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PURPOSE To study the efficacy and safety of the dienogest and the gonadotropin-releasing hormone agonist (GnRH-a) in symptomatic females with uterine adenomyosis. METHODS A total of 127 patients with adenomyosis with a chief complaint of dysmenorrhea were recruited. The first group received 2 mg of dienogest (DNG) daily, whereas the second group received goserelin acetate (GS) (3.6 mg/4 weeks) for 12 weeks. Outpatient follow-up was undertaken after 12 weeks. RESULTS Among 127 women, 56/63 (88.9%) patients completed the treatment in the DNG group, whereas 62/64 (96.9%) patients completed the treatment in the GS group. A significant decrease in dysmenorrhea symptoms as measured by the visual analog scale (VAS) and Carcinoma antigen125 (CA125) after 12 weeks of treatment was observed in both groups (p

Peritoneal inclusion cysts, which are also known as ‘peritoneal mesothelial cysts’ and ‘residual ovarian syndrome’, often form in the peritoneum or the pelvis after surgery or as a result of endome...

Purpose: To evaluate differences in key outcomes between younger and older women receiving the oral contraceptive oestradiol valerate/dienogest (E2V/DNG). Methods: We conducted a pooled post hoc analysis of primary data from 12 studies of E2V/DNG, stratified by age (≤25 [n = 1309] and >25 [n = 2132] years). Outcomes included safety, efficacy, bleeding profile and hormone-withdrawal-associated symptoms (HWAS). Bleeding and HWAS analyses are also presented for women aged ≤20 years (n = 362). Discontinuations were considered a proxy for patient satisfaction. Results: Results were generally similar for younger and older women. The percentage of women aged ≤25 and >25 years experiencing intracyclic bleeding did not differ between groups (13.4% and 12.8% at cycle 12, respectively), with similar results in women aged ≤20 years (12.7%, cycle 12). Rates of withdrawal bleeding were very similar in women aged ≤25 and >25 years (78.5% and 78.9%, respectively, cycle 12). We also found a similar adjusted Pearl index in the two age groups (0.45 vs 0.57, respectively), similar rates of AEs and HWAS and no difference in discontinuations. Conclusions: Women aged ≤25 and >25 years have a similar experience with an E2V/DNV oral contraceptive, supporting this as an appropriate contraceptive option in younger and older women.

Studies have been published on the efficacy of Dienogest in the management of pain symptoms in endometriosis. Nonetheless, few data are available on the reducing effect on endometrioma's size. The aim of the study was to evaluate if Dienogest could determine significant changes in size, as well as in symptoms. In this prospective observational study, patients were enrolled with pain symptoms and at least one endometrioma diagnosed via TV-US. The volume of the endometrioma and pain symptoms was measured according to the LxDxWx0.5233 formula and VAS, respectively. Dienogest 2 mg was administered daily. Follow-up visits were scheduled after 6 and 12 months of treatment to assess changes in patients' symptoms and endometrioma's volume. Seventy patients were enrolled, 63 patients completed a 6-month treatment. The reduction of the mean volume after 6 months was 66.71%. Fifty-eight patients completed the 12 month-treatment. The reduction of the mean volume after 12 months was 76.19%. Dysmenorrhea showed a 74.05% reduction after 6 months and a 96.55% reduction after 12 months. Patients reported a reduction in dyspareunia and chronic pelvic pain of 42.71% and 48.91% after 6 months and 51.93% and 59.96% after 12 months, respectively. Dienogest leads to a statistically significant reduction of endometrioma's volume and pain symptoms.

The aim of the present study was to evaluate whether hormone therapy containing dienogest is effective in reducing endometrioma size. A retrospective observational study was conducted on 116 women with endometrioma which was evaluated after 6 and 12 months of either no treatment (

This study elucidated the degree of adenomyosis recurrence following gonadotropin-releasing hormone agonist (GnRHa) discontinuation and dienogest efficiency for recurrent adenomyosis. This retrospective cohort study included 30 patients, divided into a group of patients whose progress was observed without providing additional therapy following GnRHa administration for six months (Group G) and a group of patients administered dienogest for six months following six months of GnRHa administration (Group D). Menorrhagia, dysmenorrhea, chronic pelvic pain, abdominal fullness, and uterine volume were recorded prior to treatment, six months after the start of therapy (6 M), and 12 months after the start of therapy (12 M). In Group G (

Objectives: To estimate the real-use contraceptive effectiveness of the combined oral contraceptive (COC) containing dienogest and oestradiol valerate (DNG/oEV) compared to other combined o...

