Use of dienogest in endometriosis: a narrative literature review and expert commentary

Figures & data

Figure 1. Search strategy for PubMed. Note: Searches were conducted based on the listed terminology and following additional terms (NOT ‘bladder’ and NOT ‘colorectal’) before combining and filtering for relevant results.

Table 1. Dienogest efficacy and safety studies with a duration ≥1 year.

Study	Duration, months	Outcomes	Treatment	Population	Main outcomes with dienogest 2 mg daily
Del Forno et al.^36	12	Pain, endometrioma size, tolerability	Dienogest 2 mg daily for up to 12 months	Retrospective chart study 135 women with symptomatic endometriosis Median age: 37 years (dienogest group), 36 years (norethindrone acetate group)	Pain: greater improvements in dysmenorrhea, chronic pelvic pain and dyspareunia with dienogest vs. norethindrone acetate with 6- and 12-months’ treatment Endometrioma size: reduction of 2.51 mm at 6 months and 6.54 mm at 12 months of treatment No treatment discontinuation due to side effects
Paulo Leonardo-Pinto et al.^19	12	Pain, sexual function	Dienogest 2 mg daily for 12 months postoperatively	Prospective cohort study 30 women with deep infiltrating endometriosis and complaint of deep dyspareunia Mean age: 36.1 years	Pain: significant decrease in pelvic pain (p = .0007), dysmenorrhea (p < .0001), dyspareunia (p = .0093) after 12 months’ treatment Significantly improved sexual function after 12 months’ treatment (p = .0023) No treatment discontinuation due to side effects
Lee et al.^35	13.3	Pain, size of recurrent endometriomas	Dienogest 2 mg daily postoperatively	Retrospective cohort study 121 women with a clinical diagnosis of recurrent endometriosis Mean age: 34.8 years Endometrioma size: 105 analyzed in 88 patients	Pain: significant decrease in mean VAS score from baseline to 24- and 48-weeks after treatment Endometrioma size: significant decrease in mean overall size from baseline after 12 months’ treatment; 3.77 (1.59) to 2.04 (1.58)
Petraglia et al.^25	15	Pain, bleeding, safety	Dienogest 2 mg daily for up to 65 weeks	Open-label prospective extension following a 12-week placebo-controlled study 152 women, aged 18–45 years Patients who completed ≥52 weeks of treatment: n = 135	Pelvic pain: decrease of mean overall VAS score by 43.2 mm over 65 weeks of treatment (placebo-controlled + extension study; p < .001) Menstrual bleeding: no bleeding in up to 23.5% of women during treatment and up to 9.8% of women experienced a decrease in the “heavy bleeding” category, in the extension study Acceptable safety profile
Strowitzki et al.^41	15	Safety and tolerability analysis	Dienogest 2 mg daily for 12−65 weeks	Pooled analysis of four trials in the dienogest European study program 332 women with endometriosis, aged 16–47 years across studies Mean age in pooled dienogest group: 30.9 years Patients who completed ≥52 weeks of treatment: n = 152	Generally mild/moderate intensity of adverse events, and premature study discontinuation in 4.5% of women Well-tolerated bleeding pattern associated with treatment, and 0.6% of women reporting bleeding events as primary reason for premature study discontinuation
Lee et al.^29	16.8	Endometrioma recurrence, pain, amenorrhea	Dienogest 2 mg daily for ≥48 weeks postoperatively	Retrospective chart study 514 women with endometriosis, aged 20‒49 years Mean age: 33.9 years Mean duration of patients completing dienogest treatment was 67.4 weeks: n = 305	Endometrioma recurrence: in 1.8% (n = 9) of women over 41 months Pain: mean VAS score decrease of 3.3 and 2.3 mm at 72 and 96 weeks, respectively Amenorrhea: most common adverse event, reported in 66.2% of women
Park et al.^30	16.8	Endometrioma size and recurrence, pain, BMD	Dienogest 2 mg daily for ≥12 months postoperatively	Retrospective chart review 188 women with endometriosis, aged 17‒48 years Mean age: 32.6 years Patients who had completed ≥52 weeks of dienogest treatment: n = 188	Endometrioma size: significant decrease of total cyst diameter at 12 months vs. baseline in both unilateral (n = 40) and bilateral (n = 19) endometrioma (–10.1 and –31.4 mm, respectively, and in both unilateral (n = 24) and bilateral (n = 11) endometrioma at 18 months vs 12 months (n = 35) (–5.8 and –9.2 mm, respectively) (p<.01 for all) Endometrioma recurrence: one case (for a median of 17 months, n = 1/114) Pain: Mean VAS score reduced by 33.5 mm, p<.01, following 12 months of treatment (n = 34)
Seo et al.^49	18.6	BMD, pain	Dienogest 2 mg daily for ≥12 months postoperatively	Prospective cohort study 60 women with endometriosis Mean age: 30.5 years Patients who had completed ≥52 weeks of treatment: n = 60	Pain: Significant decrease of VAS score at 12 months vs baseline (–5.5 mm)
Sugimoto et al.^31	20	Endometrioma size, safety	Dienogest 2 mg daily	Retrospective chart review 75 women with endometriosis Mean age: 42.5 years Patients who had completed ≥52 weeks of treatment: n = 75	Endometrioma size: reduction of average largest cyst diameter to approximately 30% of its initial size at 12 months, 50% of its initial size at 18 months, and <30% of its initial size at 24 months Long-term treatment proved safe
Morelli et al.^32	24	Recurrence	Dienogest + estradiol or LNG-IUD postoperatively	Retrospective chart review 92 women who had undergone laparoscopic conservative surgery for endometriosis Mean age: 33.42 years (dienogest group) and 32.36 years (LNG-IUD group) Patients who completed ≥52 weeks of dienogest treatment: n = 48	Recurrence: in up to 13.6% of patients at 12 months and up to 20.5% at 24 months (n = 92)
Caruso et al.^37	24	Pain, sexual life and function, quality of life	Dienogest 2 mg daily	Prospective study 92 women with endometriosis Mean age: 29.4 years (dienogest group) and 27.4 years (control group)	Pain: dysmenorrhea reduction of 50.3%, 74.5%, 87.2%, 94.6%, and 95.5% at 3-, 6-, 12-, 18-, and 24-months of follow-up vs. baseline, respectively. Dyspareunia reduction of 74.4% at 24-month follow-up vs. baseline (p < .001) Quality of life: improved physical function, physical role, body pain, general health, vitality, mental health, social function, emotional role categories at 24-months vs. baseline (p<.001), and significant improvements in all but vitality and mental health at 3 months (p<.01) Sexual activity: increased quality from 6- to 24-months of follow-up (p<.001) and monthly frequency of sexual activity from baseline to study end (p<.001)
Chandra et al.^33	30.2	Endometrioma recurrence, safety	Dienogest 2 mg daily postoperatively	Retrospective chart review 203 women who had undergone laparoscopic/robotic surgery for ovarian endometrioma Mean age: 34.1 years Patients who had received treatment continuously for 12 ± 7.1 months of treatment: n = 182	Endometrioma recurrence: in three patients (1.5%) for an average follow-up period of 5.7 months from last dienogest treatment to recurrence Tolerable and safe for long-term use
Römer 2018^34	60	Pain, symptom recurrence, safety	Dienogest 2 mg daily for up to 5 years	Retrospective analysis at a single center 37 women with endometriosis Mean age: 39.0 years 22 women postlaparoscopy, 15 women receiving medical treatment without surgery Patients who completed ≥52 weeks of treatment: n = 37	Pain: median decreases in VAS score:  ^ 60 mm at 12 months and 24 months  ^ 50 mm at 36, 48, and 60 months Safety: continued long-term dienogest treatment in daily practice was further studied and annual safety checks are recommended

