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Evaluation of dienogest treatment efficacy in patients with endometriosis

Abstract

Background

The aim of the study was to evaluate the efficacy and safety of postoperative dienogest treatment in endometriosis patients.

Materials and methods

A total of 53 patients suffering from endometriosis were enrolled. All participants underwent laparoscopic operative treatment. Afterwards, all patients were divided into 2 groups: Group 1 (control group) and Group 2 (receiving dienogest 2 mg/day after surgery). Comparative analysis was performed evaluating patients’ condition and complaints in the postoperative period, the disease dynamics at 3 and 6 months after the surgery, pain assessment (visual analogue scale) and severity of metrorrhagia in both groups.

Results

Postoperative dienogest treatment reduces the severity of symptoms and improves treatment outcomes in endometriosis patients, leading to the improvement of the quality of life in these patients.

Conclusions

Dienogest (2 mg/day) is a highly effective drug for postoperative treatment of patients with endometriosis. Dienogest (2 mg/day) significantly decreases the severity of pelvic pain and metrorrhagia after surgery. The medication is safe and side effects are rare.

J Endometr Pelvic Pain Disord 2017; 9(1): 44 - 49

Article Type: ORIGINAL RESEARCH ARTICLE

DOI:10.5301/je.5000268

OPEN ACCESS ARTICLE

Authors

Julia E. Dobrokhotova, Irina J. Ilyina, Igor I. Grishin, Djamilya M. Ibragimova, Donna M. Kalimatova, Metanat R. Narimanova, Karina R. Bondarenko, Vera J. Ilchenko

Article History

Disclosures

Financial support: No grants or funding have been received for this study.
Conflict of interest: All authors declare that they have no competing interests or financial interest related to this study and have nothing to disclose.

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Introduction

The problem of genital endometriosis is of special importance nowadays due to a steady increase in its prevalence among gynecological patients (10% in recent years) (1, 2). The disease mainly affects women in their reproductive age (90%-99% of patients are aged 20-50 years), regardless of their ethnicity or socio-economic status (2).

Despite the thorough attention to this problem worldwide, many aspects of etiology and pathogenesis of this disease remain controversial (3, 4). Genetic predisposition, retrograde menstruation, coelomic metaplasia, activation of embryonic remnants, changes in the metabolism of endometrial cells, increased proliferative activity and autonomous growth of endometrioid heterotopias, and iatrogenic causes are considered to be the main etiological factors of endometriosis. Risk factors for the development of endometriosis include hyperestrogenemia, early menarche, heavy and prolonged menstrual bleeding, obesity, smoking, stress and unfavorable ecology (2).

Nowadays, it is well recognized that treatment of endometriosis should be comprehensive and divided into several stages. In particular, some authors believe that such treatment should include a combination of operative treatment and hormonal suppressive therapy. One of the most perspective drugs in this scope is dienogest, which has been registered in the Russian Federation in 2011.

Dienogest is distinct from the other derivatives of 19-nortestosterone: it contains 17-alpha-cyanomethyl group instead of 17-alpha-ethynyl group, and an additional double bond in the B-ring. As a result, the size of the molecule, its hydrophobicity and polarity is changed, which affects the absorption, distribution, metabolism and pharmacodynamics of dienogest (1, 5). This drug is a synthetic steroid with a pronounced progestogenic activity (including endometrial), which, at the same time, does not possess any androgenic, estrogenic, antiestrogenic and corticosteroid-like effects (1, 5).

Evaluation of dienogest in a number of clinical studies has demonstrated that the standard dose (2 mg/day for 6-9 months) does not affect lipid metabolism; in this regard, it is similar to progesterone. Another important feature of dienogest is a beneficial effect on the central nervous system (6, 7).

Patients receiving dienogest notice that their sleep, concentration and ability to memorize improve, it also seems to reduce irritability and depression, which is of major importance in patients with endometriosis. Another potential mechanism of dienogest action, important for endometriosis treatment, is associated with its effect on prostaglandin E2, which is involved in the inflammation, proliferation, apoptosis, migration, infiltration and angiogenesis in endometriosis (8). According to some authors, this drug is highly effective at minimal, mild and moderate stages of endometriosis, it is well tolerated and causes fewer side effects than other progestogens (2, 9-10-11). The advantages of dienogest treatment are the absence of menopause-like symptoms, hyperandrogenism, hematological changes and effects on bone mineral density (12, 13).