Purpose: The aim of the study was to examine the discontinuation rate of hormonal contraception with estradiol valerate (E2V) and dienogest (DNG). Patients and methods: We collected data at the Family Planning Clinics of the Departments of Obstetrics and Gynecology of Pisa and Cagliari. We included in the analysis 354 consecutive women using oral contraceptive pills containing E2V and DNG. We analyzed the rate and the reason for discontinuation, classifying the reasons in 5 categories: 1) minor side effects, 2) adverse events, 3) other events not directly caused by the drug or conditions for which the pill could represent a risk factor, 4) no compliance with the method and 5) no further need. Results: Of the 354 women examined, 50.8% had discontinued E2V/DNG pill. Excluding women who stopped the pill because of no further need (10.5%), 27.4% discontinued because of minor side effects, 1.7% discontinued for adverse events, 9.9% because of other events not directly caused by the drug or conditions for which the pill could represent a risk factor and 1.4% because of difficulties with compliance. Irregular bleedings were the main reasons reported for discontinuation. The time to discontinuation for irregular bleedings was significantly (p

The aim of the study was to evaluate dyspareunia and sexual function (SF) in women with deep infiltrating endometriosis (DIE) who were treated with dienogest (DNG) for 12 months. The prospective cohort study took place at the University of Campinas, Brazil, and included 30 women with sonographic diagnosis of DIE and sexual dysfunction treated with 2 mg/daily DNG for 12 months. SF parameters were assessed by the Female Sexual Function Index (FSFI) before and after treatment, and dyspareunia was quantified through the visual analog scale (VAS) during the follow-ups performed every three months. Statistical analysis was performed by ANOVA test and through the use of software SAS, Version 9.4. Women were on average 36.13 ± 6.24 years old, and all of them showed sexual dysfunction (FSFI =17.6 ± 5.7) before DNG; 88.3% had dyspareunia as the main symptom related to DIE (VAS before: 5.3 ± 3.1). At the end of the treatment, dyspareunia showed a decrease of intensity (VAS after: 3.7 ± 3.3; p = .0093) and an improvement on FSFI index was accomplished (p = .0023); however, it did not restore SF completely, considering the FSFI cutoff < 26.55. Long-term treatment for DIE with DNG has provided a decrease in dyspareunia and also an enhancement of SF, although SF has not been restored to normal levels Fechado

Ovarian endometriosis is a common gynecological disorder. To date, progestins are recommended as the first-line medical treatment for symptomatic ovarian endometriosis. The aim of this study was to evaluate the main histopathological effects of short-term dienogest therapy in patients with ovarian endometriomas scheduled for surgery. A prospective, nonrandomized controlled trial, including 70 symptomatic women with single ovarian endometriotic cyst (diameter between 30–50 mm) was conducted. Women scheduled for surgery were divided into two groups, depending on the treatment established at enrollment: 36 women received progestin therapy with dienogest (P group) and 34 women received no therapy (C group). At histopathological examination necrosis, inflammation, decidualization, glandular atrophy and angiogenesis were blindly evaluated. At tissue level, decidualization was significantly more frequent in P group compared to C group (p = .001). A nonsignificant tendency (p = .29) towards a slight decreased inflammation in P group was found. No significant differences were observed between the two groups in terms of necrosis, glandular atrophy and angiogenesis. The study suggests that high decidualization rate and the tendency to reduced inflammatory reaction in the short-term administration of dienogest might contribute to its therapeutic efficacy.

John Palacio-Cardona,1 Diana María Caicedo Borrero2 1Student Welfare Service – Health Area, Santiago de Cali University, 2Support for Research, Academic, Scientific and Technological Services (SEACIT), Cali, Colombia Abstract: Acne vulgaris is the most common skin disease. It affects the young adult female population and generates great impact on physical and mental health. One of the treatments with good results for affected women is combined oral contraceptive pills (COCPs). The aim of this study was to determine the clinical effect of facial acne management with ethinylestradiol 20µg/dienogest 2mg in a cohort of Colombian adult women. A cohort of 120 female university students was followed for 12months. These participants were enrolled in the Sexual and Reproductive Health Program of the Santiago de Cali University. This cohort admitted women between 18and 30years old who had chosen to start birth control with ethinylestradiol 20 µg/dienogest 2 mg COCPs, did not have contraindi­cations to the use of COCPs, and had been diagnosed with acne. Monthly monitoring of facial acne lesion count was performed. Relative changes in facial lesion count were identified. At the end of follow-up, the percentage of reduction of lesions was 94% and 23% of women had a 100% reduction in acne lesions. In conclusion, the continued use of the ethinylestradiol 20 µg/dienogest 2 mg COCPs reduced inflammatory and non-inflammatory acne lesions in reproductive-age women between 18 and 30years of age with no severe acne. Keywords: skin diseases, acne vulgaris, reproductive control agents, contraceptive agents, female contraceptive agents, oral, hormonal

Endometriosis is an estrogen-dependent chronic inflammatory disorder that requires a life-long management plan. Long-term adherence to treatment is pivotal to ensure an effective clinical management. In this optic, one of the cornerstone of endometriosis medical treatment is represented by progestins. Areas covered: This narrative review examines the clinical efficacy, safety and tolerability of oral and depot progestins used in the treatment of endometriosis. The material included in the current manuscript was obtained with a MEDLINE search through PubMed from inception until February 2017. Expert opinion: Progestins are effective in controlling pain symptoms in the majority of women with endometriosis, and their effect seems not inferior to that achieved with other compounds used to treat the disease, such as gonadotropin-releasing hormone agonist. Available progestins include a broad range of both oral and depot compounds, and represent, in most cases, an inexpensive treatment option. In addition, progestins do not increase significantly thrombotic risk and could be adopted in those women with metabolic or cardiovascular contraindication to estrogen-progestins. The choice between the different available compounds should be tailored for every woman with preference to the most cost-effective treatment, depending on the most complained symptom and disease location.

