 315–320.

Vercellini

, Chapron

, De Giorgi

, Consonni

, Frontino

, Crosignani

P.G.

. Coagulation or excision of ovarian endometriomas? Am J Obstet Gynecol. 2003; 188(3): 606–610.

Koga

, Takemura

, Osuga

. Recurrence of ovarian endometrioma after laparoscopic excision. Hum Reprod. 2006; 21(8): 2171–2174.

10.

Köhler

, Faustmann

T.A.

, Gerlinger

, Seitz

, Mueck

A.O.

. A dose-ranging study to determine the efficacy and safety of 1, 2, and 4 mg of dienogest daily for endometriosis. Int J Gynaecol Obstet. 2010; 108(1): 21–25.

11.

Vercellini

, DE Matteis

, Somigliana

, Buggio

, Frattaruolo

M.P.

, Fedele

. Long-term adjuvant therapy for the prevention of postoperative endometrioma recurrence: a systematic review and meta-analysis. Acta Obstet Gynecol Scand. 2013; 92(1): 8–16.

12.

Vercellini

, Eskenazi

, Consonni

. Oral contraceptives and risk of endometriosis: a systematic review and meta-analysis. Hum Reprod Update. 2011; 17(2): 159–170.

13.

Halleen

J.M.

, Alatalo

S.L.

, Janckila

A.J.

, Woitge

H.W.

, Seibel

M.J.

, Väänänen

H.K.

. Serum tartrate-resistant acid phosphatase 5b is a specific and sensitive marker of bone resorption. Clin Chem. 2001; 47(3): 597–600.

14.

Harada

, Taniguchi

. Dienogest: a new therapeutic agent for the treatment of endometriosis. Womens Health (Lond Engl). 2010; 6(1): 27–35.

15.

Sasagawa

, Shimizu

, Kami

. Dienogest is a selective progesterone receptor agonist in transactivation analysis with potent oral endometrial activity due to its efficient pharmacokinetic profile. Steroids. 2008; 73(2): 222–231.

16.

Coccia

M.E.

, Rizzello

, Mariani

, Bulletti

, Palagiano

, Scarselli

. Ovarian surgery for bilateral endometriomas influences age at menopause. Hum Reprod. 2011; 26(11): 3000–3007.

17.

Harada

, Momoeda

, Taketani

. Dienogest is as effective as intranasal buserelin acetate for the relief of pain symptoms associated with endometriosis: a randomized, double-blind, multicenter, controlled trial. Fertil Steril. 2009; 91(3): 675–681.

18.

Sasagawa

, Shimizu

, Nagaoka

, Tokado

, Imada

, Mizuguchi

. Dienogest, a selective progestin, reduces plasma estradiol level through induction of apoptosis of granulosa cells in the ovarian dominant follicle without follicle-stimulating hormone suppression in monkeys. J Endocrinol Invest. 2008; 31(7): 636–641.

19.

Klipping

, Duijkers

, Faustmann

, Klein

S.F.

, Schuett

. Pharmacodynamic study of four oral dosages of dienogest. Fertil Steril. 2010; 94(4)(Suppl 1): S181.

20.

Barbieri

R.L.

. Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am J Obstet Gynecol. 1992; 166(2): 740–745.

21.

Momoeda

, Taketani

. [Randomized double-blind, multi-center, parallel-group dose–response study of dienogest in patients with endometriosis] [article in Japanese]. Jpn Pharmacol Ther. 2007; 35: 769–783.

22.

Kitawaki

, Kusuki

, Yamanaka

, Suganuma

. Maintenance therapy with dienogest following gonadotropin-releasing hormone agonist treatment for endometriosis-associated pelvic pain. Eur J Obstet Gynecol Reprod Biol. 2011; 157(2): 212–216.

23.

Granese

, Perino

, Calagna

. Gonadotrophin-releasing hormone analogue or dienogest plus estradiol valerate to prevent pain recurrence after laparoscopic surgery for endometriosis: a multi-center randomized trial. Acta Obstet Gynecol Scand. 2015; 94(6): 637–645.