Laparoscopy is recognized as the most accurate method for the diagnosis and treatment of endometriosis. Laparoscopy not only allows detection of endometriosis lesions and differentiation between endometriosis and malignancies, but it also reveals the cause of chronic pelvic pain and/or infertility in 75% of cases (14). If endometriosis lesions are localized on the surface of peritoneum, the method is 100% informative.

The advantages of dienogest treatment in combination with laparoscopy in endometriosis patients remains largely unexplored, which was the basis for this study.

Material and method

A total of 53 female patients from the gynecological department of the NI Pirogov Moscow City Clinical Hospital No 1 were enrolled.

Inclusion criteria for these 53 patients were: endometriosis, endometrial cysts, chronic pelvic pain syndrome, age (25-40 years).

Exclusion criteria were: endometrial hyperplasia, clinically relevant uterine fibroids.

Deep infiltrative endometriosis was detected in 52% of patients; superficial – in 48% (peritoneum, rectum, appendix). The size of endometrial heterotopias in deep infiltrative endometriosis varied between 0.5 and 4 cm.

Surgical treatment was carried out as the first step. Laparoscopy was performed for all the patients. Surgical treatment included removal of endometrial ovarian cysts in 45 (85%) patients, peritoneal deep infiltrative endometriosis removal in 8 (15%) patients, sacrouterine deep infiltrative endometriosis removal in 12 (23%) patients, removal of endometrial heterotopias of other localizations in 5 (9.4%) patients. Laparoscopy in all participants was performed by the same surgical team.

After the surgery, all the participants were divided into two groups. Group 2 included 33 patients, who underwent operative treatment in 2014-2015 and were treated with dienogest 2 mg/day for 6 months afterwards. Group 1 (control group) included 20 patients whose postoperative period was evaluated retrospectively (operative treatment was performed in 2011-2012, hormone therapy was not prescribed after the surgery). During the course of treatment Protescal was used as an anti-adhesive barrier, containing hyaluronic acid, carboxymethylcellulose and sodium alginate, that provides healing, anti-adhesive and hemostatic effects.

Mean age of the participants was 31 ± 2.5 years in Group 2 and 30 ± 1.5 years in Group 1. The two groups did not differ significantly in terms of patient age and size of endometrial lesions.

Before and after the surgery patients did not receive any other hormonal treatment.

The early postoperative period (up to 1 month after surgery) was being evaluated in all the patients, as well as the dynamics of the manifestations of the disease 3, 6 and 12 months after treatment. Pain assessment was performed according to visual analogue scale (VAS). The severity of metrorrhagia was also estimated.

Pain assessment was differentiated by dysmenorrhea, dyspareunia, dyschezia and chronic pelvic pain.

The severity of metrorrhagia was assessed with the Pictorial Blood loss Assessment Chart scale (PBAC), comparing the proportion of patients in whom blood loss control was achieved (<75 PBAC points during 4 weeks).

Since patients with adenomyosis were included in this study, the bleeding in this group of patients was considered to be associated with adenomyosis.

Superficial endometriosis was accompanied by adenomyosis in 38% of patients in Group 2 and in 32% of patients in Group 1.

Clinical examination included medical history assessment, physical examination, gynecological examination, and a thorough laboratory examination, including CA-125 (Cancer Antigen 125) tests, hormonal status examination, ultrasound examination, abdominal and pelvic computer tomography scan. Examinations were repeated 3, 6 and 12 months after the onset of hormonal treatment.

The most frequent complaints before the treatment were pain - in 47 (88%) cases, pain increasing during menstruation - in 17 (36.6 %) cases, pain during sexual activity - in 10 (21.2%) cases, dysmenorrhea – in 21 (41.5%) cases.