The most recent evidences suggest the use of progesterone mimicking drugs for the treatment of endometriosis. Particularly, dienogest has been largely tested. However, the standard treatment of extra-pelvic endometriosis is debated. Particularly, cerebral localization of endometriosis is a very rare clinical condition. The surgical approach for such a particular disorder would consist in difficult procedures, thus leading to prefer the medical treatment. We hereby report the clinical case of a cerebral localization of endometriosis treated with dienogest who experienced a complete remission of the disease.

Endometriosis affects up to 10% of reproductive-aged women; with higher prevalence among patients suffering from dysmenorrhea, infertility and chronic pelvic pain (CPP). Early detection is the basis of targeting at time therapy. Administration of GnRH-agonists (GnRHa) is limited with its safety and portability. Dienogest administration as the stage of preparation to in vitro fertilization (IVF) may provide the preparative pre-gravid reserve. Fifty-six infertile patients with adenomyosis and previous IVF failures were recruited for prospective cohort study. The treatment followed the unique algorithm created using clinical experience. Post-transfer support was also considered. The aims included evaluation of dienogest effectiveness for different stages of adenomyosis; working out the schemes of dienogest therapy prior to IVF; evaluation of IVF effectiveness after dienogest administration. Patients with adenomyosis grade I–II demonstrated encouraging results: normalisation of menstrual function in 6...

Endometriosis is a chronic, estrogen-dependent, inflammatory disease that mainly affects women of reproductive age and is defined by the presence of endometrial glands and stroma at ectopic sites. Spontaneous hemoperitoneum due to bleeding of pelvic endometriotic foci represents a very rare and severe complication of endometriosis, although most cases described in literature regard pregnant women. We hereby present a case of a severe hemoperitoneum in a non-pregnant, 42 years old woman, under dienogest therapy for deep endometriosis. This life-threatening condition was promptly managed by performing an exploratory laparoscopy where the source of bleeding was found and hemostasis successfully achieved.Bleeding from pelvic endometriotic foci ought to be considered in the differential diagnosis of gynecological causes of acute abdomen and hemoperitoneum, even under medical therapy.

This study assessed the relief of uterine bleeding and clinical symptoms during cyclic administration of dienogest for the treatment of endometriosis.In total, 25 patients undergoing ovarian cyst enucleation and given dienogest participated in this study. Dienogest 2 mg/day was administered for 3 weeks, and the drug was then withdrawn for 1 week (cyclic administration of dienogest). This 4-week cycle was repeated six times. Patients' records were prospectively analyzed for the number of days on which any uterine bleeding occurred, as well as menstrual pain before and after the start of dienogest administration were evaluated with a view to using the data obtained herein as the basis.During the period of cyclic administration of dienogest, uterine bleeding occurred on 5.8 to 7.7 days per 4-week period on an average through cycles. Of uterine bleeding episodes, menstruation-like uterine bleeding was present in about 80% of patients. The visual analog scale (VAS) value for menstrual pain significantly decreased from 3.8 before dienogest administration after surgery to 1.5 at the completion of cycle 1, VAS remained low thereafter.These results raise the possibility that cyclic administration of dienogest may relieve lessen uterine bleeding, a major adverse event and menstrual pain.

Adenomyosis is a common disorder in premenopausal women that causes dysmenorrhea, pelvic pain and menorrhagia. Considering that adenomyosis is an estrogen-dependent disease, the medical treatment is based on this hormone. Effective and well-tolerated medical treatments for symptomatic adenomyosis are needed. Dienogest, an oral progestin, has been extensively investigated in the treatment of endometriosis. In this report, we present the results on the efficacy and safety of dienogest in the treatment of symptomatic adenomyosis. Seventeen patients with symptomatic adenomyosis were included in this study, of which 15 continued dienogest for up to 24 weeks. Dienogest significantly reduced adenomyosis-associated pelvic pain as well as serum CA-125 and CA19-9 levels. It also demonstrated a modest suppression of estradiol (50 pg/ mL), which is consistent with the findings of other reports. During treatment, five patients experienced worsening anemia because of metrorrhagia, which is the most frequent adverse effect associated with dienogest. This report suggests that dienogest is an effective and well-tolerated therapy for symptomatic adenomyosis.