Abbreviations. BMD, bone mineral density; LNG-IUD, levonorgestrel-releasing intrauterine device; VAS, visual analog scale.

Table 2. Summary of impact of dienogest treatment on lumbar BMD across studies.

Study	Country	N	Mean age, years	BMD time points and duration of treatment	Change in BMD from baseline	Notes
Momoeda et al.^48	Japan	135	34.1	6 months 1 year Mean duration of treatment = 341.5 days	6 months = −1.6 ± 2.4% 1 year = −1.7 ± 2.2%	BMD decrease observed at 24 weeks, no cumulative increase to 48 weeks
Seo et al.^49	Korea	60	30.5	6 months 1 year 2 years Mean duration of treatment = 18.6 months	6 months = −2.2 ± 4.5% 1 year = −2.7 ± 5.4% 2 years = not reported	BMD after 2 years was not significantly different compared with BMD at 1 year (n = 24) 75% of patients experienced a decrease in BMD at 1 year (n = 60) BMD: BMD at the lumbar spine decreased significantly at 12 months vs. baseline (–2.7%) and at the femur neck (–2.8%) with dienogest treatment (p=.001 for both)
Ebert et al.^24 (VISADO)	Europe	103	15.4	1 year Mean duration of treatment = not reported	−1.2 ± 2.3%	70.9% of patients experienced a mean change in BMD of −2.3%, but the majority of patients achieved partial recovery 6 months after the end of treatment (−0.6%)
Park et al.^30	Korea	50	32.6	Patients who received treatment for >18 months Median duration of treatment = 17 months	20% of patients had a BMD lower than expected for age	N/A

Abbreviation. BMD, bone mineral density.

Table 3. Data supporting the efficacy of dienogest for the prevention of postsurgical recurrence.

Study	Duration of dienogest administration	Duration of follow-up	Ovarian recurrence	Pain symptoms
Takaesu et al.^85	6 months	24 months	4/54	N/A
Park et al.^30	17 (12−32) months	18 months	1/114	Pain improvement in 72.6% of patients
Ouchi et al.^82	13.28 ± 4.85 months	13.3 ± 4.9 months	0/7	N/A
Lee et al.^29	72.2 ± 5.2 weeks (range, 48−164)	41 months	9/514	Pain improvement in 82.2% of patients (61.6% “improved”; 20.6% “much improved”)
Chandra et al.^33	12.0 ± 7.1 months (range, 6−35)	30.2 ± 20.9 months	3/203	N/A
Adachi et al.^83	6−36 months	24 months	0/40	Improved
Ota et al.^81	–	61.2 ± 1.1 months	4/151	N/A
Yamanaka et al.^84	31 ± 17.6 months	35 ± 17.6 months	3/59	Endometriosis-related symptoms after operation (VAS >4) 4/59 (6.7%)
Total	6−36 months	13−61 months	24/1142 (2.1%)

Abbreviations. N/A, not available; VAS, visual analog scale.

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