Thorough patient medical history assessment included investigation of the major factors affecting the development of endometriosis (age, heredity, menstrual and reproductive function, the presence and nature of extragenital and gynecological disorders). Other gynecological disorders were estimated, infertility was diagnosed in 31 (58%) patients, uterine fibroids (isolated interstitial nodes up to 1 cm) in 4 (7%) cases, fibrocystic breast disease in 4 (7%), cervical ectopia in 7 (13%) women, chronic inflammatory diseases of the genital tract in 7 (13%) women, adenomyosis in 30 (56%) patients.

Various manifestations of pain syndrome were registered: chronic pelvic pain was found in 35 (66%) women, dysmenorrhea in 21 (42%) women, dyspareunia in 32 (60%) patients (Figs. 1 and 2).

The frequency of various pain manifestations among patients of the control group (Group 1) before treatment and 12 months after the surgery.

The frequency of various pain manifestations among patients of the dienogest 2 mg group (Group 2) before treatment and 12 months after the surgery.

The study was conducted in accordance with ethical principles of the Declaration of Helsinki and approved by NI Pirogov Russian National Research Medical University Ethics Committee. Written informed consent was obtained from all participants.

Statistical analysis was performed using the statistical software “STATISTICA 10”. The normality of the parameters distribution in groups was verified using the Kolmogorov-Smirnov criterion. In the case of normal distribution of data, an arithmetic mean (M) and standard deviation (SD) were calculated. Tests of hypotheses for equality of two means were performed using Student’s t-test. In small groups and vagueness of the rule of values distribution, the descriptive statistics included the definition of the median (Me) and interquartile range (25-75), for significant differences non-parametric Mann-Whitney U-test was used. To assess the validity of the changes within the same group before and after the treatment paired Student’s t-test and the non-parametric Wilcoxon singed-rank test were used. We made calculations of structure indicators (in%). Determination of the significance of differences between the quality parameters was performed using chi-square test (χ2), the odds ratio (OR) and confidence interval (CI). A probability value of p<0.05 was considered statistically significant.

Results

Before the treatment, most patients complained of apparent pain - the average value of subjective pain assessment by VAS was above 7 in both groups (Tab. I). One month after the onset of hormonal treatment the majority of patients noted a reduction of pain syndrome, with no significant differences between groups. However, 3 months after treatment VAS points were significantly lower (p<0.05) in Group 2. At 6 and 12 months after the onset of this study, most of the patients in Group 2 had no pain at all, while among the patients of the control group a slight increase in VAS indices was registered.

The dynamics of dysmenorrhea, dyspareunia and chronic pelvic pain intensity before and after the onset of treatment, assessed with VAS (points)

   Symptoms
Dysmenorrhea Dyspareunia Chronic pelvic pain
Visits Group 1 (controls) (n = 9) Group 2 (dienogest 2 mg/day) (n = 12) Group 1 (controls) (n = 9) Group 2 (dienogest 2 mg/day) (n = 12) Group 1 (controls) (n = 9) Group 2 (dienogest 2 mg/day) (n = 12)
Medians and limits of interquartile range are presented (25%-75%).
** p<0.05 = statistically significant differences in comparison to initial indices (Wilcoxon signed-rank test).
VAS = visual analogue scale.
Before treatment 8 (7-9) 8 (7-9) 7 (5-9) 7 (4-8) 4 (1-6) 4 (1-5)
After surgery
 1 month 6 (5-7) 5 (4-6) 5 (3-7) 4 (2-6) 3 (0-5) 2 (1-4)
 3 months 5 (4-6) 3 (2-4)** 5 (4-6) 4 (1-5)** 3 (0-6) 2 (1-4)
 6 months 6 (5-7) 2 (1-3)** 4 (5-7) 3 (1-4)** 2 (0-5) 2 (0-3)
 12 months 6 (5-7) 2 (1-3)** 5 (3-7) 3 (1-5)** 2 (0-5) 1 (0-2)**

Menstrual pain severity was almost 3 times lower among patients receiving dienogest.

Dienogest therapy after surgical treatment of endometriosis reduces the severity of dyspareunia (1.5 times lower in dienogest group), and chronic pelvic pain intensity (2 times lower in dienogest group) (Figs. 1, 2).