This systematic review examined the use of progestogens or oral contraceptives and gonadotropin-releasing hormone (GnRH) agonists for the treatment of endometriosis.Inclusion criteria were: i) randomized controlled trials (RCTs); ii) comparison of progestogens with GnRH agonists for treatment of endometriosis; and iii) endometriosis diagnosed by laparoscopy or laparotomy.Pelvic pain, bone mineral density, serum estradiol level, and side effects.Of 128 articles identified, there were four RCTs comparing the use of progestogens and GnRH agonists. In three studies a progestogen (gestrinone, lynestrenol, or dienogest) was compared with leuprolide. In one study, ethinyl estradiol/norethindrone was compared with leuprolide/norethindrone. A meta-analysis was not possible as the studies varied markedly in their protocols, inclusion criteria, and the drugs and doses administered. Leuprolide was as effective as gestrinone, dienogest, and continuous oral contraceptives (OCs) for the relief of endometriosis-related pain, whereas it was superior to lynestrenol. Leuprolide was associated with a significant reduction in bone mineral density and estradiol levels and a higher incidence of hot flushes, headaches, mood changes, and vaginal dryness, whereas progestogens were associated with higher incidences of weight gain and acne.These results suggest that progestogens or OCs may be used as first-line therapy for endometriosis.

Introduction: The pharmacodynamic effects of various combined oral estrogen-progestin combinations (COC) are examined for their components alone or in the various combined formulations. Special emphasis is given to products containing natural estrogens.Areas covered: Recent information on the effect of androgens, estrogens, progestins, as well as various COC combinations on the coagulation cascade will be reviewed aiming at providing an updated picture.The present article reviews hemostatic changes occurring during use of classic and modern combinations of estrogens (ethinyl estradiol, estradiol, estradiol valerate and estetrol) and new progestins (desogestrel, gestodene, dienogest, drospirenone, nomegestrol acetate), compared to classic compounds, such as levonorgestrel.Both pro- and anti-coagulatory effects of COC in healthy women are detailed and possible links with incidence of thromboembolic events are discussed.Expert commentary: Overall, the picture is reassuring: the use of natural estroge...

Deep endometriosis involvement of the bladder is uncommon but it is symptomatic in most of the cases. Although laparoscopic excision is very effective, some patients with no pregnancy desire require a medical approach. We performed a pilot study on the effect of a new progestin dienogest on bladder endometriosis. Six patients were treated for 12 months with dienogest 2 mg/daily. Pain, urinary symptoms, quality of life, nodule volume and side effects were recorded. During treatment, symptoms improved very quickly and the nodules exhibit a remarkable reduction in size. Dienogest may be an alternative approach to bladder endometriosis.

Evaluation of: Jensen JT, Parke S, Mellinger U, Machlitt A, Fraser I. Effective treatment of heavy menstrual bleeding with estradiol valerate and dienogest: a randomized controlled trial. Obstet. Gynecol. 117(4), 777–787 (2011).Heavy menstrual bleeding (HMB) is one of the most common reasons for women to seek gynecological care. Surgical and medical treatments have been proposed, including hysterectomy, endometrial ablation, oral progestins, the levonorgestrel-releasing intrauterine system, mefenamic acid and combined oral contraceptives (COCs). Although COCs have been used extensively to control HMB, there is little evidence of their efficacy. A new COC containing estradiol valerate and dienogest was compared with placebo in a randomized clinical trial that included women with objectively confirmed HMB in whom blood loss was measured using the alkaline hematin method. Over 6 months of treatment, results showed that blood loss decreased significantly in COC users, both when compared with a placebo group a...

Objectives To evaluate the efficacy of oestradiol valerate/dienogest (E2V/DNG) for the treatment of heavy and/or prolonged menstrual bleeding without organic pathology based on the analysis of data from two identically designed double-blind, randomised studies. Methods Women aged ≥ 18 years with heavy and/or prolonged menstrual bleeding were randomised to E2V/DNG (n = 269) or placebo (n = 152) for 196 days. Objective changes in menstrual blood loss (MBL) volume were assessed using the alkaline haematin method. Results After six months of treatment, median MBL decreased by 88% with E2V/DNG compared with 24% with placebo. The greatest reduction was achieved at the first withdrawal bleed after treatment initiation and it was sustained with no loss of effect throughout treatment. Conclusion E2V/DNG was more effective than placebo in reducing MBL in women with heavy and/or prolonged menstrual bleeding without organic pathology. The reduction was largely achieved as early as the first withdrawal bleed, with further gradual improvement throughout treatment.

Dienogest is a progestogen that combines the pharmacological properties of 19-norprogestins and progesterone derivatives. Dienogest has a potent effect on endometrial tissue, producing antiproliferative effects on endometriotic cells, as well as anti-inflammatory and antiangiogenic actions. Dienogest has been systematically investigated for the treatment of endometriosis through comprehensive study programs in Europe and Japan. Clinical experience of dienogest at 2 mg daily orally demonstrates that it significantly reduces endometriotic lesions and provides effective pain relief comparable to the current efficacy standard, combined with a favorable safety and tolerability profile that allows long-term use. Study data over 15 months show sustained pain relief and low incidences of treatment-related adverse events. As with other progestogens, spotting or breakthrough bleeds are common, but usually lessen during long-term treatment. Dienogest does not produce antiestrogenic side effects, such as bone mass lo...

Extragenital endometriosis severely impairs the quality of life for affected women but its standard management has not yet been well established because of its relatively low incidence. As extragenital organs, intestine, followed by urinary tract, is the most common place affected by endometriosis, for which surgical treatment is sometimes difficult and accompanied by severe complications. Recently, dienogest, a novel progestin, has emerged as a new alternative for endometriosis, especially for endometriosis-associated pain. In this report, we presented four cases with rectosigmoidal and one with bladder endometriosis, treated with oral 2 mg/day dienogest for over 6 months. For all cases, the measurable extragenital lesions exhibited the reduction in their size after 10 to 11 months of use, accompanied with immediate relief of subjective symptoms related with extragenital lesions. This report suggests that dienogest can be a novel conservative alternative for extragenital endometriosis.

Dienogest (DNG) has the essential properties of an effective progestogen for use in a new contraceptive pill using estradiol valerate as estrogenic component -- it inhibits ovulation and protects against endometrial proliferation. DNG is a derivative of norethisterone (NET), but has a cyanomethyl- instead of an ethinyl-group in C17 position which may offer a variety of benefits regarding hepatic effects. The similarity to NET is reflected in the high endometriotropy and in similar pharmacokinetics like short plasma half-live and high bioavailability. However, DNG also elicits properties of progesterone derivatives like neutrality in metabolic and cardiovascular system and considerable antiandrogenic activity, the latter increased by lack of binding to SHBG as specific property of DNG. It has no glucocorticoid and antimineralocorticoid activity and has no antiestrogenic activity with the consequence that possible beneficial estradiol effects should not be antagonized. This may be of special importance for the tolerability and safety of the first pill with estradiol valerate instead of ethinylestradiol, although well-designed postmarketing studies are still ongoing to demonstrate what can be expected on the basis of pharmacology.

High-dose dienogest (20 mg/day) was used for the treatment of endometriosis in women aged 18-52 years after laparoscopic and histological diagnosis of endometriosis and staging according to the revised American Fertility Society criteria. Treatment efficacy was analyzed objectively by second-look laparoscopy, and serum hormone measurements and evaluation of endometriosis-related symptoms were performed done and side-effects recorded. Compared with other high-dose progestin therapies, treatment with dienogest was shown to be effective even in stage IV endometriosis. The side-effect profile of the high-dose dienogest treatment appears to be highly favorable compared with other treatments. Neither the menopausal symptoms caused by therapy with gonadotropin-releasing hormone agonists nor the adverse androgen-related effects induced by danazol were observed. Therefore, long-term high-dose dienogest therapy can be recommended particularly for women with progressive endometriosis.

Objective To compare the effect of different formulations of continuous combined hormone therapy on sexual performance in naturally postmenopausal women.Material and methods A total of 158 postmenopausal women were enrolled and prospectively randomized to the single-blind study. Fifty-four women received tibolone 2.5 mg, 53 received 2 mg estradiol and 2 mg dienogest (E2/dienogest), and 51 did not receive any menopausal therapy. The patients were monitored after 6 months. Attitudes of sexuality were evaluated by using the Rosen's female sexual function index.Results Compared with E2/dienogest and the control group, tibolone treatment was associated with more improvement of sexual performance, including sexual desire, sexual arousal and satisfaction. Both of the hormone therapies decreased frequencies of vaginal dryness and painful intercourse.Conclusions Tibolone has more positive effects on the sexual dysfunction of postmenopausal women and may be an alternative to the E2/dienogest preparation in postmeno...

Several studies have verified that hormone replacement therapy (HRT) has protective effects on postmenopausal women's cardiovascular condition. However, highly significant recent studies have reported that women treated with HRT have more cardiovascular events than untreated women. An elevated homocysteine level is one important risk factor for cardiovascular disease (CVD). As a good indicator of CVD risk, we examined the changes in plasma homocysteine levels of postmenopausal women treated with HRT. In our study, we administered estradiol valerate (2 mg) and dionegest (2 mg) to 34 postmenopausal women recruited randomly from our menopause clinic, and measured plasma homocysteine levels of patients at baseline and after 3 and 6 months of therapy. The changes in plasma homocysteine levels of treated patients were not statistically significant (p = 0.241). Our results indicate that 6 months of estradiol valerate and dionegest therapy does not change homocysteine levels in postmenopausal women.