Dysmenorrhea was registered in 9 (45%) cases, dyspareunia in 13 (65%) cases, chronic pelvic pain in 12 (60%) patients in the control group. Twelve months after the onset of hormonal therapy, a statistically significant decrease in the incidence of dyspareunia - 5 (25%) cases, (p<0.05), and chronic pelvic pain – 4 (20%) cases, (p<0.05) was registered. In contrast, we found no statistical significance for a two-fold reduction in the prevalence of dysmenorrhea 1 year after the surgery 4 (20%) cases (p<0.05).

In Group 2, dysmenorrhea was registered in 12 (37%) cases, dyspareunia in 19 (58%), chronic pelvic pain in 23 (70%) cases (Fig. 2). Twelve months after the onset of the hormonal therapy, rates of these disorders decreased significantly compared to the relevant indicators before the treatment. None of the patients suffered from dysmenorrhea (p<0.05), dyspareunia rates demonstrated 4.7-fold reduction in 4 (12%) patients, p<0.05), and the prevalence of chronic pelvic pain decreased 7.7-fold in 3 (9%) cases, p<0.05).

The likelihood of uterine bleeding control at 6 months after the onset of treatment was 3.82 times higher (OR 3.82; 95% CI 1.62-12.5, p<0.05) in dienogest (postoperative treatment) group compared to surgery alone. Similar trends and risk ratios were registered 1 year after the onset of therapy (OR 3.71; 95% CI 1.11-12.5, p<0.05).

In Group 2 the pain almost disappeared during first months of treatment.

Menstrual cycle normalization in 32 (97%) patients of the Group 2 was observed within 1.5-2 months after the onset of hormonal therapy (normalization of the menstrual cycle implies a reduction of pain syndrome, decrease of blood loss), whereas in the control group, pain and dysmenorrhea returned in some patients 6 months after treatment.

In one (3%) patient (Group 2) a spontaneous pregnancy occurred in the 6th week of dienogest treatment. Therapy was discontinued at that point. The patient was under supervision during the pregnancy. Pregnancy terminated with spontaneous labor at 38 weeks. A female healthy child was born, Apgar score 8-9.

Analysis of clinical examination and instrumental data results did not reveal any pathological signs throughout the study. There were no adverse events.

Evaluation of laboratory tests results performed during the study demonstrated no changes beyond the reference values neither in a total blood count (Tab. II) nor in biochemical parameters (Tab. III) and coagulogram tests (Tab. IV) before the treatment, 6 and 12 months after the onset of the study.

Results of full blood count in patients with endometriosis before the treatment, 6 and 12 months from the onset of dosing

Parameters Before treatment 6 months after treatment 12 months after treatment
Group 1 (n = 20) Group 2 (n = 33) Group 1 (n = 20) Group 2 (n = 33) Group 1 (n = 20) Group 2 (n = 33)
Data are presented as mean ± standard error of the mean.
* p<0.05 = statistically significant differences in respect to similar indicators in the comparison group (Student’s t-test).
** p<0.05 = the differences were statistically significant compared to baseline (paired Student’s t-test).
RBC = red blood cells; PLT = blood platelets; WBC = white blood cells; ESR = erythrocyte sedimentation rate.
RBC, ×10E6/uL 4.30 ± 0.28 4.46 ± 0.35 4.39 ± 0.26 4.35 ± 0.16 4.26 ± 0.18 4.31 ± 0.22
Hemoglobin, g/dL 13.6 ± 0.8 14.1 ± 0.4 13.7 ± 0.6 13.9 ± 0.5 13.2 ± 1.5 13.5 ± 0.7
Hematocrit, % 43.2 ± 2.8 44.1 ± 0.8 42.8 ± 0.6 44.0 ± 1.8 43.6 ± 2.8 44.4 ± 3.0
PLT, ×10E3/uL 242.5 ± 23.4 256.7 ± 18.6 253.1 ± 21.4 261.3 ± 27.2 246.5 ± 31.0 256.7 ± 23.4
WBC, ×10E3/uL 5.12 ± 0.63 5.25 ± 0.19 5.36 ± 0.21 5.29 ± 0.30 5.32 ± 0.18 5.24 ± 0.23
ESR, mm/h 6.1 ± 0.8 6.6 ± 1.3 7.0 ± 0.8 7.1 ± 1.2 6.8 ± 1.1 7.0 ± 0.8

Results of clinical biochemistry in patients with endometriosis before the treatment, 6 and 12 months from the onset of dosing

Parameters Before treatment 6 months after surgery 12 months after surgery
Group 1 (n = 20) Group 2 (n = 33) Group 1 (n = 20) Group 2 (n = 33) Group 1 (n = 20) Group 2 (n = 33)
Data are presented as mean ± standard error of the mean.
* p<0.05 = statistically significant differences in respect to similar indicators in the comparison group (Student’s t-test).
** p<0.05 = the differences were statistically significant compared to baseline (paired Student's t-test).
HDL-cholesterol = high-density lipoprotein cholesterol; LDL-cholesterol = low-density lipoprotein cholesterol; VLDL-cholesterol = very low-density cholesterol; AST = aspartate aminotransferase; ALT = alanine aminotransferase.
Total cholesterol, mmol/L 4.52 ± 0.28 4.82 ± 0.23 4.68 ± 0.22 4.51 ± 0.12 4.56 ± 0.31 4.45 ± 0.22
HDL-cholesterol, mmol/L 1.22 ± 0.09 1.30 ± 0.12 1.15 ± 0.16 1.25 ± 0.16 1.20 ± 0.12 1.28 ± 0.26
LDL-cholesterol, mmol/L 2.58 ± 0.23 2.75 ± 0.18 2.80 ± 0.21 2.70 ± 0.31 2.97 ± 0.32 2.80 ± 0.27
VLDL-cholesterol, mmol/L 0.59 ± 0.07 0.70 ± 0.04 0.65 ± 0.07 0.68 ± 0.05 0.74 ± 0.11 0.65 ± 0.09
Triglyceride, mmol/L 1.58 ± 0.21 1.42 ± 0.15 1.51 ± 0.13 1.57 ± 0.23 1.60 ± 0.14 1.55 ± 0.17
Fasting glucose, mmol/L 5.38 ± 0.19 5.42 ± 0.21 5.51 ± 0.16 5.60 ± 0.26 5.43 ± 0.22 5.57 ± 0.16
Urea, mmol/L 4.32 ± 0.30 4.45 ± 0.18 4.26 ± 0.22 4.31 ± 0.41 4.19 ± 0.30 4.33 ± 0.29
Uric acid, mmol/L 248 ± 30 256 ± 24 260 ± 19 239 ± 31 244 ± 23 248 ± 30
Total bilirubin, mmol/L 8.8 ± 1.5 9.0 ± 0.8 7.6 ± 1.2 8.5 ± 1.1 7.2 ± 1.1 8.3 ± 0.9
АSТ, U/L 18.4 ± 2.1 20.5 ± 1.8 19.2 ± 3.0 16.0 ± 3.8 18.4 ± 4.2 17.1 ± 2.6
АLТ, U/L 16.5 ± 1.8 18.2 ± 2.0 17.0 ± 1.6 16.9 ± 2.5 16.8 ± 2.4 16.4 ± 3.2

Coagulogram results in patients with endometriosis before the treatment, 6 and 12 months from the onset of dosing

Parameters Before treatment 6 months after surgery 12 months after surgery
Group 1 (n = 20) Group 2 (n = 33) Group 1 (n = 20) Group 2 (n = 33) Group 1 (n = 20) Group 2 (n = 33)
Data are presented as mean ± standard error of the mean.
* p<0.05 = statistically significant differences in respect to similar indicators in the comparison group (Student’s t-test).
** p<0.05 = the differences were statistically significant compared to baseline (paired Student's t-test).
INR = international normalized ratio; aPPT = activated partial thromboplastin time.
INR 1.06 ± 0.18 1.12 ± 0.07 1.08 ± 0.15 1.02 ± 0.21 1.05 ± 0.11 1.10 ± 0.16
aPPT, sec 31.2 ± 2.9 30.5 ± 4.1 29.3 ± 5.0 31.4 ± 3.8 32.3 ± 4.9 30.9 ± 3.5
Fibrinogen, g/L 2.18 ± 0.31 2.28 ± 0.15 2.21 ± 0.33 2.34 ± 0.19 2.33 ± 0.18 2.24 ± 0.21
Antithrombin III, % 102.3 ± 5.9 97.4 ± 10.3 104.5 ± 6.2 101.8 ± 12.4 107.3 ± 7.6 99.2 ± 9.0