This study shows the effect of a 1 year treatment with an estradiol valerate/dienogest pill in 36 women suffering from polycystic ovaries and mild or moderate acne. At beginning of the study, 24 patients (66.7%) had grade 1-2 (mild) acne and 12 patients (33.3%) had grade 3 (moderate) acne. After 12 cycles of therapy, we found an improvement of acne in 19 (52.8%) patients and a worsening of acne in 3 (8.4%) patients. The percentage of patients recovered was statistically significant (p 0.01). SHBG levels were significantly higher after 6 and 12 months of therapy (p 0.001), while total testosterone levels were lower in all patients at 6 and 12 months although this trend did not reach statistical significance. In conclusion, the present study suggests that the E2V/DNG pill could exert a positive influence on acne and hyperandrogenism. Since this is an observational study on a very limited population number, additional randomized controlled studies on larger populations are needed also to determine the effects of this contraceptive over longer periods of use.

This randomized, double-blind, placebo-controlled study was planned to investigate the effects of continuous combined hormone replacement therapy (HRT) with 2 mg estradiol valerate and 2 mg dienogest (Climodien/Lafamme) over 24 weeks on postmenopausal depression.A total of 129 patients with a mild to moderate depressive episode according to ICD-10: F32.0, F32.1 in the context of a postmenopausal syndrome (ICD-10: N95.1) and a baseline score in the Hamilton depression scale (HAMD)or =16 were included in the study. The primary target variable was depression severity as measured by the HAMD after 24 weeks of treatment. A four-point difference between HRT and placebo at the end of the study and, in addition, a final scoreor =8 (corresponding to an improvement ofor =50% as compared to baseline) for the individual patient (responders analysis) were considered clinically relevant. Clinical global impression (CGI) of investigators (therapeutic and side-effects) at the end of the study was investigated. Secondary effects of HRT on depression severity caused by its effect on vasomotor symptoms or sleep disturbances (domino hypothesis) were taken into consideration. Also, the study addressed the question of whether the effect of HRT on depression severity depends on a history of premenstrual syndrome (PMS) or postnatal depression (PND).The results showed a clear and clinically relevant reduction of depression severity under HRT after 24 weeks of treatment and superiority over placebo (p0.0005) in spite of a strong placebo effect. The effects of the estrogen-progestin combination thereby seemed only partially to be dependent on the improvement of vasomotor symptoms and sleep disturbances. Also, the effects of HRT could not be shown to be dependent on a history of PMS and/or PND, even though women with and without this history clearly differed in baseline depression scores (p0.0001). The assessment of CGI was positive: whereas HRT was clearly superior to placebo with regard to therapeutic effects (p = 0.0014), there were no differences with regard to side-effects (p = 0.35).The combination of 2 mg estradiol valerate and 2 mg dienogest can be regarded as an effective and safe treatment option for women with mild to moderate depression in the context of postmenopausal syndrome.

Dienogest (DNG) is already used in hormone therapy, since recently being also the progestogenic component of the first estradiol based contraceptive pill. Data on breast cancer risk are currently not available. Progesterone receptor membrane component 1 (PGRMC1) is highly expressed in tissues of breast cancer patients and has already been proposed as a predictor for breast cancer risk.MCF-7 cells overexpressing PGRMC1 were stimulated with DNG, medroxyprogesterone acetate (MPA), norethisterone (NET) and progesterone (P) as well as sequentially and continuously combined with estradiol (E2).DNG and MPA alone elicited a significant proliferation at 10⁻⁶ and 10⁻⁵ M. NET increased cell proliferation at all concentrations tested whereas P showed no effect. E2 alone elicited a significant increase at 10⁻¹⁰ M, no effect was seen at 10⁻¹² M. Addition of the progestins (10⁻⁶ M) to E2 at 10⁻¹⁰ M had, compared to E2 only, no additional proliferating effect. However, at the low E2 concentration, DNG, MPA and NET significantly increased the E2-stimulated cell proliferation.DNG increased proliferation alone and in combination with low E2 concentrations. Thus a progestogen-derived breast cancer risk in the presence of low E2 concentrations cannot be excluded at least in women overexpressing PGRMC1.

The ‘ depletion’ of the granulosa cells and associated cessation of the secretion of 17 b-estradiol by the ovary mark the menopause. The well-known 17 b-estradiol deficiency syndrome occurs. Replacement with 17 b-estradiol (in the most varying dosages and in different administration regimens) will remain the ‘ gold standard’ in times to come. Combination with a progestin-delivering intrauterine system can optimize 17 b-estradiol replacement. Future developments include dietary measures (so-called ‘ nutriceuticals’ ) or the potency-enhanced phytoestrogens, essentially improved selective estrogen receptor modulators (SERMs) including central nervous system-focused estrogens with reduced peripheral action, and the estrogen sulfamates with a unique pharmacokinetic pattern after oral administration (‘ oral patch’ ). In the field of progestins, the so-called hybrid progestins (e.g. dienogest, drospirenone, and the selective progesterone receptor modulators (mesoprogestins)) will probably predominate. A very attractive approach is the use of selective androgen-receptor modulators (SARMs) as non-masculinizing androgens.

Republished from: The European Journal of Contraception and Reproductive Health Care, 2010;15:1–3

In a clinical pilot study, 21 women with endometriosis have been primarely treated with dienogest 2 × 10 mg daily p.o. for 24 weeks. Besides the effect on endometriosis the action of such high-dose progestogen treatment on the breast was evaluated by breast ultrasound prior to medication and at 24 weeks of medical treatment. In all women, a significant size reduction of the mammary gland (p < 0.023) and regression of mastopathic changes were observed. There was a non-significant reduction (p = 0.089) of the maximum diameter of the ducts. The portion of the fatty tissue increased slightly, but not significantly (p = 0.348).

Oral contraceptives have over 70 million users world-wide and are regarded as one of the most reliable forms of contraception, but unfortunately their full potential is not yet completely realized. Many women associate long-term oral contraceptive usage with health problems, and experience inadequate cycle control and nuisance side-effects, that often result in non-compliance and treatment discontinuation. Although reduction of the estrogen content has improved safety, new, more selective progestins and different estrogen/progestin ratios may offer greater benefits in terms of both efficacy and safety.Recent advances to combine the desirable activities of both 19-norprogestins and C21-progestins, and develop a hybrid progestin, have led to the introduction of dienogest. Unlike other 19-norprogestin derivatives, dienogest has a substituted cyanomethyl group in place of an ethinyl group at position 17α and, as a result, has a unique endocrinopharmacological profile. Dienogest demonstrates high specificity t...

Objectives and methods A postmarketing survey was carried out to determine the efficacy and tolerability of Valette® (dienogest 2.0 mg and ethinylestradiol 0.03 mg) in routine gynecological practice.Results Valette had excellent contraceptive efficacy (unadjusted Pearl index 0.14), with 11 unplanned pregnancies from a total of 92 146 cycles of exposure, of which at least four were attributable to user failure.Cycle control was good, with spotting and breakthrough bleeding, which affected 5.0% and 3.4% of women, respectively, during the first cycle, becoming less frequent thereafter. Silent menstruation, i.e. the absence of withdrawal bleeding, affected on average 2.0% of women per cycle and 5.9% within the observation period.Valette was well tolerated. The most common adverse drug reactions were mastalgia (1.46% of all users), weight gain (1.11%), headache (0.98%), nausea/vomiting (0.96%), dysmenorrhea (0.35%), decreased libido (0.31%) and depressive moods (0.28%). The dropout rate due to adverse drug rea...

The objectives of the studies were to determine the contraceptive efficacy, cycle stability and tolerability of a low-dose monophasic preparation containing dienogest 2 mg and ethinylestradiol 0.03 mg, and to investigate its influence on excessive sebaceous gland secretion of the scalp and skin over six cycles.Two open, multicenter postmarketing surveillance studies involving healthy women were carried out. Study 1 enrolled 16 087 subjects with a mean age of 24.3 ± 7.2 years to investigate contraceptive reliability, cycle control and tolerability; Study 2 involved 10 718 subjects with a mean age of 23.6 ± 6.9 years to assess sebaceous gland activity by the presence of grease on the hair and skin, and frequency of hair washes per week.Eleven pregnancies occurred during the first study, giving an unadjusted Pearl index of 0.14. The incidence of intermenstrual bleeding (spotting and breakthrough bleeding) and amenorrhea progressively declined during the study to ≤ 1% by cycle 6. A total of 353 (2.2%) women d...

Dienogest is the first non-alkylated 19-norprogestin on the market. This so-called hybrid progestin combines the typical qualities of the modern 19-norprogestins with those of natural progesterone ...

Three estradiol (E 2 )-containing oral contraceptives, estradiol valerate/cyproterone acetate (E 2 V/CPA, Femilar ® ), estradiol valerate/dienogest (E 2 V/DNG, Qlaira ® /Natazia™), and estradiol/nomegestrol acetate (E 2 /NOMAC; Zoely ® ), have received approval for use in general practice. Only Finnish women currently have access to all three E 2 -based formulations. E 2 /NOMAC is currently approved only in Europe, while E 2 V/DNG is approved globally. To assist clinicians counseling women considering use of one of these formulations, we conducted a review of the published information about the current E 2 -containing oral contraceptives. A literature search was conducted using the Ovid interface and a combination of free search terms relevant to estradiol and oral contraception to identify suitable articles for inclusion in this review. The available data show that E 2 V/DNG, E 2 /NOMAC, and E 2 V/CPA are all effec- tive oral contraceptives. While direct comparisons are lacking, indirect evidence suggests that E 2 V/DNG and E 2 /NOMAC may have better bleeding profiles than E 2 V/CPA. E 2 V/DNG is also approved for the treatment of heavy menstrual bleeding. Both E 2 V/DNG and E 2 /NOMAC have minimal influence on hemostatic, lipid, and carbohydrate metabolism parameters, or induce less change in these parameters relative to ethinylestradiol-based oral contraceptives. However, the predictive value of these surrogate parameters is a matter of debate, and whether these differences can be translated into meaningful clinical outcomes needs to be established in large-scale, post-marketing, prospective, Phase IV cohort studies. Future studies are required to determine whether E 2 -based oral contraceptives confer additional benefits compared with those of ethinylestradiol-based COCs.