Low libido during treatment was reported by 1 (3%) patient from Group 2. No other side effects were registered.

Discussion

The study revealed that postoperative dienogest treatment (2 mg/day) in endometriosis patients reduces severity of symptoms and improves treatment outcomes. These symptoms are the main causes of life quality decline among patients suffering from endometriosis.

In particular, dyspareunia caused by endometriosis develops due to the presence of endometrial nodes on the sacrouterine ligaments, in the pouch of Douglas, on the posterior wall of the vagina and anterior wall of the rectum. Pain during sexual activity in this group of patients is generally caused by the mechanical stimulation of the endometrial lesions and stretching of parametrium, which elasticity is decreased, and by the fixation of rectouterine structures of pelvis.

Researchers currently believe that the basic principle of hormonal therapy of endometriosis is suppression of estradiol secretion by the ovaries to the levels below 40 pg/mL in the peripheral blood, which corresponds to a postmenopausal level (15-16-17). The calculation is based on the ability of the drug to maintain systemic hypoestrogenia over a long period – at least for 6 months – which is believed to be enough for irreversible atrophic changes in endometriosis lesions (2). It has been demonstrated that progestogens have high efficacy in endometriosis treatment. These drugs help to successfully reduce manifestations of the disease, decrease the frequency of relapses, complement a comprehensive treatment, and, if necessary, restore the reproductive function (18). The results obtained in our study are consistent with these data.

The search for an effective and long-term method of treatment that would be acceptable for women of different ages with various forms of endometriosis, which would have had a systemic therapeutic effect and anti-recurrence success, minimizing the risk of estrogen-deficiency consequences, in recent decades has been directed towards the progestogens, and has become possible since the advent of dienogest. Pronounced antiproliferative properties were observed, on the one hand, in a number of studies, showing that the molecule of dienogest, along with the ability to induce secretory conversion due to activation of specific receptors – common for all gestagens – is also an antagonist of angiogenesis, and promotes the inhibition of protein kinase C, providing an additional impact on endometrial cells, that is not associated with the effect of progestogens. Several clinical studies have demonstrated a significant reduction in menstrual blood loss in women who used combined oral contraceptives (COCs) containing dienogest (3, 8-9-10-11).

Our strategy is consistent with most researchers, recognizing the dominant role of surgery in the treatment of all forms of endometriosis, and therefore we give preference to a combination of surgical treatment with subsequent hormone therapy in endometriosis patients.

This study is ongoing; this article presents the preliminary results.

At the same time, it should be emphasized that without prejudice to the merits of surgery, hormone therapy should also be considered in treatment of endometriosis.

Results of this study lead to an important insight about the possibility of long-term dienogest monotherapy in out-patients suffering from pelvic pain, and postoperative anti-recurrence treatment in women who are not planning their pregnancies right after surgical treatment.

Conclusion

Results of this study demonstrate that dienogest 2 mg/day can be recommended for postoperative hormonal treatment in patients suffering from endometriosis. Dienogest 2 mg/day is highly effective in reducing the severity of pain and metrorrhagia. This medicine is safe and side effects are rare. More prospective studies are needed in this field. In future studies, we plan to compare various modes of postoperative hormonal treatment in endometriosis patients.