We have reported good control of atypical genital bleeding when using a cyclic administration of dienogest (repeated 4-week cycles, each consisting of the administration of 2 mg/day of dienogest for 3 weeks, followed by 1 week of drug withdrawal) in patients with endometriosis. Herein, we report the effectiveness of the long-term cyclic administration (22 months) of dienogest in a case of pathological disappearance of intestinal endometriosis diagnosed by endoscopy and histology of the lower gastrointestinal tract. There is no recurrent sign after 16 months of the treatment being stopped. Atypical genital bleeding during treatment was 3–5 days a month in each cycle. Compliance was good, so we could continue the therapy. The long-term cyclic administration of dienogest in patients with intestinal endometriosis may have significant merit.

Abnormal uterine bleeding (AUB) is associated with significant direct medical costs and impacts both society and the quality of life for individual women. Heavy menstrual bleeding, a subset of AUB, also referred to as menorrhagia, is defined as menstrual blood loss greater than 80 mL or the patient’s perception of excessive blood loss. The newest treatment option available is a novel combination oral contraceptive product containing estradiol valerate (E2V) and dienogest (DNG). As with other combination oral contraceptives, E2V/DNG works primarily by preventing ovulation. However, in contrast with other combination oral contraceptives, it is the progestin component of E2V/DNG that is responsible for endometrial stabilization. Use of E2V/DNG for six months has led to significant reductions in heavy menstrual bleeding with an average 65% reduction in mean blood loss. Approximately half of the women with heavy menstrual bleeding who received E2V/DNG for six months demonstrated an 80% reduction in mean blood loss. Additionally, significant improvements in hematologic indicators (ie, ferritin, hemoglobin, and hematocrit) have been shown. Based on its chemical properties, E2V/DNG may have fewer adverse effects on lipid and glucose metabolism and reduced risk of thromboembolic complications compared with other combination oral contraceptives. This has not yet been shown in clinical trials and until then it should be assumed that E2V/DNG has a safety profile similar to other combination oral contraceptives containing 35 μg or less of ethinyl estradiol. E2V/DNG has been compared with another combination oral contraceptive in healthy women without heavy menstrual bleeding and demonstrated improved bleeding patterns. E2V/DNG has not been compared with the levonorgestrel intrauterine device or other treatments for heavy menstrual bleeding. When compared with some other treatment options for AUB, E2V/DNG provides the added advantage of effective contraception.

Natazia® is a new oral contraceptive with estradiol valerate and dienogest in a unique multiphasic formulation that includes a shortened hormone-free interval. This new formulation has been approved for both contraception and also as a treatment for heavy menstrual bleeding in women who desire to use oral contraceptives as their method of birth control. It is marketed in the US as Natazia® and elsewhere as Qlaira®. This article will review the properties of each of the major new features of this pill: estradiol used in place of ethinyl estradiol dienogest as the progestin and the unique dosing pattern of this product. It will also summarize the results of the pivotal clinical trials of contraceptive effectiveness bleeding patterns safety and tolerability. The lessons learned from the clinical trials about the effectiveness of this formulation in the treatment of excessive menstrual bleeding will be summarized. Also results of trials comparing this new pill to other popular formulations for "menstrually-related" symptoms and for potential female sexual dysfunction related to use of oral contraceptives will be presented. This review will suggest how all this information might be used to counsel women about how to use this pill most successfully.

Most combination oral contraceptives contain ethinyl estradiol and a progestin. A new and novel oral contraceptive formulation combines estradiol valerate (E2V) with dienogest (DNG) in a four-phase dosing regimen. 17β-estradiol is a naturally-occurring estrogen, and a contraceptive pill containing such an estrogen offers potential benefits with regard to metabolic side effects and adverse events. Dienogest is derived from 19-nortestosterone and exerts profound progestational effects on the endometrium, but it differs from other progestins in its class by its antiandrogenic activity. Estradiol valerate plus dienogest (E2V/DNG) is now available in a four-phasic regimen that integrates an estrogen stepdown and progestin stepup dosing approach along with a short two-day hormone-free interval. This regimen offers safe, reliable contraception and has been shown to be an effective treatment for heavy menstrual bleeding. Metabolic effects and adverse events appear similar to those reported with oral contraceptives containing ethinyl estradiol.