Disclosures

Financial support: No grants or funding have been received for this study.
Conflict of interest: All authors declare that they have no competing interests or financial interest related to this study and have nothing to disclose.
References
  • 1. Caruso S Iraci M Cianci S Casella E Fava V Cianci A Quality of life and sexual function of women affected by endometriosis-associated pelvic pain when treated with dienogest. J Endocrinol Invest 2015 38 11 1211 1218 Google Scholar
  • 2. Greco E Pellicano M Di Spiezio Sardo A et al. (Etiopathogenesis of endometriosis related infertility). Minerva Ginecol 2004 56 3 259 270 Google Scholar
  • 3. Harada T Taniguchi F Dienogest: a new therapeutic agent for the treatment of endometriosis. Womens Health (Lond) 2010 6 1 27 35 Google Scholar
  • 4. Petraglia F Hornung D Seitz C et al. Reduced pelvic pain in women with endometriosis: efficacy of long-term dienogest treatment. Arch Gynecol Obstet 2012 285 1 167 173 Google Scholar
  • 5. Köhler G Faustmann TA Gerlinger C Seitz C Mueck AO A dose-ranging study to determine the efficacy and safety of 1, 2, and 4mg of dienogest daily for endometriosis. Int J Gynaecol Obstet 2010 108 1 21 25 Google Scholar
  • 6. Shimizu Y Mita S Takeuchi T Notsu T Mizuguchi K Kyo S Dienogest, a synthetic progestin, inhibits prostaglandin E2 production and aromatase expression by human endometrial epithelial cells in a spheroid culture system. Steroids 2011 76 1-2 60 67 Google Scholar
  • 7. Sugimoto K Nagata C Hayashi H Yanagida S Okamoto A Use of dienogest over 53 weeks for the treatment of endometriosis. J Obstet Gynaecol Res 2015 41 12 1921 1926 Google Scholar
  • 8. Cosson M Querleu D Donnez J et al. Dienogest is as effective as triptorelin in the treatment of endometriosis after laparoscopic surgery: results of a prospective, multicenter, randomized study. Fertil Steril 2002 77 4 684 692 Google Scholar
  • 9. Strowitzki T Faustmann T Gerlinger C Seitz C Dienogest in the treatment of endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebo-controlled study. Eur J Obstet Gynecol Reprod Biol 2010 151 2 193 198 Google Scholar
  • 10. Strowitzki T Marr J Gerlinger C Faustmann T Seitz C Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial. Hum Reprod 2010 25 3 633 641 Google Scholar
  • 11. Strowitzki T Faustmann T Gerlinger C Schumacher U Ahlers C Seitz C Safety and tolerability of dienogest in endometriosis: pooled analysis from the European clinical study program. Int J Womens Health 2015 7 393 401 Google Scholar
  • 12. Momoeda M Harada T Terakawa N et al. Long-term use of dienogest for the treatment of endometriosis. J Obstet Gynaecol Res 2009 35 6 1069 76 Google Scholar
  • 13. Schindler AE Dienogest in long-term treatment of endometriosis. Int J Womens Health 2011 3 175 184 Google Scholar
  • 14. Bassi MA Podgaec S Dias JA Jr DAmico Filho N Petta CA Abrao MS Quality of life after segmental resection of the rectosigmoid by laparoscopy in patients with deep infiltrating endometriosis with bowel involvement. J Minim Invasive Gynecol 2011 18 6 730 733 Google Scholar
  • 15. Bizzarri N Remorgida V Leone Roberti Maggiore U et al. Dienogest in the treatment of endometriosis. Expert Opin Pharmacother 2014 15 13 1889 1902 Google Scholar
  • 16. Granese R Perino A Calagna G et al. 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 Google Scholar
  • 17. Vercellini P Bracco B Mosconi P et al. Norethindrone acetate or dienogest for the treatment of symptomatic endometriosis: a before and after study. Fertil Steril 2015 Epub ahead of print. Google Scholar
  • 18. Grandi G Mueller M Bersinger NA Cagnacci A Volpe A McKinnon B Does dienogest influence the inflammatory response of endometriotic cells? A systematic review. Inflamm Res 2015 Epub ahead of print. Google Scholar

Authors

Affiliations

  • Department of Obstetrics and Gynecology, N.I. Pirogov Russian National Research Medical University, Moscow - Russian Federation

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